Aspirin use associated with increased birthweight without increasing the rate of LGA neonate: Study

Pre-eclampsia (PE) is a major cause of maternal and
perinatal morbidity and mortality. In the Combined Multimarker Screening and
Randomised Patient Treatment with Aspirin for Evidence-based Preeclampsia
Prevention (ASPRE) trial, treatment of high-risk women with aspirin 150mg daily
from the first trimester to 36 weeks led to 62% and nearly 90% lower rates of
PE with delivery before 37 and 32weeks of gestation, respectively. The study
was conducted from 2014 to 2016, and the high-risk group was identified using
the first trimester Fetal Medicine Foundation (FMF) competing risks algorithm
that combines maternal characteristics and medical history with mean arterial
pressure, mean uterine artery pulsatility index on Doppler ultrasound, and
serum biomarkers. In a secondary analysis of the ASPRE data, authors
demonstrated that this protective effect may be, at least partly, driven by
improvements in placental perfusion.

Pre-existing diabetes mellitus (DM) is considered a major
risk factor for the development of PE. This has led to recommendations from
prominent institutions such as the National Institute for Health and Care
Excellence (NICE) in the UK and the American College of Obstetricians and
Gynaecologists (ACOG) to treat type 1 and type 2 DM as major risk factors for
PE and to offer aspirin prophylaxis to all women with these conditions.
However, previous studies on PE prediction and prevention in diabetic women are
limited, and the effectiveness of aspirin in this high-risk subgroup has been
debated. Observational studies and randomised trials have questioned the
efficacy of aspirin in the prevention of PE among diabetic women and raised
concerns that it might increase the risk of large-for-gestational-age (LGA)
neonates, as well as complications such as traumatic birth and shoulder
dystocia. It is biologically plausible that, by increasing placental perfusion,
aspirin leads to larger placental mass, higher circulating levels of
hyperglycaemic hormones such as placental lactogen, and further increased
glucose availability to the foetus. On the other hand, previous studies have
suggested that aspirin stimulates insulin and glucagon secretion, increasing
glucose tolerance in non-pregnant individuals.

In this secondary analysis of the ASPRE trial, authors
examined the effects of aspirin on the birthweight distribution and the rates
of LGA neonates among participants at increased risk of preterm PE, stratified
according to the presence of pre-existing DM and the development of PE.

This is a post hoc secondary analysis of the ASPRE trial
data. The ASPRE trial was conducted in 2014–2016 at 13 maternity hospitals in
the United Kingdom, Spain, Italy, Belgium, Greece and Israel. In the
participating hospitals, screening for preterm PE was carried out at 11–13+6
weeks of gestation using the FMF first trimester competing risks algorithm that
combines maternal demographic characteristics and medical and obstetric history
with the measurements of mean arterial pressure, mean uterine artery
pulsatility index on Doppler ultrasound, and serum pregnancy-associated plasma
protein A (PAPP-A) and placental growth factor (PlGF) measured on the day of
the ultrasound examination.

Of 26,941 women with singleton pregnancies screened, 1776
high-risk participants were randomly allocated in a double-blind manner to
receive treatment with aspirin 150mg daily, or placebo, at night from
11–14weeks to 36weeks or delivery, whichever came first. A total of 152 women
(8%) withdrew consent during the study, four (0.2%) were lost to follow-up, and
the remaining 1620 participants were included in the intention-to treat
analysis.

The primary outcome was PE with delivery before 37 weeks of
gestation, which was reduced by 62% in the aspirin group compared to the
placebo group (1.6% vs. 4.3%, odds ratio adjusted for site and estimated risk
0.38, 95% confidence interval (CI) 0.20 to 0.74; p=0.004). The effect of
aspirin was stronger in participants with good adherence to treatment. Only
live births were included in this secondary analysis. Miscarriages, pregnancy
terminations and stillbirths were excluded.

Among 1571 singleton, live neonates (777 from the aspirin
group and 794 from the placebo group), aspirin was associated with a shift in
birthweight from <2500 to 2500–4000 g, and birthweight percentile from <25th
to 25th—75th percentiles, with no significant increase in LGA neonates (5.5%
vs. 6.2%, p=0.667). Logistic regression demonstrated a significant interaction
between treatment and pre-existing diabetes (p-value 0.034), and a positive
association between maternal weight and LGA neonates (adjusted odds ratio
1.040, 95% confidence interval 1.030–1.051, p <0.001).

In this secondary analysis of the ASPRE trial, authors
investigated the effects of aspirin on birthweight and the rates of LGA
neonates among women at high risk of preterm PE. Although in the main trial
there was no significant reduction in SGA neonates, in this secondary analysis
aspirin was associated with a shift in the birthweight distribution by reducing
the rates of neonates born with weights below 2500 g and the 25th percentile.
It increased the rate of birthweight between the 25th and the 75th percentiles,
without increasing the rate of LGA or macrosomic neonates among non-diabetic
women. Our findings suggest, however, a possible shift in the birthweight
distribution and an increase in LGA neonates among women with DM who received
aspirin, and with increasing maternal weight. Although this may be partly
explained by a reduction in preterm births, a shift in gestational age-adjusted
percentiles may also suggest a higher rate of large neonates irrespective of
gestational age.

Aspirin is associated with an increase in birthweight
without increasing the rate of LGA neonates. However, in women with
pre-existing diabetes, aspirin may be associated with a stronger shift in
birthweight and a higher risk of LGA neonates, warranting further
investigation.

Source: Daniel L. Rolnik, Liona C. Poon,
Argyro Syngelaki; BJOG: An International Journal of Obstetrics &
Gynaecology, 2025; 0:1–9 https://doi.org/10.1111/1471-0528.18263