Elsevier

The Lancet

Volume 395, Issue 10220, 25–31 January 2020, Pages 285-293
The Lancet

Articles
Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(19)32973-3Get rights and content

Summary

Background

Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation.

Methods

ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks' gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970.

Findings

From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14–40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73–1·00], p=0·048), fetal loss (infant death after 16 weeks' gestation and before 7 days post partum; 0·86 [0·74–1·00], p=0·039), early preterm delivery (<34 weeks; 0·75 [0·61–0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17–0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups.

Interpretation

In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality.

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Introduction

Preterm birth, defined as delivery before 37 weeks, remains a predominant driver of infant mortality worldwide, with the greatest burden of disease occurring in low-income and middle-income countries (LMICs).1, 2 Although improvements in neonatal care have resulted in improved survival in high-income countries (HICs) and some LMIC regions,3 this care is often limited or unavailable in regions with the highest burden of mortality. Beyond the newborn period, longitudinal adverse effects on health and socioeconomic outcomes have been associated with preterm birth, when compared with individuals delivered at term.4, 5, 6 Despite numerous trials of secondary prevention and tocolytic therapies, effective strategies for the prevention of preterm birth have proved either elusive or resource-intensive when used in large populations of potentially at-risk groups.7, 8, 9, 10

Research in context

Evidence before this study

We searched PubMed for articles published in English on low-dose aspirin therapy in pregnancy for improvement of birth outcomes, published between Jan 1, 2000 and Sept 27, 2019, using the search terms “aspirin” AND “pregnancy” OR “hypertensive disease” OR “preterm birth” OR “preeclampsia”. A secondary analysis of the Maternal-Fetal Medicine Units Network trial of aspirin and a single trial of preconception aspirin (the EAGeR trial) suggested a reduced risk of preterm birth among women who received low-dose aspirin compared with a placebo control. Meta-analyses and systematic reviews of trials of low-dose aspirin in pregnant women to prevent pre-eclampsia have suggested that the occurrence of preterm birth is reduced in women receiving aspirin, with this effect possibly increased when low-dose aspirin is started early in pregnancy.

Added value of this study

This study is the first large trial of low-dose aspirin initiated early in pregnancy with the prevention of preterm birth as the primary outcome. This trial was designed to test the hypothesis that low-dose aspirin (81 mg) administered daily and initiated in the first trimester reduces the incidence of preterm delivery in nulliparous women with a singleton pregnancy. Additionally, our data suggested that the intervention is safe for women across the six low-income and middle-income countries (LMICs) that were represented in the trial.

Implications of all the available evidence

This trial confirms the previously suggested benefit of low-dose aspirin in reducing the risk of preterm birth. Nulliparous women with a singleton pregnancy who were allocated to low-dose aspirin in early pregnancy (between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation, until 36 weeks) were 11% less likely to deliver before 37 weeks. In addition, low-dose aspirin reduced the risk of early preterm delivery (before 34 weeks) by 25%, and perinatal mortality by 14%. These outcomes are consistent with previous meta-analyses that showed similar reductions in preterm birth and perinatal mortality. Because of the large sample size, this trial was able to show these benefits definitively in a diverse group of women from various LMICs. The low cost and proven tolerability of aspirin in this population suggests that our aspirin regimen can be readily and safely adopted across a range of clinical sites globally.

Meta-analyses and systematic reviews of trials of low-dose aspirin (60–150 mg a day) in pregnant women for the prevention of pre-eclampsia suggest that women receiving aspirin have a reduced occurrence of preterm birth and a reduced frequency of pre-eclampsia.11, 12, 13 Secondary analyses of two trials of low-dose aspirin in pregnancy have also suggested that the frequency of preterm birth might be decreased in pregnant women taking aspirin.14, 15 This effect might be enhanced when low-dose aspirin is started before 16 weeks of gestation.12 Although promising as a strategy, no large-scale definitive trial has examined low-dose aspirin initiated early in pregnancy for the primary prevention of preterm birth, as the main outcome. The ASPIRIN (Aspirin Supplementation for Pregnancy Indicated risk Reduction In Nulliparas) trial was therefore designed to test the hypothesis that low-dose aspirin (81 mg) administered daily and initiated early in pregnancy (between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation) reduces the incidence of preterm delivery in nulliparous women with a singleton pregnancy. In recognising the scarcity of data on the maternal and neonatal safety of aspirin in settings where resources might be limited, we also prospectively assessed potential harmful effects of this therapy as part of our trial.

Section snippets

Study design

ASPIRIN was a multinational, randomised, double-masked, placebo-controlled trial. The trial was led by the ASPIRIN Study Group (appendix p 3) of the Global Network for Women's and Children's Health Research (Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD], Bethesda, MA) and took place at seven community sites in six countries (two sites in India, and one site each in Pakistan, Zambia, the Democratic Republic of the Congo, Guatemala, and Kenya) between

Results

From March 23, 2016 to June 30, 2018, 14 361 nulliparous pregnant women aged 14–40 years provided informed consent and were screened for eligibility. 2385 women were excluded or declined randomisation, and the remaining 11 976 were consented for randomisation: 5990 were assigned to low-dose aspirin and 5986 were allocated to placebo (figure). The low-dose aspirin group had 5787 women in the mITT population, and the placebo group had 5771. Baseline characteristics and sites of delivery were

Discussion

In this randomised, double-masked, placebo-controlled trial, nulliparous women with a singleton pregnancy who were allocated to receive low-dose aspirin early in pregnancy (between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation, until 36 weeks) were 11% less likely to deliver before 37 weeks' gestation than were women on a placebo regimen. Additionally, in the aspirin group, the risk of early preterm birth before 34 weeks was lowered by 25%, and perinatal mortality was

Data sharing

Deidentified participant data from the study will be available at the National Institute of Child Health and Human Development data repository (N-DASH): https://dash.nichd.nih.gov/. Data sharing will be accessed and governed according to the procedures and policies of N-DASH. A data dictionary will be provided. These data will be provided within 12 months of primary publication.

Acknowledgments

The ultrasound equipment for the trial in Pakistan, Zambia, Kenya, The Democratic Republic of the Congo, and Guatemala was made available by GE Healthcare.

References (32)

  • L Alkema et al.

    Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Maternal Mortality Estimation Inter-Agency Group

    Lancet

    (2016)
  • S Roberge et al.

    Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis

    Am J Obstet Gynecol

    (2018)
  • CV Ananth et al.

    Maternal-fetal conditions necessitating a medical intervention resulting in preterm birth

    Am J Obstet Gynecol

    (2006)
  • D Moster et al.

    Long-term medical and social consequences of preterm birth

    N Engl J Med

    (2008)
  • JF Bilsteen et al.

    Gestational age and socioeconomic achievements in young adulthood: a Danish population-based study

    JAMA Netw Open

    (2018)
  • H Blencowe et al.

    Preterm birth-associated neurodevelopmental impairment estimates at regional and global levels for 2010

    Pediatr Res

    (2013)
  • Cited by (211)

    • Prevention of preeclampsia

      2024, Best Practice and Research: Clinical Obstetrics and Gynaecology
    • Solving the Puzzle of Preterm Birth

      2024, Clinics in Perinatology
    View all citing articles on Scopus

    All members of the ASPIRIN Study Group are provided in the appendix

    View full text