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

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