NIHR Signal Aspirin reduces a woman’s chance of developing pre-eclampsia in pregnancy

Published on 31 October 2017

Giving low dose aspirin to high-risk women reduced their risk of pre-eclampsia before 37 weeks of pregnancy. Preterm pre-eclampsia developed in 1.6% of women given 150mg aspirin daily compared with 4.3% who took a placebo.

Pre-eclampsia is a condition which can harm mother and baby. In the mother, it causes high blood pressure and protein in the urine, which can show in pregnancy after 20 weeks. Women with risk factors, such as previous pre-eclampsia, diabetes or high blood pressure, are often prescribed 75mg aspirin from 12 weeks onwards. This study aimed to test double this dose (still classified as a `low dose’) after using a new risk assessment with additional clinical tests to better identify those at high risk of the condition. Aspirin did not affect other pregnancy outcomes and didn’t increase the risk of adverse effects.

This research adds to current knowledge about the range of doses that is effective and refines the definition and detection of women at high risk. The research did not compare 75mg with 150mg doses.

Aspirin reduces a woman’s chance of developing pre-eclampsia in pregnancy

Share your views on the research.

Why was this study needed?

Pre-eclampsia affects 2 to 8% of pregnancies worldwide, and complications are a leading cause of maternal death in the UK. Though rates have fallen in recent decades, pre-eclampsia and the more severe complications, such as seizures, were responsible for 0.08 deaths per 100,000 maternities in 2012 to 2014.

Aspirin is known to prevent pre-eclampsia. Women at high risk are currently identified at the 12-week check by risk factors such as diabetes and elevated blood pressure before pregnancy. Low doses (around 75mg) are commonly recommended in other countries.

However, it’s estimated that these risk factors alone identify only 40% of women who’ll develop preterm pre-eclampsia. Based on a previous study these researchers added an ultrasound assessment of blood flow in the uterine arteries, and blood levels of pregnancy proteins (placental growth factor and pregnancy-associated plasma protein A) to the usual assessments. This new assessment is thought to identify three-quarters of women who develop preterm pre-eclampsia.

The current research aimed to see whether 150mg of aspirin could reduce the rate of preterm pre-eclampsia in high-risk women defined using this alternative algorithm.

What did this study do?

The Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial took place in 13 hospitals across six countries, including the UK.

Nearly 30,000 women with single pregnancies were offered pre-eclampsia screening at the 11-13 week antenatal visit using the new algorithm. About one in 10 were found to be at high-risk of preterm pre-eclampsia, and 1,776 of them (67%) agreed to take part in the trial. They were randomly assigned to take 150mg aspirin or an identical placebo daily for the remaining pregnancy up to 36 weeks (or labour if delivery was preterm).

The analysis excluded 152 women (9%) who withdrew consent to treatment during pregnancy. Among the remaining women, adherence was good, and 80% took at least 85% of the prescribed aspirin.

What did it find?

  • Preterm pre-eclampsia developed in 13 women (1.6%) who took aspirin compared with 35 women (4.3%) who took placebo (Odds Ratio [OR] 0.38 95% confidence interval [CI] 0.20 to 0.74). The benefits of aspirin were consistent across women with any risk factors or reproductive history.
  • Aspirin did not affect any other pregnancy outcomes including high blood pressure of pregnancy, miscarriage or stillbirth, baby being small for gestational age, preterm delivery (without pre-eclampsia), or pre-eclampsia at term (≥37 weeks).
  • A quarter of women in both groups reported at least one side effect, the most common of which was a headache or dizziness followed by nausea and vomiting. There was also no difference in the rate of serious side effects, which occurred in 1.6% of the aspirin group and 3.2% of the placebo group.

What does current guidance say on this issue?

2011 NICE guidelines on hypertension in pregnancy recommend that women at high risk of pre-eclampsia take 75mg of aspirin daily from 12 weeks until the birth of the baby. High-risk factors are high blood pressure or pre-eclampsia during a previous pregnancy, chronic kidney disease, some autoimmune diseases (such as systemic lupus erythematosus or antiphospholipid syndrome), type 1 or type 2 diabetes, and high blood pressure before pregnancy.

NICE also recommends that women with more than one moderate risk factor take 75mg aspirin from 12 weeks. These are first pregnancy, age ≥40 years, pregnancy interval ≥10 years, body mass index ≥35kg/m2, family history of pre-eclampsia, and multiple pregnancies.

What are the implications?

This trial provides further evidence that aspirin can prevent pre-eclampsia in women at high risk. Aspirin is a low cost, effective intervention.

The dose used here, 150mg, was double that of the currently recommended 75mg but still classified as “low-dose”. As the 75mg dose was not included in this study, we cannot determine which dose is better from this study.

The authors suggest that the accuracy of risk-factor-based screening is improved by adding a new combination of tests. But the combined protocol with additional blood tests and ultrasound-based uterine flow measurements may need yet further exploration.

For example, an evaluation of the accuracy of the new algorithm, costs and cost-effectiveness in the UK will be needed if it is to become a widely available screening procedure in pregnancy.

Citation and Funding

Rolnik DL, Wright D, Poon LC et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017. [Epub ahead of print].

This project was funded by grants from the European Union Seventh Framework Program (FP7-HEALTH-2013-INNOVATION-2; ASPRE Project number, 601852) and the Fetal Medicine Foundation.

Bibliography

NHS Choices. Pre-eclampsia. London: Department of Health; updated 2015.

NICE. Hypertension in Pregnancy. QS35 London: National Institute for Health and Care Excellence; 2013.

NICE. Hypertension in pregnancy: diagnosis and management. CG107. London: National Institute for Health and Care Excellence; 2010, updated 2011.

Mothers and Babies: Reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK). Saving Lives, Improving Mothers’ Care. Surveillance of maternal deaths in the UK 2012-2014 and lesson learned to inform maternity care form the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity. 2009-2014. Oxford: National Perinatal Epidemiology Unit; 2016.

Why was this study needed?

Pre-eclampsia affects 2 to 8% of pregnancies worldwide, and complications are a leading cause of maternal death in the UK. Though rates have fallen in recent decades, pre-eclampsia and the more severe complications, such as seizures, were responsible for 0.08 deaths per 100,000 maternities in 2012 to 2014.

Aspirin is known to prevent pre-eclampsia. Women at high risk are currently identified at the 12-week check by risk factors such as diabetes and elevated blood pressure before pregnancy. Low doses (around 75mg) are commonly recommended in other countries.

However, it’s estimated that these risk factors alone identify only 40% of women who’ll develop preterm pre-eclampsia. Based on a previous study these researchers added an ultrasound assessment of blood flow in the uterine arteries, and blood levels of pregnancy proteins (placental growth factor and pregnancy-associated plasma protein A) to the usual assessments. This new assessment is thought to identify three-quarters of women who develop preterm pre-eclampsia.

The current research aimed to see whether 150mg of aspirin could reduce the rate of preterm pre-eclampsia in high-risk women defined using this alternative algorithm.

What did this study do?

The Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial took place in 13 hospitals across six countries, including the UK.

Nearly 30,000 women with single pregnancies were offered pre-eclampsia screening at the 11-13 week antenatal visit using the new algorithm. About one in 10 were found to be at high-risk of preterm pre-eclampsia, and 1,776 of them (67%) agreed to take part in the trial. They were randomly assigned to take 150mg aspirin or an identical placebo daily for the remaining pregnancy up to 36 weeks (or labour if delivery was preterm).

The analysis excluded 152 women (9%) who withdrew consent to treatment during pregnancy. Among the remaining women, adherence was good, and 80% took at least 85% of the prescribed aspirin.

What did it find?

  • Preterm pre-eclampsia developed in 13 women (1.6%) who took aspirin compared with 35 women (4.3%) who took placebo (Odds Ratio [OR] 0.38 95% confidence interval [CI] 0.20 to 0.74). The benefits of aspirin were consistent across women with any risk factors or reproductive history.
  • Aspirin did not affect any other pregnancy outcomes including high blood pressure of pregnancy, miscarriage or stillbirth, baby being small for gestational age, preterm delivery (without pre-eclampsia), or pre-eclampsia at term (≥37 weeks).
  • A quarter of women in both groups reported at least one side effect, the most common of which was a headache or dizziness followed by nausea and vomiting. There was also no difference in the rate of serious side effects, which occurred in 1.6% of the aspirin group and 3.2% of the placebo group.

What does current guidance say on this issue?

2011 NICE guidelines on hypertension in pregnancy recommend that women at high risk of pre-eclampsia take 75mg of aspirin daily from 12 weeks until the birth of the baby. High-risk factors are high blood pressure or pre-eclampsia during a previous pregnancy, chronic kidney disease, some autoimmune diseases (such as systemic lupus erythematosus or antiphospholipid syndrome), type 1 or type 2 diabetes, and high blood pressure before pregnancy.

NICE also recommends that women with more than one moderate risk factor take 75mg aspirin from 12 weeks. These are first pregnancy, age ≥40 years, pregnancy interval ≥10 years, body mass index ≥35kg/m2, family history of pre-eclampsia, and multiple pregnancies.

What are the implications?

This trial provides further evidence that aspirin can prevent pre-eclampsia in women at high risk. Aspirin is a low cost, effective intervention.

The dose used here, 150mg, was double that of the currently recommended 75mg but still classified as “low-dose”. As the 75mg dose was not included in this study, we cannot determine which dose is better from this study.

The authors suggest that the accuracy of risk-factor-based screening is improved by adding a new combination of tests. But the combined protocol with additional blood tests and ultrasound-based uterine flow measurements may need yet further exploration.

For example, an evaluation of the accuracy of the new algorithm, costs and cost-effectiveness in the UK will be needed if it is to become a widely available screening procedure in pregnancy.

Citation and Funding

Rolnik DL, Wright D, Poon LC et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017. [Epub ahead of print].

This project was funded by grants from the European Union Seventh Framework Program (FP7-HEALTH-2013-INNOVATION-2; ASPRE Project number, 601852) and the Fetal Medicine Foundation.

Bibliography

NHS Choices. Pre-eclampsia. London: Department of Health; updated 2015.

NICE. Hypertension in Pregnancy. QS35 London: National Institute for Health and Care Excellence; 2013.

NICE. Hypertension in pregnancy: diagnosis and management. CG107. London: National Institute for Health and Care Excellence; 2010, updated 2011.

Mothers and Babies: Reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK). Saving Lives, Improving Mothers’ Care. Surveillance of maternal deaths in the UK 2012-2014 and lesson learned to inform maternity care form the UK and Ireland Confidential Enquiries into Maternal Deaths and Morbidity. 2009-2014. Oxford: National Perinatal Epidemiology Unit; 2016.

Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia

Published on 29 June 2017

Rolnik, D. L.,Wright, D.,Poon, L. C.,O'Gorman, N.,Syngelaki, A.,de Paco Matallana, C.,Akolekar, R.,Cicero, S.,Janga, D.,Singh, M.,Molina, F. S.,Persico, N.,Jani, J. C.,Plasencia, W.,Papaioannou, G.,Tenenbaum-Gavish, K.,Meiri, H.,Gizurarson, S.,Maclagan, K.,Nicolaides, K. H.

N Engl J Med , 2017

Background Preterm preeclampsia is an important cause of maternal and perinatal death and complications. It is uncertain whether the intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. Methods In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1776 women with singleton pregnancies who were at high risk for preterm preeclampsia to receive aspirin, at a dose of 150 mg per day, or placebo from 11 to 14 weeks of gestation until 36 weeks of gestation. The primary outcome was delivery with preeclampsia before 37 weeks of gestation. The analysis was performed according to the intention-to-treat principle. Results A total of 152 women withdrew consent during the trial, and 4 were lost to follow up, which left 798 participants in the aspirin group and 822 in the placebo group. Preterm preeclampsia occurred in 13 participants (1.6%) in the aspirin group, as compared with 35 (4.3%) in the placebo group (odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004). Results were materially unchanged in a sensitivity analysis that took into account participants who had withdrawn or were lost to follow-up. Adherence was good, with a reported intake of 85% or more of the required number of tablets in 79.9% of the participants. There were no significant between-group differences in the incidence of neonatal adverse outcomes or other adverse events. Conclusions Treatment with low-dose aspirin in women at high risk for preterm preeclampsia resulted in a lower incidence of this diagnosis than placebo. (Funded by the European Union Seventh Framework Program and the Fetal Medicine Foundation; EudraCT number, 2013-003778-29 ; Current Controlled Trials number, ISRCTN13633058 .).

Expert commentary

It is excellent to see a paper that clearly demonstrates an effect of low dose aspirin on the development of pre-eclampsia before 37 weeks. One consideration that clinicians should take into account before changing practice is the question of how the dose used here compares to 75mg of aspirin used in the same clinical circumstance?

Many clinicians in the UK have used the lower dose for this purpose for many years, with an excellent safety profile. Perhaps this evidence with the 150mg dose may lead us to consider using the higher dose in clinical situations where 75mg has previously failed.

Dr Sonji D Clarke, Deputy Head, London School of Obstetrics and Gynaecology, Senior Clinical Adviser and Honorary Senior Lecturer, King’s College London