NIHR Signal Daily aspirin reduces pre-eclampsia for ‘at-risk’ women

Published on 24 January 2017

Starting daily low-dose aspirin before 16 weeks of pregnancy in women at risk reduces pre-eclampsia, severe pre-eclampsia and foetal growth restriction. Aspirin started after 16 weeks is less beneficial, giving smaller risk reduction for pre-eclampsia and no effect on other outcomes. Defining who is ‘at risk’ remains challenging.

Pre-eclampsia is a rare pregnancy complication, but one that can be dangerous for both mother and baby. Pregnant women are screened for pre-eclampsia risk factors at the antenatal booking appointment. NICE recommend women identified to be at risk are given preventative treatment with 75mg of aspirin from 12 weeks onwards.

This large systematic review assessed doses between 50 and 150mg daily and suggests the higher of these low dose options started before 16 weeks may be better than the very low (60mg) doses. Most studies assessed 100mg or 60mg doses; 100mg aspirin was effective, whereas 60mg was not. Only two small studies assessed the recommended 75mg but it was effective. Aspirin is readily available and a cheap drug.

The findings require confirmation in larger trials that directly compare different doses.

Daily aspirin reduces pre-eclampsia for ‘at-risk’ women

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Why was this study needed?

Pre-eclampsia is a rare but serious condition affecting around 6% of pregnant women in the UK. It usually occurs in the second half of pregnancy (20 weeks onwards), presenting as high blood pressure and protein in the urine. Later symptoms may include vision problems, headache, vomiting, severe pain just below the ribs and sudden swelling of the face, hands or feet.

Complications can include preterm birth, low birth weight, foetal growth restriction (where the baby does not grow properly in the womb), maternal death and stillbirth. In the UK all women have their blood pressure and urine tested at every antenatal appointment. They are also screened for pre-eclampsia risk factors at their first booking appointment.

Women at risk of pre-eclampsia are given a preventative low dose (75mg) of aspirin. This systematic review investigated the effectiveness of different doses of aspirin for preventing pre-eclampsia and foetal growth restriction.

What did this study do?

This systematic review and meta-analysis included 48 randomised controlled trials comparing aspirin with either no treatment or placebo in women with variable risk factors for pre-eclampsia. Twenty-one studies (5130 women) looked at the effect of starting aspirin before 16 weeks of pregnancy, and the remainder (15,779 women) assessed starting after 16 weeks. Aspirin doses ranged from 50mg to 150mg.

The studies were mostly of low risk of bias. However, the authors suspected publication bias because there was a lack of small trials showing no beneficial effect. The meta-analysis of aspirin initiated before 16 weeks included mainly small studies or subgroups from larger studies, which the authors acknowledge may affect the reliability of their analysis. The small numbers involved meant that no conclusion could be drawn about the optimal dose.

What did it find?

  • Aspirin initiated at less than 16 weeks’ pregnancy reduced risk of pre-eclampsia (relative risk [RR] 0.57, 95% confidence interval [CI] 0.43 to 0.75), severe pre-eclampsia (RR 0.47, 95% CI 0.26 to 0.83) and foetal growth restriction (RR 0.56, 95% CI 0.44 to 0.70).
  • Aspirin started later than 16 weeks into pregnancy was associated with reduced risk of pre-eclampsia (RR 0.81, 95% CI 0.66 to 0.99), but had no effect on risk of severe pre-eclampsia (RR 0.85, 95% CI 0.64 to 1.14) or foetal growth restriction (RR 0.95, 95% CI 0.86 to 1.05).
  • For treatment started before 16 weeks, a general dose-response effect was observed, where higher aspirin doses were associated with greater reduced risks. The two most frequently studied doses across all outcomes were 60mg and 100mg. 100mg aspirin reduced rates of pre-eclampsia, severe pre-eclampsia and foetal growth restriction, while 60mg aspirin did not. Only two studies (373 women) had examined the UK recommended dose of 75mg, and found that it reduced risk of all outcomes. Only a single study had examined the highest 150mg dose, which found a preventative effect on foetal growth restriction only.
  • There was no dose-response effect observed in studies of aspirin started after 16 weeks of pregnancy.

What does current guidance say on this issue?

NICE antenatal care guidance (2008) recommends that all pregnant women have their blood pressure measured and urine tested at every antenatal appointment to screen for pre-eclampsia.

At the 8 to 12 week “booking appointment” women should be formally assessed for pre-eclampsia risk factors such as age, weight, personal or family history of pre-eclampsia and pre-existing high blood pressure.

2011 NICE guidelines recommend that women at high risk of pre-eclampsia, or with two or more moderate risk factors, take 75mg of aspirin from 12 weeks until birth. This guidance is due for review in January 2017. This may take into account this new research which suggests benefits of slightly higher doses.

What are the implications?

This systematic review reinforces current NICE recommendations that a daily dose of aspirin started from 12 weeks onwards reduces the risk of pre-eclampsia for at-risk women. The findings suggest 75mg may be the minimally-effective dose, and there may a case for increasing to a slightly higher dose (100mg). However, trials assessing the recommended dose were notably lacking.

These dose-related findings require confirmation in large randomised controlled trials that directly compare the safety and effectiveness of standard low dose aspirin with higher doses when started in women at less than 16 weeks’ pregnancy.

Citation and Funding

Roberge S, Nicolaides K, Demers S, et al. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2016. [Epub ahead of print].

The study was funded by the Jeanne and Jean-Louis Lévesque Perinatal Research Chair at Université Laval.

Bibliography

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

NHS Choices. Your antenatal care. London: Department of Health; 2015.

NICE. Antenatal care for uncomplicated pregnancies. CG62. London: National Institute for Health and Care Excellence; 2008.

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

Why was this study needed?

Pre-eclampsia is a rare but serious condition affecting around 6% of pregnant women in the UK. It usually occurs in the second half of pregnancy (20 weeks onwards), presenting as high blood pressure and protein in the urine. Later symptoms may include vision problems, headache, vomiting, severe pain just below the ribs and sudden swelling of the face, hands or feet.

Complications can include preterm birth, low birth weight, foetal growth restriction (where the baby does not grow properly in the womb), maternal death and stillbirth. In the UK all women have their blood pressure and urine tested at every antenatal appointment. They are also screened for pre-eclampsia risk factors at their first booking appointment.

Women at risk of pre-eclampsia are given a preventative low dose (75mg) of aspirin. This systematic review investigated the effectiveness of different doses of aspirin for preventing pre-eclampsia and foetal growth restriction.

What did this study do?

This systematic review and meta-analysis included 48 randomised controlled trials comparing aspirin with either no treatment or placebo in women with variable risk factors for pre-eclampsia. Twenty-one studies (5130 women) looked at the effect of starting aspirin before 16 weeks of pregnancy, and the remainder (15,779 women) assessed starting after 16 weeks. Aspirin doses ranged from 50mg to 150mg.

The studies were mostly of low risk of bias. However, the authors suspected publication bias because there was a lack of small trials showing no beneficial effect. The meta-analysis of aspirin initiated before 16 weeks included mainly small studies or subgroups from larger studies, which the authors acknowledge may affect the reliability of their analysis. The small numbers involved meant that no conclusion could be drawn about the optimal dose.

What did it find?

  • Aspirin initiated at less than 16 weeks’ pregnancy reduced risk of pre-eclampsia (relative risk [RR] 0.57, 95% confidence interval [CI] 0.43 to 0.75), severe pre-eclampsia (RR 0.47, 95% CI 0.26 to 0.83) and foetal growth restriction (RR 0.56, 95% CI 0.44 to 0.70).
  • Aspirin started later than 16 weeks into pregnancy was associated with reduced risk of pre-eclampsia (RR 0.81, 95% CI 0.66 to 0.99), but had no effect on risk of severe pre-eclampsia (RR 0.85, 95% CI 0.64 to 1.14) or foetal growth restriction (RR 0.95, 95% CI 0.86 to 1.05).
  • For treatment started before 16 weeks, a general dose-response effect was observed, where higher aspirin doses were associated with greater reduced risks. The two most frequently studied doses across all outcomes were 60mg and 100mg. 100mg aspirin reduced rates of pre-eclampsia, severe pre-eclampsia and foetal growth restriction, while 60mg aspirin did not. Only two studies (373 women) had examined the UK recommended dose of 75mg, and found that it reduced risk of all outcomes. Only a single study had examined the highest 150mg dose, which found a preventative effect on foetal growth restriction only.
  • There was no dose-response effect observed in studies of aspirin started after 16 weeks of pregnancy.

What does current guidance say on this issue?

NICE antenatal care guidance (2008) recommends that all pregnant women have their blood pressure measured and urine tested at every antenatal appointment to screen for pre-eclampsia.

At the 8 to 12 week “booking appointment” women should be formally assessed for pre-eclampsia risk factors such as age, weight, personal or family history of pre-eclampsia and pre-existing high blood pressure.

2011 NICE guidelines recommend that women at high risk of pre-eclampsia, or with two or more moderate risk factors, take 75mg of aspirin from 12 weeks until birth. This guidance is due for review in January 2017. This may take into account this new research which suggests benefits of slightly higher doses.

What are the implications?

This systematic review reinforces current NICE recommendations that a daily dose of aspirin started from 12 weeks onwards reduces the risk of pre-eclampsia for at-risk women. The findings suggest 75mg may be the minimally-effective dose, and there may a case for increasing to a slightly higher dose (100mg). However, trials assessing the recommended dose were notably lacking.

These dose-related findings require confirmation in large randomised controlled trials that directly compare the safety and effectiveness of standard low dose aspirin with higher doses when started in women at less than 16 weeks’ pregnancy.

Citation and Funding

Roberge S, Nicolaides K, Demers S, et al. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2016. [Epub ahead of print].

The study was funded by the Jeanne and Jean-Louis Lévesque Perinatal Research Chair at Université Laval.

Bibliography

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

NHS Choices. Your antenatal care. London: Department of Health; 2015.

NICE. Antenatal care for uncomplicated pregnancies. CG62. London: National Institute for Health and Care Excellence; 2008.

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

The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis

Published on 20 September 2016

Roberge, S.,Nicolaides, K.,Demers, S.,Hyett, J.,Chaillet, N.,Bujold, E.

Am J Obstet Gynecol , 2016

BACKGROUND: Preeclampsia (PE) and fetal growth restriction (FGR) are major causes of perinatal death and handicap in survivors. Randomized clinical trials (RCTs) have reported that the risk of PE, severe PE and FGR can be reduced by the prophylactic use of aspirin in high-risk women, but the appropriate dose of the drug to achieve this objective is not certain. OBJECTIVE: To estimate the impact of aspirin dosage on the prevention of PE, severe PE and FGR. STUDY DESIGN: We performed a systematic review and meta-analysis of RCTs comparing the effect of daily aspirin or placebo (or no treatment) during pregnancy. We searched MEDLINE, EMBASE, Web of Science and Cochrane CENTRAL up to December 2015, and study bibliographies were reviewed. Authors were contacted to obtain additional data when needed. Relative risks (RR) for PE, severe PE and FGR were calculated with 95% confidence intervals (CI) using random-effect models. Dose-response effect was evaluated using meta-regression and reported as an adjusted R-square (R2). Analyses were stratified according to gestational age at initiation of aspirin (</=16 and >16 weeks) and repeated after exclusion of studies at high-risk of biases. RESULTS: Forty-five RCTs including a total of 20,909 pregnant women randomized to between 50 mg and 150 mg of aspirin daily. When aspirin was initiated at </=16 weeks, there was a significant reduction and a dose-response effect for the prevention of PE (RR: 0.57; 95%CI: 0.43-0.75; p<0.001; R2=44%; p=0.036), severe PE (RR: 0.47; 95%CI: 0.26-0.83; p=0.009; R2=100%; p=0.008) and FGR (RR: 0.56; 95%CI: 0.44-0.70; p<0.001; R2=100%; p=0.044), with higher dosages of aspirin being associated with greater reduction of the three outcomes. Similar results were observed after the exclusion of studies at high-risk of biases. When aspirin was initiated at >16 weeks, there was a smaller reduction of PE (RR: 0.81; 95%CI: 0.66-0.99; p=0.04) without relationship with aspirin dosage (R2= 0%; p=0.941). Aspirin initiated at >16 weeks was not associated with a risk reduction or a dose-response effect for severe PE (RR: 0.85; 95%CI: 0.64-1.14; p=0.28; R2=0%; p=0.838) and FGR (RR: 0.95; 95%CI: 0.86-1.05; p=0.34; R2=not available; p=0.563). CONCLUSION: Prevention of PE and FGR using aspirin in early pregnancy is associated with a dose-response effect. Low-dose aspirin initiated after 16 week's gestation has a modest or no impact on the risk of PE, severe PE and FGR. Women at high-risk for those outcomes should be identified in early pregnancy.

Expert commentary

There is accumulating evidence that low-dose aspirin might reduce the incidence and complications from placental syndromes such as pre-eclampsia and foetal growth restriction. This Signal justifies the change in conventional prescribing from 75mg/100mg of aspirin to the higher dose of 150mg to achieve optimum effects. What remains elusive is the identification of the correct population for whom aspirin should be prescribed. In the absence of an effective and practical risk assessment for these pregnancy complications, this therapeutic approach will continue to be used in women with a history of pre-eclampsia or foetal growth restriction when the majority of complications will occur in women with no such history.

Professor Basky Thilaganathan, Director, Foetal Medicine Unit, Directorate of Children and Women's Services, St George's University Hospitals NHS Foundation Trust