Katherine Kirley, MD, MS

Illustrative case

A 75-year-old woman with hypertension and diabetes mellitus presents to the emergency department with shortness of breath, cough, and fever that she’s had for 4 days. On examination, her temperature is 38.2°C (100.7°F), heart rate is 110 beats/min, respiratory rate is 28 breaths/min, oxygen saturation is 91%, and rhonchi are heard in her right lower lung field. A chest x-ray reveals an infiltrate in her right lower lobe. The patient is admitted and started on intravenous (IV) antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than one million hospitalizations annually in the United States, and is the 8th leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures such as IV fluids and antipyretics. Because the disease process of CAP involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Cochrane systematic review published in 2011 identified 6 small randomized controlled trials (RCTs) that evaluated the impact of corticosteroids on recovery from CAP.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk of bias.

Subsequently, a 2012 meta-analysis of 9 RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of 8 moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays, but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY: Prednisone hastens clinical stabilization, cuts length of hospital stay

In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP admitted to 7 tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible for the study if they were ≥18 years old, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had one of several possible contraindications to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for 7 days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital Days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on Day 30.

The median time to clinical stability was shorter for the prednisone group (3 days) than for the placebo group (4.4 days).

The primary outcome was length of time to clinical stability, which was defined as at least 24 hours of stable vital signs. Stable vital signs was a composite endpoint that required all of the following: temperature ≤37.8°C (≤100°F), heart rate ≤100 beats/min, spontaneous respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mm Hg (≥100 mm Hg for patients diagnosed with hypertension) without vasopressor support, mental status back to baseline, ability to take food by mouth, and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR]=2.5-3.4) compared to the placebo group at 4.4 days (IQR=4-5; hazard ratio [HR]=1.33; 95% confidence interval [CI], 1.15-1.50; P<.0001). Median time to hospital discharge was also shorter for the prednisone group (6 days vs 7 days; HR=1.19; 95% CI, 1.04-1.38; P=.012) as was duration of IV antibiotic treatment (4 days vs 5 days, difference=-0.89 days; 95% CI, -1.57 to -0.20; P=.011).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio=1.96; 95% CI, 1.31-2.93; P=.001).

WHAT'S NEW: This large, good-quality study reinforces previous evidence

This is the largest good-quality RCT to explore the impact of corticosteroid treatment on less severe CAP. Previous studies suggested that corticosteroids may decrease the duration of illness, but this is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay.

Also, this study used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS: It's unclear whether steroids can benefit nonhospitalized patients

Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, while this was a large, well performed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP. Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the United States.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION: Steroids carry a risk of adverse events, including hyperglycemia

Treatment with prednisone increases the risk of corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these adverse effects appear to resolve quickly after treatment, and do not impact the overall time to clinical stability.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 75-year-old woman with hypertension and diabetes mellitus presents to the emergency department with shortness of breath, cough, and fever that she’s had for 4 days. On examination, her temperature is 38.2°C (100.7°F), heart rate is 110 beats/min, respiratory rate is 28 breaths/min, oxygen saturation is 91%, and rhonchi are heard in her right lower lung field. A chest x-ray reveals an infiltrate in her right lower lobe. The patient is admitted and started on intravenous (IV) antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than one million hospitalizations annually in the United States, and is the 8th leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures such as IV fluids and antipyretics. Because the disease process of CAP involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Cochrane systematic review published in 2011 identified 6 small randomized controlled trials (RCTs) that evaluated the impact of corticosteroids on recovery from CAP.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk of bias.

Subsequently, a 2012 meta-analysis of 9 RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of 8 moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays, but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY: Prednisone hastens clinical stabilization, cuts length of hospital stay

In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP admitted to 7 tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible for the study if they were ≥18 years old, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had one of several possible contraindications to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for 7 days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital Days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on Day 30.

The median time to clinical stability was shorter for the prednisone group (3 days) than for the placebo group (4.4 days).

The primary outcome was length of time to clinical stability, which was defined as at least 24 hours of stable vital signs. Stable vital signs was a composite endpoint that required all of the following: temperature ≤37.8°C (≤100°F), heart rate ≤100 beats/min, spontaneous respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mm Hg (≥100 mm Hg for patients diagnosed with hypertension) without vasopressor support, mental status back to baseline, ability to take food by mouth, and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR]=2.5-3.4) compared to the placebo group at 4.4 days (IQR=4-5; hazard ratio [HR]=1.33; 95% confidence interval [CI], 1.15-1.50; P<.0001). Median time to hospital discharge was also shorter for the prednisone group (6 days vs 7 days; HR=1.19; 95% CI, 1.04-1.38; P=.012) as was duration of IV antibiotic treatment (4 days vs 5 days, difference=-0.89 days; 95% CI, -1.57 to -0.20; P=.011).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio=1.96; 95% CI, 1.31-2.93; P=.001).

WHAT'S NEW: This large, good-quality study reinforces previous evidence

This is the largest good-quality RCT to explore the impact of corticosteroid treatment on less severe CAP. Previous studies suggested that corticosteroids may decrease the duration of illness, but this is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay.

Also, this study used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS: It's unclear whether steroids can benefit nonhospitalized patients

Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, while this was a large, well performed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP. Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the United States.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION: Steroids carry a risk of adverse events, including hyperglycemia

Treatment with prednisone increases the risk of corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these adverse effects appear to resolve quickly after treatment, and do not impact the overall time to clinical stability.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 75-year-old woman with hypertension and diabetes mellitus presents to the emergency department with shortness of breath, cough, and fever that she’s had for 4 days. On examination, her temperature is 38.2°C (100.7°F), heart rate is 110 beats/min, respiratory rate is 28 breaths/min, oxygen saturation is 91%, and rhonchi are heard in her right lower lung field. A chest x-ray reveals an infiltrate in her right lower lobe. The patient is admitted and started on intravenous (IV) antibiotics, IV fluids, acetaminophen for fever, and oxygen. Can anything else be done to speed her recovery?

Community-acquired pneumonia (CAP) is responsible for more than one million hospitalizations annually in the United States, and is the 8th leading cause of death.^2,3 Treatment of CAP typically consists of antibiotics and supportive measures such as IV fluids and antipyretics. Because the disease process of CAP involves extensive inflammation, adjunct treatment with corticosteroids may be beneficial.

Multiple studies have shown that treatment with corticosteroids can help patients with severe CAP, but the potential benefit in patients with less severe CAP has been uncertain.^4,5 A Cochrane systematic review published in 2011 identified 6 small randomized controlled trials (RCTs) that evaluated the impact of corticosteroids on recovery from CAP.⁴ It suggested that corticosteroids may decrease time to recovery, but the studies that included patients with less severe CAP had a relatively high risk of bias.

Subsequently, a 2012 meta-analysis of 9 RCTs explored whether corticosteroids affected mortality in CAP; no benefit was observed in patients with less severe CAP.⁵ Most recently, a 2013 meta-analysis of 8 moderate-quality RCTs showed that corticosteroid use was associated with shorter hospital stays, but no change in mortality.⁶

The synthesis of small or moderate-quality studies suggests some potential benefit in treating less severe CAP with corticosteroids, but there has been a need for a large, definitive, high-quality RCT. This study investigated the impact of a short course of oral steroids on inpatients with less severe CAP.

STUDY SUMMARY: Prednisone hastens clinical stabilization, cuts length of hospital stay

In a multicenter, double-blind RCT, Blum et al¹ enrolled 785 patients with CAP admitted to 7 tertiary care hospitals in Switzerland from 2009 to 2014. Patients were eligible for the study if they were ≥18 years old, had a new infiltrate on chest x-ray, and had at least one additional sign or symptom of respiratory illness (eg, cough, dyspnea, fever, abnormal breathing signs or rales, or elevated or decreased white blood cell count). Patients were excluded if they had one of several possible contraindications to corticosteroids, cystic fibrosis, or active tuberculosis.

Patients were randomized to receive either prednisone 50 mg/d or placebo for 7 days. They were treated with antibiotics according to accepted local guidelines; most patients received either amoxicillin/clavulanic acid or ceftriaxone. Antibiotic treatment was adjusted according to susceptibility whenever a specific pathogen was identified. Nurses assessed all patients every 12 hours during hospitalization, and laboratory tests were obtained on hospital Days 1, 3, 5, and 7, and before discharge. Follow-up telephone interviews were conducted on Day 30.

The median time to clinical stability was shorter for the prednisone group (3 days) than for the placebo group (4.4 days).

The primary outcome was length of time to clinical stability, which was defined as at least 24 hours of stable vital signs. Stable vital signs was a composite endpoint that required all of the following: temperature ≤37.8°C (≤100°F), heart rate ≤100 beats/min, spontaneous respiratory rate ≤24 breaths/min, systolic blood pressure ≥90 mm Hg (≥100 mm Hg for patients diagnosed with hypertension) without vasopressor support, mental status back to baseline, ability to take food by mouth, and adequate oxygenation on room air.

Secondary outcomes included length of hospital stay, pneumonia recurrence, hospital readmission, intensive care unit (ICU) admission, all-cause mortality, and duration of antibiotic treatment. Researchers also explored whether the rates of complications from pneumonia or corticosteroid use differed between the prednisone and placebo groups.

In an intention-to-treat analysis, the median time to clinical stability was shorter for the prednisone group at 3 days (interquartile range [IQR]=2.5-3.4) compared to the placebo group at 4.4 days (IQR=4-5; hazard ratio [HR]=1.33; 95% confidence interval [CI], 1.15-1.50; P<.0001). Median time to hospital discharge was also shorter for the prednisone group (6 days vs 7 days; HR=1.19; 95% CI, 1.04-1.38; P=.012) as was duration of IV antibiotic treatment (4 days vs 5 days, difference=-0.89 days; 95% CI, -1.57 to -0.20; P=.011).

There were no statistically significant differences in pneumonia recurrence, hospital readmission, ICU admission, or all-cause mortality. Patients treated with prednisone were more likely to experience hyperglycemia that required insulin treatment during admission (19% vs 11%; odds ratio=1.96; 95% CI, 1.31-2.93; P=.001).

WHAT'S NEW: This large, good-quality study reinforces previous evidence

This is the largest good-quality RCT to explore the impact of corticosteroid treatment on less severe CAP. Previous studies suggested that corticosteroids may decrease the duration of illness, but this is the first rigorous study to show a clear decrease in both time to clinical stability and length of hospital stay.

Also, this study used an easy-to-administer dose of oral steroids, instead of the several-day course of IV steroids used in most other studies. The findings from this study were incorporated into a 2015 meta-analysis that confirmed that corticosteroid treatment in patients with less severe CAP results in a shorter length of hospital stay and decreased time to clinical stability.⁷

CAVEATS: It's unclear whether steroids can benefit nonhospitalized patients

Because this study included hospitalized patients only, it’s not clear whether corticosteroids have a role in outpatient treatment of CAP. Additionally, while this was a large, well performed study, it did not have a sufficient number of patients to examine whether corticosteroids impact mortality among patients with CAP. Finally, the average length of hospital stay reported in this study was approximately 1.5 days longer than the typical length of stay in the United States.² The average length of stay has varied widely in studies examining corticosteroids in CAP, but good-quality studies have consistently shown a median reduction in length of stay of one day.⁷

CHALLENGES TO IMPLEMENTATION: Steroids carry a risk of adverse events, including hyperglycemia

Treatment with prednisone increases the risk of corticosteroid-related adverse events, primarily hyperglycemia and the need for insulin. This may not be well received by patients or providers. However, these adverse effects appear to resolve quickly after treatment, and do not impact the overall time to clinical stability.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

PRACTICE CHANGER 
Prescribe low-dose aspirin (eg, 81 mg/d) to pregnant women who are at high risk for preeclampsia because it reduces the risk for this complication, as well as preterm birth and intrauterine growth ­restriction.¹

STRENGTH OF RECOMMENDATION
A: Based on a systematic review and meta-analysis of 23 studies, including 21 randomized controlled trials.¹

ILLUSTRATIVE CASE
A 22-year-old G2P1 pregnant woman at 18 weeks’ gestation who has a history of preeclampsia comes to your office for a routine prenatal visit. On exam, her blood pressure continues to be in the 110s/60s, as it has been for several visits. Her history puts her at risk for preeclampsia again, and you wonder if anything can be done to prevent this from happening.

The incidence of preeclampsia, which occurs in 2% to 8% of pregnancies worldwide and 3.4% of pregnancies in the United States, appears to be steadily increasing.^2,3 Preeclampsia is defined as new-onset hypertension at > 20 weeks’ gestation, plus proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and/or cerebral or visual symptoms.⁴

The condition is associated with several adverse maternal and fetal outcomes, including ­eclampsia, abruption, intrauterine growth restriction (IUGR), preterm birth, stillbirth, and maternal death.^2,4 Risk factors include previous preeclampsia, maternal age 40 or older, chronic medical conditions, and multifetal pregnancy.⁵

The only effective treatment for preeclampsia is delivery.⁴ Given the lack of other treatments, strategies for prevention would be highly valuable.

In 1996, the US Preventive Services Task Force (USPSTF) addressed this issue and concluded that there was insufficient evidence to recommend for or against using aspirin to prevent preeclampsia.⁶ More recently, Henderson et al¹ conducted a  systematic review and meta-­analysis to support the USPSTF in a revision of its earlier recommendation.

STUDY SUMMARY
Aspirin lowers risk for preeclampsia and preterm birth
Henderson et al¹ evaluated the impact of low-dose aspirin on maternal and fetal outcomes among pregnant women at risk for preeclampsia. The review of 23 studies included 21 randomized, placebo-controlled trials that evaluated 24,666 patients. Slightly more than half of the studies that evaluated maternal and fetal health benefits were graded as good quality, and 67% of those that evaluated maternal, perinatal, and developmental harms were rated good quality.

Most study participants were white and ages 20 to 33. Aspirin doses ranged from 60 to 150 mg/d; most studies used doses of 60 or 100 mg/d. Aspirin was initiated between 12 to 36 weeks’ gestation, with nine trials initiating aspirin before 16 weeks. In most trials, aspirin was continued until delivery.

Among women at high preeclampsia risk (10 studies), the pooled relative risk (RR) for perinatal death was 0.81 for low-dose aspirin, compared to placebo. However, this finding was not statistically significant (P = .78).

Among women who received low-dose aspirin, researchers noted a 14% risk reduction for preterm birth (RR, 0.86), a 20% risk reduction for IUGR (RR, 0.80), and a 24% risk reduction for preeclampsia (RR, 0.76). The absolute risk reduction for preeclampsia was estimated to be 2% to 5%.

While the results for preterm birth, IUGR, and preeclampsia were statistically significant, the authors noted that these results could have been biased by “small study effects” (the tendency of smaller studies to report positive findings, which in turn can skew the results of a meta-analysis based primarily on such studies). The timing and dosage of aspirin had no significant effect on outcomes.

There was no evidence of increased maternal postpartum hemorrhage with aspirin use (RR, 1.02). Aspirin use did not seem to increase perinatal mortality among all risk levels (RR, 0.92; P = .65). No differences were noted in the toddlers’ development at 18 months.

WHAT’S NEW
Low-dose aspirin use is now recommended
The 1996 USPSTF recommendation concluded that there was insufficient evidence to recommend aspirin use for preventing preeclampsia. This systematic review and meta-analysis, along with findings from a 2007 Cochrane review⁷ and a ­meta-analysis from the PARIS Collaborative Group,⁸ provide good-quality evidence that aspirin reduces negative maternal and fetal outcomes associated with preeclampsia. In 2014, the USPSTF cited this evidence when it decided to recommend using low-dose aspirin  (81 mg/d) to prevent preeclampsia in women who are at high risk for the complication (Grade B).⁹

CAVEATS
Much of the data came from small studies
A substantial portion of the data in this systematic review and meta-analysis came from small studies with positive findings. Because small studies with null findings tend not to be published, there is concern that the results reported by Henderson et al1 may be somewhat biased, and that future studies may push the overall observed effect toward a null finding.

Also, the criteria used to define “high risk” for preeclampsia varied by study, so it’s unclear which groups of women would benefit most from aspirin use during pregnancy. Finally, there is a lack of high-quality data on the effects of aspirin use during pregnancy on long-term outcomes in children. Despite these caveats, the cumulative evidence strongly points to greater benefit than harm.

CHALLENGES TO IMPLEMENTATION
You need to determine which patients are at highest risk
The principle challenge lies in the identification of patients who are at high risk for preeclampsia and thus will likely benefit from this intervention. This systematic review and meta-analysis used a large variety of risk factors to determine whether a woman was at high risk. A 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy report defined as high risk women with a history of preeclampsia in more than one previous pregnancy or women with a previous preterm delivery due to preeclampsia.⁴

The updated USPSTF recommendation suggests that women be considered high risk if they have any of the following: previous preeclampsia, multifetal gestation, chronic hypertension, diabetes, renal disease, or autoimmune disease.⁹ We consider both sets of criteria reasonable for identifying women who may benefit from low-dose aspirin during pregnancy.

REFERENCES
1. Henderson J, Whitlock E, O’Connor E, et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Ann Intern Med. 2014;160:695-703.
2. Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36:56-59.
3. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. BMJ. 2013;347:f6564.
4. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Obstet Gynecol. 2013;122:1122-1131.
5. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005; 330:565.
6. US Preventive Services Task Force. Aspirin prophylaxis in pregnancy. In: Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. 2nd ed. Washington, DC: US Department of Health and Human Services; 1996.
7. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007(2):CD004659. 8. Askie LM, Duley L, Henderson-Smart DJ, et al; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369: 1791-1798. 9. LeFevre ML; US Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia [recommendation statement]. Ann Intern Med. 2014;161:819-826.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from The Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(5):301-303.

PRACTICE CHANGER 
Prescribe low-dose aspirin (eg, 81 mg/d) to pregnant women who are at high risk for preeclampsia because it reduces the risk for this complication, as well as preterm birth and intrauterine growth ­restriction.¹

STRENGTH OF RECOMMENDATION
A: Based on a systematic review and meta-analysis of 23 studies, including 21 randomized controlled trials.¹

ILLUSTRATIVE CASE
A 22-year-old G2P1 pregnant woman at 18 weeks’ gestation who has a history of preeclampsia comes to your office for a routine prenatal visit. On exam, her blood pressure continues to be in the 110s/60s, as it has been for several visits. Her history puts her at risk for preeclampsia again, and you wonder if anything can be done to prevent this from happening.

The incidence of preeclampsia, which occurs in 2% to 8% of pregnancies worldwide and 3.4% of pregnancies in the United States, appears to be steadily increasing.^2,3 Preeclampsia is defined as new-onset hypertension at > 20 weeks’ gestation, plus proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and/or cerebral or visual symptoms.⁴

The condition is associated with several adverse maternal and fetal outcomes, including ­eclampsia, abruption, intrauterine growth restriction (IUGR), preterm birth, stillbirth, and maternal death.^2,4 Risk factors include previous preeclampsia, maternal age 40 or older, chronic medical conditions, and multifetal pregnancy.⁵

The only effective treatment for preeclampsia is delivery.⁴ Given the lack of other treatments, strategies for prevention would be highly valuable.

In 1996, the US Preventive Services Task Force (USPSTF) addressed this issue and concluded that there was insufficient evidence to recommend for or against using aspirin to prevent preeclampsia.⁶ More recently, Henderson et al¹ conducted a  systematic review and meta-­analysis to support the USPSTF in a revision of its earlier recommendation.

STUDY SUMMARY
Aspirin lowers risk for preeclampsia and preterm birth
Henderson et al¹ evaluated the impact of low-dose aspirin on maternal and fetal outcomes among pregnant women at risk for preeclampsia. The review of 23 studies included 21 randomized, placebo-controlled trials that evaluated 24,666 patients. Slightly more than half of the studies that evaluated maternal and fetal health benefits were graded as good quality, and 67% of those that evaluated maternal, perinatal, and developmental harms were rated good quality.

Most study participants were white and ages 20 to 33. Aspirin doses ranged from 60 to 150 mg/d; most studies used doses of 60 or 100 mg/d. Aspirin was initiated between 12 to 36 weeks’ gestation, with nine trials initiating aspirin before 16 weeks. In most trials, aspirin was continued until delivery.

Among women at high preeclampsia risk (10 studies), the pooled relative risk (RR) for perinatal death was 0.81 for low-dose aspirin, compared to placebo. However, this finding was not statistically significant (P = .78).

Among women who received low-dose aspirin, researchers noted a 14% risk reduction for preterm birth (RR, 0.86), a 20% risk reduction for IUGR (RR, 0.80), and a 24% risk reduction for preeclampsia (RR, 0.76). The absolute risk reduction for preeclampsia was estimated to be 2% to 5%.

While the results for preterm birth, IUGR, and preeclampsia were statistically significant, the authors noted that these results could have been biased by “small study effects” (the tendency of smaller studies to report positive findings, which in turn can skew the results of a meta-analysis based primarily on such studies). The timing and dosage of aspirin had no significant effect on outcomes.

There was no evidence of increased maternal postpartum hemorrhage with aspirin use (RR, 1.02). Aspirin use did not seem to increase perinatal mortality among all risk levels (RR, 0.92; P = .65). No differences were noted in the toddlers’ development at 18 months.

WHAT’S NEW
Low-dose aspirin use is now recommended
The 1996 USPSTF recommendation concluded that there was insufficient evidence to recommend aspirin use for preventing preeclampsia. This systematic review and meta-analysis, along with findings from a 2007 Cochrane review⁷ and a ­meta-analysis from the PARIS Collaborative Group,⁸ provide good-quality evidence that aspirin reduces negative maternal and fetal outcomes associated with preeclampsia. In 2014, the USPSTF cited this evidence when it decided to recommend using low-dose aspirin  (81 mg/d) to prevent preeclampsia in women who are at high risk for the complication (Grade B).⁹

CAVEATS
Much of the data came from small studies
A substantial portion of the data in this systematic review and meta-analysis came from small studies with positive findings. Because small studies with null findings tend not to be published, there is concern that the results reported by Henderson et al1 may be somewhat biased, and that future studies may push the overall observed effect toward a null finding.

Also, the criteria used to define “high risk” for preeclampsia varied by study, so it’s unclear which groups of women would benefit most from aspirin use during pregnancy. Finally, there is a lack of high-quality data on the effects of aspirin use during pregnancy on long-term outcomes in children. Despite these caveats, the cumulative evidence strongly points to greater benefit than harm.

CHALLENGES TO IMPLEMENTATION
You need to determine which patients are at highest risk
The principle challenge lies in the identification of patients who are at high risk for preeclampsia and thus will likely benefit from this intervention. This systematic review and meta-analysis used a large variety of risk factors to determine whether a woman was at high risk. A 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy report defined as high risk women with a history of preeclampsia in more than one previous pregnancy or women with a previous preterm delivery due to preeclampsia.⁴

The updated USPSTF recommendation suggests that women be considered high risk if they have any of the following: previous preeclampsia, multifetal gestation, chronic hypertension, diabetes, renal disease, or autoimmune disease.⁹ We consider both sets of criteria reasonable for identifying women who may benefit from low-dose aspirin during pregnancy.

REFERENCES
1. Henderson J, Whitlock E, O’Connor E, et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Ann Intern Med. 2014;160:695-703.
2. Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36:56-59.
3. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. BMJ. 2013;347:f6564.
4. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Obstet Gynecol. 2013;122:1122-1131.
5. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005; 330:565.
6. US Preventive Services Task Force. Aspirin prophylaxis in pregnancy. In: Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. 2nd ed. Washington, DC: US Department of Health and Human Services; 1996.
7. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007(2):CD004659. 8. Askie LM, Duley L, Henderson-Smart DJ, et al; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369: 1791-1798. 9. LeFevre ML; US Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia [recommendation statement]. Ann Intern Med. 2014;161:819-826.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from The Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(5):301-303.

PRACTICE CHANGER 
Prescribe low-dose aspirin (eg, 81 mg/d) to pregnant women who are at high risk for preeclampsia because it reduces the risk for this complication, as well as preterm birth and intrauterine growth ­restriction.¹

STRENGTH OF RECOMMENDATION
A: Based on a systematic review and meta-analysis of 23 studies, including 21 randomized controlled trials.¹

ILLUSTRATIVE CASE
A 22-year-old G2P1 pregnant woman at 18 weeks’ gestation who has a history of preeclampsia comes to your office for a routine prenatal visit. On exam, her blood pressure continues to be in the 110s/60s, as it has been for several visits. Her history puts her at risk for preeclampsia again, and you wonder if anything can be done to prevent this from happening.

The incidence of preeclampsia, which occurs in 2% to 8% of pregnancies worldwide and 3.4% of pregnancies in the United States, appears to be steadily increasing.^2,3 Preeclampsia is defined as new-onset hypertension at > 20 weeks’ gestation, plus proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and/or cerebral or visual symptoms.⁴

The condition is associated with several adverse maternal and fetal outcomes, including ­eclampsia, abruption, intrauterine growth restriction (IUGR), preterm birth, stillbirth, and maternal death.^2,4 Risk factors include previous preeclampsia, maternal age 40 or older, chronic medical conditions, and multifetal pregnancy.⁵

The only effective treatment for preeclampsia is delivery.⁴ Given the lack of other treatments, strategies for prevention would be highly valuable.

In 1996, the US Preventive Services Task Force (USPSTF) addressed this issue and concluded that there was insufficient evidence to recommend for or against using aspirin to prevent preeclampsia.⁶ More recently, Henderson et al¹ conducted a  systematic review and meta-­analysis to support the USPSTF in a revision of its earlier recommendation.

STUDY SUMMARY
Aspirin lowers risk for preeclampsia and preterm birth
Henderson et al¹ evaluated the impact of low-dose aspirin on maternal and fetal outcomes among pregnant women at risk for preeclampsia. The review of 23 studies included 21 randomized, placebo-controlled trials that evaluated 24,666 patients. Slightly more than half of the studies that evaluated maternal and fetal health benefits were graded as good quality, and 67% of those that evaluated maternal, perinatal, and developmental harms were rated good quality.

Most study participants were white and ages 20 to 33. Aspirin doses ranged from 60 to 150 mg/d; most studies used doses of 60 or 100 mg/d. Aspirin was initiated between 12 to 36 weeks’ gestation, with nine trials initiating aspirin before 16 weeks. In most trials, aspirin was continued until delivery.

Among women at high preeclampsia risk (10 studies), the pooled relative risk (RR) for perinatal death was 0.81 for low-dose aspirin, compared to placebo. However, this finding was not statistically significant (P = .78).

Among women who received low-dose aspirin, researchers noted a 14% risk reduction for preterm birth (RR, 0.86), a 20% risk reduction for IUGR (RR, 0.80), and a 24% risk reduction for preeclampsia (RR, 0.76). The absolute risk reduction for preeclampsia was estimated to be 2% to 5%.

While the results for preterm birth, IUGR, and preeclampsia were statistically significant, the authors noted that these results could have been biased by “small study effects” (the tendency of smaller studies to report positive findings, which in turn can skew the results of a meta-analysis based primarily on such studies). The timing and dosage of aspirin had no significant effect on outcomes.

There was no evidence of increased maternal postpartum hemorrhage with aspirin use (RR, 1.02). Aspirin use did not seem to increase perinatal mortality among all risk levels (RR, 0.92; P = .65). No differences were noted in the toddlers’ development at 18 months.

WHAT’S NEW
Low-dose aspirin use is now recommended
The 1996 USPSTF recommendation concluded that there was insufficient evidence to recommend aspirin use for preventing preeclampsia. This systematic review and meta-analysis, along with findings from a 2007 Cochrane review⁷ and a ­meta-analysis from the PARIS Collaborative Group,⁸ provide good-quality evidence that aspirin reduces negative maternal and fetal outcomes associated with preeclampsia. In 2014, the USPSTF cited this evidence when it decided to recommend using low-dose aspirin  (81 mg/d) to prevent preeclampsia in women who are at high risk for the complication (Grade B).⁹

CAVEATS
Much of the data came from small studies
A substantial portion of the data in this systematic review and meta-analysis came from small studies with positive findings. Because small studies with null findings tend not to be published, there is concern that the results reported by Henderson et al1 may be somewhat biased, and that future studies may push the overall observed effect toward a null finding.

Also, the criteria used to define “high risk” for preeclampsia varied by study, so it’s unclear which groups of women would benefit most from aspirin use during pregnancy. Finally, there is a lack of high-quality data on the effects of aspirin use during pregnancy on long-term outcomes in children. Despite these caveats, the cumulative evidence strongly points to greater benefit than harm.

CHALLENGES TO IMPLEMENTATION
You need to determine which patients are at highest risk
The principle challenge lies in the identification of patients who are at high risk for preeclampsia and thus will likely benefit from this intervention. This systematic review and meta-analysis used a large variety of risk factors to determine whether a woman was at high risk. A 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy report defined as high risk women with a history of preeclampsia in more than one previous pregnancy or women with a previous preterm delivery due to preeclampsia.⁴

The updated USPSTF recommendation suggests that women be considered high risk if they have any of the following: previous preeclampsia, multifetal gestation, chronic hypertension, diabetes, renal disease, or autoimmune disease.⁹ We consider both sets of criteria reasonable for identifying women who may benefit from low-dose aspirin during pregnancy.

REFERENCES
1. Henderson J, Whitlock E, O’Connor E, et al. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the US Preventive Services Task Force. Ann Intern Med. 2014;160:695-703.
2. Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36:56-59.
3. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United States, 1980-2010: age-period-cohort analysis. BMJ. 2013;347:f6564.
4. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Obstet Gynecol. 2013;122:1122-1131.
5. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ. 2005; 330:565.
6. US Preventive Services Task Force. Aspirin prophylaxis in pregnancy. In: Guide to Clinical Preventive Services: Report of the US Preventive Services Task Force. 2nd ed. Washington, DC: US Department of Health and Human Services; 1996.
7. Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007(2):CD004659. 8. Askie LM, Duley L, Henderson-Smart DJ, et al; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369: 1791-1798. 9. LeFevre ML; US Preventive Services Task Force. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia [recommendation statement]. Ann Intern Med. 2014;161:819-826.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from The Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(5):301-303.

Illustrative case

A 22-year-old G2P1 pregnant woman at 18 weeks gestation who has a history of preeclampsia comes to your office for a routine prenatal visit. On exam, her blood pressure continues to be in the 110s/60s, as it has been for several visits. Her history puts her at risk of developing preeclampsia again, and you wonder if anything can be done to prevent this from happening.

The incidence of preeclampsia, which occurs in 2% to 8% of pregnancies worldwide and 3.4% of pregnancies in the United States, appears to be steadily increasing.^2,3 Preeclampsia is defined as new-onset hypertension at >20 weeks gestation, plus proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and/or cerebral or visual symptoms.⁴ The condition is associated with several adverse maternal and fetal outcomes, including eclampsia, abruption, intrauterine growth restriction (IUGR), preterm birth, stillbirth, and maternal death.^2,4 Risk factors for preeclampsia include previous preeclampsia, maternal age ≥40 years, chronic medical conditions, and multi-fetal pregnancy.⁵

The only effective treatment for preeclampsia is delivery.⁴ Given the lack of other treatments, strategies for preventing preeclampsia would be highly valuable.

In 1996, the US Preventive Services Task Force (USPSTF) addressed this issue and concluded that there was insufficient evidence to recommend for or against using aspirin to prevent preeclampsia.⁶ More recently, Henderson et al¹ conducted a systematic review and meta-analysis to support the USPSTF in a revision of its earlier recommendation.

STUDY SUMMARY: Aspirin use lowers risk of preeclampsia and preterm birth

Henderson et al¹ evaluated the impact of low-dose aspirin on maternal and fetal outcomes among pregnant women at risk for preeclampsia. The review of 23 studies included 21 randomized placebo-controlled trials that evaluated 24,666 patients. Slightly more than half of the studies that evaluated maternal and fetal health benefits were graded as good-quality, and 67% of those that evaluated maternal, perinatal, and developmental harms were rated good-quality.

Most women were white and ages 20 to 33 years. Aspirin doses ranged from 60 mg/d to 150 mg/d; most studies used 60 mg/d or 100 mg/d. Aspirin was initiated between 12 to 36 weeks gestation, with 9 trials initiating aspirin before 16 weeks. In most trials, aspirin was continued until delivery.

Among women at high preeclampsia risk (10 studies), the pooled relative risk (RR) for perinatal death was 0.81 (95% confidence interval [CI], 0.65-1.01) for low-dose aspirin compared to placebo. However, this finding was not statistically significant (P=.78).

Researchers found no evidence of increased maternal postpartum hemorrhage with aspirin use.

Among women who received low-dose aspirin, researchers noted a 14% risk reduction for preterm birth (RR=0.86; 95% CI, 0.76-0.98); a 20% risk reduction for IUGR (RR=0.80; 95% CI, 0.65-0.99), and a 24% risk reduction for preeclampsia (RR=0.76; 95% CI, 0.62-0.95). The absolute risk reduction for preeclampsia was estimated to be 2% to 5%.

While the results for preterm birth, IUGR, and preeclampsia were statistically significant, the authors noted that these results could have been biased by small study effects (the tendency of smaller studies to report positive findings, which in turn can skew the results of a meta-analysis based primarily on such studies). The timing and dosage of aspirin had no significant effect on outcomes.

There was no evidence of increased maternal postpartum hemorrhage with aspirin use (RR=1.02; 95% CI, 0.96-1.09). Aspirin use did not seem to increase perinatal mortality among all risk levels (RR=0.92; 95% CI, 0.76-1.11; P=.65). No differences were noted in the toddlers’ development at 18 months.

WHAT'S NEW: Low-dose aspirin use is now recommended

The 1996 USPSTF recommendation concluded that there was insufficient evidence to recommend aspirin use for preventing preeclampsia. This systematic review and meta-analysis, along with findings from a 2007 Cochrane review⁷ and a meta-analysis from the PARIS Collaborative Group,⁸ provide good-quality evidence that aspirin reduces negative maternal and fetal outcomes associated with preeclampsia. In 2014, the USPSTF cited this evidence when it decided to recommend using low-dose aspirin (81 mg/d) to prevent preeclampsia in women who are at high risk for preeclampsia (Grade B).⁹ (For more on the USPSTF, see “Catching up on the latest USPSTF recommendations”.)

CAVEATS: Much of the data came from small studies

A substantial portion of the data in this systematic review and meta-analysis came from small studies with positive findings. Because small studies with null findings tend to not be published, there is concern that the results reported by Henderson et al¹ may be somewhat biased, and that future studies may push the overall observed effect toward a null finding.

Also, the criteria used to define “high risk” for preeclampsia varied by study, so it’s unclear which groups of women would benefit most from aspirin use during pregnancy. Finally, there is a lack of high-quality data on the effects of aspirin use during pregnancy on long-term outcomes in children. Despite these caveats, the cumulative evidence strongly points to greater benefit than harm.

CHALLENGES TO IMPLEMENTATION: You need to determine which patients are at highest risk

The principle challenge lies in identifying which patients are at high risk for preeclampsia, and thus, will likely benefit from this intervention. This systematic review and meta-analysis used a large variety of risk factors to determine whether a woman was high risk. A 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy report defined high-risk as women with a history of preeclampsia in more than one previous pregnancy or women with a previous preterm delivery due to preeclampsia.⁴

The updated USPSTF recommendation suggests that women be considered high risk if they have any of the following: 1) previous preeclampsia, 2) multifetal gestation, 3) chronic hypertension, 4) diabetes, 5) renal disease, or 6) autoimmune disease.⁹ We consider both sets of criteria reasonable for identifying women who may benefit from low-dose aspirin during pregnancy.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 22-year-old G2P1 pregnant woman at 18 weeks gestation who has a history of preeclampsia comes to your office for a routine prenatal visit. On exam, her blood pressure continues to be in the 110s/60s, as it has been for several visits. Her history puts her at risk of developing preeclampsia again, and you wonder if anything can be done to prevent this from happening.

The incidence of preeclampsia, which occurs in 2% to 8% of pregnancies worldwide and 3.4% of pregnancies in the United States, appears to be steadily increasing.^2,3 Preeclampsia is defined as new-onset hypertension at >20 weeks gestation, plus proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and/or cerebral or visual symptoms.⁴ The condition is associated with several adverse maternal and fetal outcomes, including eclampsia, abruption, intrauterine growth restriction (IUGR), preterm birth, stillbirth, and maternal death.^2,4 Risk factors for preeclampsia include previous preeclampsia, maternal age ≥40 years, chronic medical conditions, and multi-fetal pregnancy.⁵

The only effective treatment for preeclampsia is delivery.⁴ Given the lack of other treatments, strategies for preventing preeclampsia would be highly valuable.

In 1996, the US Preventive Services Task Force (USPSTF) addressed this issue and concluded that there was insufficient evidence to recommend for or against using aspirin to prevent preeclampsia.⁶ More recently, Henderson et al¹ conducted a systematic review and meta-analysis to support the USPSTF in a revision of its earlier recommendation.

STUDY SUMMARY: Aspirin use lowers risk of preeclampsia and preterm birth

Henderson et al¹ evaluated the impact of low-dose aspirin on maternal and fetal outcomes among pregnant women at risk for preeclampsia. The review of 23 studies included 21 randomized placebo-controlled trials that evaluated 24,666 patients. Slightly more than half of the studies that evaluated maternal and fetal health benefits were graded as good-quality, and 67% of those that evaluated maternal, perinatal, and developmental harms were rated good-quality.

Most women were white and ages 20 to 33 years. Aspirin doses ranged from 60 mg/d to 150 mg/d; most studies used 60 mg/d or 100 mg/d. Aspirin was initiated between 12 to 36 weeks gestation, with 9 trials initiating aspirin before 16 weeks. In most trials, aspirin was continued until delivery.

Among women at high preeclampsia risk (10 studies), the pooled relative risk (RR) for perinatal death was 0.81 (95% confidence interval [CI], 0.65-1.01) for low-dose aspirin compared to placebo. However, this finding was not statistically significant (P=.78).

Researchers found no evidence of increased maternal postpartum hemorrhage with aspirin use.

Among women who received low-dose aspirin, researchers noted a 14% risk reduction for preterm birth (RR=0.86; 95% CI, 0.76-0.98); a 20% risk reduction for IUGR (RR=0.80; 95% CI, 0.65-0.99), and a 24% risk reduction for preeclampsia (RR=0.76; 95% CI, 0.62-0.95). The absolute risk reduction for preeclampsia was estimated to be 2% to 5%.

While the results for preterm birth, IUGR, and preeclampsia were statistically significant, the authors noted that these results could have been biased by small study effects (the tendency of smaller studies to report positive findings, which in turn can skew the results of a meta-analysis based primarily on such studies). The timing and dosage of aspirin had no significant effect on outcomes.

There was no evidence of increased maternal postpartum hemorrhage with aspirin use (RR=1.02; 95% CI, 0.96-1.09). Aspirin use did not seem to increase perinatal mortality among all risk levels (RR=0.92; 95% CI, 0.76-1.11; P=.65). No differences were noted in the toddlers’ development at 18 months.

WHAT'S NEW: Low-dose aspirin use is now recommended

The 1996 USPSTF recommendation concluded that there was insufficient evidence to recommend aspirin use for preventing preeclampsia. This systematic review and meta-analysis, along with findings from a 2007 Cochrane review⁷ and a meta-analysis from the PARIS Collaborative Group,⁸ provide good-quality evidence that aspirin reduces negative maternal and fetal outcomes associated with preeclampsia. In 2014, the USPSTF cited this evidence when it decided to recommend using low-dose aspirin (81 mg/d) to prevent preeclampsia in women who are at high risk for preeclampsia (Grade B).⁹ (For more on the USPSTF, see “Catching up on the latest USPSTF recommendations”.)

CAVEATS: Much of the data came from small studies

A substantial portion of the data in this systematic review and meta-analysis came from small studies with positive findings. Because small studies with null findings tend to not be published, there is concern that the results reported by Henderson et al¹ may be somewhat biased, and that future studies may push the overall observed effect toward a null finding.

Also, the criteria used to define “high risk” for preeclampsia varied by study, so it’s unclear which groups of women would benefit most from aspirin use during pregnancy. Finally, there is a lack of high-quality data on the effects of aspirin use during pregnancy on long-term outcomes in children. Despite these caveats, the cumulative evidence strongly points to greater benefit than harm.

CHALLENGES TO IMPLEMENTATION: You need to determine which patients are at highest risk

The principle challenge lies in identifying which patients are at high risk for preeclampsia, and thus, will likely benefit from this intervention. This systematic review and meta-analysis used a large variety of risk factors to determine whether a woman was high risk. A 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy report defined high-risk as women with a history of preeclampsia in more than one previous pregnancy or women with a previous preterm delivery due to preeclampsia.⁴

The updated USPSTF recommendation suggests that women be considered high risk if they have any of the following: 1) previous preeclampsia, 2) multifetal gestation, 3) chronic hypertension, 4) diabetes, 5) renal disease, or 6) autoimmune disease.⁹ We consider both sets of criteria reasonable for identifying women who may benefit from low-dose aspirin during pregnancy.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative case

A 22-year-old G2P1 pregnant woman at 18 weeks gestation who has a history of preeclampsia comes to your office for a routine prenatal visit. On exam, her blood pressure continues to be in the 110s/60s, as it has been for several visits. Her history puts her at risk of developing preeclampsia again, and you wonder if anything can be done to prevent this from happening.

The incidence of preeclampsia, which occurs in 2% to 8% of pregnancies worldwide and 3.4% of pregnancies in the United States, appears to be steadily increasing.^2,3 Preeclampsia is defined as new-onset hypertension at >20 weeks gestation, plus proteinuria, thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, and/or cerebral or visual symptoms.⁴ The condition is associated with several adverse maternal and fetal outcomes, including eclampsia, abruption, intrauterine growth restriction (IUGR), preterm birth, stillbirth, and maternal death.^2,4 Risk factors for preeclampsia include previous preeclampsia, maternal age ≥40 years, chronic medical conditions, and multi-fetal pregnancy.⁵

The only effective treatment for preeclampsia is delivery.⁴ Given the lack of other treatments, strategies for preventing preeclampsia would be highly valuable.

In 1996, the US Preventive Services Task Force (USPSTF) addressed this issue and concluded that there was insufficient evidence to recommend for or against using aspirin to prevent preeclampsia.⁶ More recently, Henderson et al¹ conducted a systematic review and meta-analysis to support the USPSTF in a revision of its earlier recommendation.

STUDY SUMMARY: Aspirin use lowers risk of preeclampsia and preterm birth

Henderson et al¹ evaluated the impact of low-dose aspirin on maternal and fetal outcomes among pregnant women at risk for preeclampsia. The review of 23 studies included 21 randomized placebo-controlled trials that evaluated 24,666 patients. Slightly more than half of the studies that evaluated maternal and fetal health benefits were graded as good-quality, and 67% of those that evaluated maternal, perinatal, and developmental harms were rated good-quality.

Most women were white and ages 20 to 33 years. Aspirin doses ranged from 60 mg/d to 150 mg/d; most studies used 60 mg/d or 100 mg/d. Aspirin was initiated between 12 to 36 weeks gestation, with 9 trials initiating aspirin before 16 weeks. In most trials, aspirin was continued until delivery.

Among women at high preeclampsia risk (10 studies), the pooled relative risk (RR) for perinatal death was 0.81 (95% confidence interval [CI], 0.65-1.01) for low-dose aspirin compared to placebo. However, this finding was not statistically significant (P=.78).

Researchers found no evidence of increased maternal postpartum hemorrhage with aspirin use.

Among women who received low-dose aspirin, researchers noted a 14% risk reduction for preterm birth (RR=0.86; 95% CI, 0.76-0.98); a 20% risk reduction for IUGR (RR=0.80; 95% CI, 0.65-0.99), and a 24% risk reduction for preeclampsia (RR=0.76; 95% CI, 0.62-0.95). The absolute risk reduction for preeclampsia was estimated to be 2% to 5%.

While the results for preterm birth, IUGR, and preeclampsia were statistically significant, the authors noted that these results could have been biased by small study effects (the tendency of smaller studies to report positive findings, which in turn can skew the results of a meta-analysis based primarily on such studies). The timing and dosage of aspirin had no significant effect on outcomes.

There was no evidence of increased maternal postpartum hemorrhage with aspirin use (RR=1.02; 95% CI, 0.96-1.09). Aspirin use did not seem to increase perinatal mortality among all risk levels (RR=0.92; 95% CI, 0.76-1.11; P=.65). No differences were noted in the toddlers’ development at 18 months.

WHAT'S NEW: Low-dose aspirin use is now recommended

The 1996 USPSTF recommendation concluded that there was insufficient evidence to recommend aspirin use for preventing preeclampsia. This systematic review and meta-analysis, along with findings from a 2007 Cochrane review⁷ and a meta-analysis from the PARIS Collaborative Group,⁸ provide good-quality evidence that aspirin reduces negative maternal and fetal outcomes associated with preeclampsia. In 2014, the USPSTF cited this evidence when it decided to recommend using low-dose aspirin (81 mg/d) to prevent preeclampsia in women who are at high risk for preeclampsia (Grade B).⁹ (For more on the USPSTF, see “Catching up on the latest USPSTF recommendations”.)

CAVEATS: Much of the data came from small studies

A substantial portion of the data in this systematic review and meta-analysis came from small studies with positive findings. Because small studies with null findings tend to not be published, there is concern that the results reported by Henderson et al¹ may be somewhat biased, and that future studies may push the overall observed effect toward a null finding.

Also, the criteria used to define “high risk” for preeclampsia varied by study, so it’s unclear which groups of women would benefit most from aspirin use during pregnancy. Finally, there is a lack of high-quality data on the effects of aspirin use during pregnancy on long-term outcomes in children. Despite these caveats, the cumulative evidence strongly points to greater benefit than harm.

CHALLENGES TO IMPLEMENTATION: You need to determine which patients are at highest risk

The principle challenge lies in identifying which patients are at high risk for preeclampsia, and thus, will likely benefit from this intervention. This systematic review and meta-analysis used a large variety of risk factors to determine whether a woman was high risk. A 2013 American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy report defined high-risk as women with a history of preeclampsia in more than one previous pregnancy or women with a previous preterm delivery due to preeclampsia.⁴

The updated USPSTF recommendation suggests that women be considered high risk if they have any of the following: 1) previous preeclampsia, 2) multifetal gestation, 3) chronic hypertension, 4) diabetes, 5) renal disease, or 6) autoimmune disease.⁹ We consider both sets of criteria reasonable for identifying women who may benefit from low-dose aspirin during pregnancy.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.