Alicia Parsons, MD, MPH

Swedish Family Medicine Advanced Obstetrics Fellow

PREECLAMPSIA PREVENTION: REVIEW OF GUIDELINES & NEW AREAS OF RESEARCH

Why prevent preeclampsia?

Objectives1. Understand current guidelines for preeclampsia prevention.

2. Review studies on the efficacy of low dose aspirin use for preeclampsia prevention.

3. Discuss new areas of research in preeclampsia prevention.

Framework for PresentationAmerican College of Obstetricians and Gynecologists (ACOG)

2013 Hypertension in Pregnancy Task Force Report

U.S. Preventive Services Task Force (USPSTF)

2014 Recommendation Statement on Low-dose Aspirin in Preeclampsia Prevention

Norton, Mary. What Is New in the Prevention of Preeclampsia?: Best Articles From the Past Year. Obstetrics & Gynecology 2016;128:651-2.

Preeclampsia DefinitionACOG 2013 Guidelines:

• New onset BP>/=140/90 on 2 reads 4hr apart after 20wk GA

and

• Proteinuria

• >/= 300 mg on 24hr urine or

• P/C ratio >/= 0.3mg/dL

• Dipstick 1+ if other methods NOT available

or

• Severe Features with or without Proteinuria (other than severe range BP)

ACOG 2013

Preeclampsia with Severe Features• BP>/=160/110 on 2 reads (4 hours apart on bed rest or spaced

minutes apart if antihypertensive initiated before)

• Platelets <100,000

• LFTs 2x normal

• Severe RUQ or epigastric pain persistent and not explained by other Dx

• Cr >1.1 or doubling of baseline Cr without other renal disease

• Pulmonary edema

• New headache or visual changes

ACOG 2013

2013 Preeclampsia Definition Update• Proteinuria not required

• Massive proteinuria not a severe feature

• IUGR not criteria

• No more “mild” or “severe” preeclampsia

ACOG 2013

Preeclampsia Background• Placental dysfunction

• Maternal endothelial dysfunction

• Inflammation

• Prostacyclin-thromboxane imbalance -> vasoconstriction and platelet aggregation

ACOG 2013Duley et al. 2007

Redman and Sargent 2005

Schramm and Clowse 2014

Schramm and Clowse 2014

ACOG 2013 Guidelines

• 60-80mg aspirin daily starting in first trimester for

• Women with Hx of preeclampsia <34wk

or

• Preeclampsia in greater than one prior pregnancy

• No acute risk seen with aspirin

• Long-term fetal effects not known

ACOG 2013

ACOG 2013 Guidelines

• Calcium supplement in calcium deficient patients

• Deficiency <600mg/day at baseline

• Benefit not seen in developed countries

ACOG 2013

ACOG 2013 GuidelinesUnknown/Insufficient Evidence:

• Vitamin D

• Fish oil

• Garlic

• Moderate exercise

ACOG 2013

ACOG: What doesn’t help• Vit C or E

• Protein and calorie restriction in obese women

• Salt restriction

• Diuretics

• Bed rest/physical activity restriction

ACOG 2013

USPSTF Recommendations• Aspirin 81mg starting at 12-16wk for women at high risk for

preeclampsia

• One high risk criteria – start aspirin

• Two moderate risk criteria – consider aspirin

• Grade B evidence

USPSTF 2014

USPSTF Recommendations Risk Criteria

USPSTF 2014

High Moderate Low

-Hx preeclampsia-Multifetal gestation-CHTN-Type 1 or 2 DM-Kidney disease-Autoimmune disease

-Nulliparity-BMI>30-FHx preeclampsia (1st degree)-Sociodemographic (African American, low socioeconomic status)-AMA-Personal Hx factor (incl. low birthweight or SGA, previous adverse pregnancy outcome, >10 yr since last pregnancy)

-Previousuncomplicated term delivery

Aspirin• Anti-inflammatory

• Blocks thromboxane synthesis

ACOG 2013

Efficacy of Low Dose Aspirin• Mixed conclusions in past

• Small initial studies show aspirin effective

• 3 larger RCT did not show significant benefit

• No major adverse outcomes

ACOG 2013

Efficacy of Low Dose AspirinCochrane meta-analysis 2007 (updated 2010)

• Anti-platelet agents to prevent preeclampsia

• 37,560 women

• 59 trials (51 studied aspirin alone)

• 17% risk reduction preeclampsia (RR 0.83, 95% CI 0.77-0.89)

ACOG 2013Duley et al. 2007

Cochrane Meta-analysis 2007

• NNT with antiplatelet agent to prevent preeclampsia

• 72 women (52, 119)

• 19 high risk women (13, 34)

• 119 moderate risk women (73, 333)

ACOG 2013Duley et al. 2007

Cochrane Meta-analysis 2007 • 8% risk reduction preterm birth (RR 0.92, 95% CI 0.88-0.97)

• 14% risk reduction fetal/newborn/infant death (RR 0.86, 95% CI 0.76-0.98)

• 10% risk reduction small for gestational age births (RR 0.9, 95% CI 0.83-0.98)

• Safe

• No significant increased risk abruption, maternal death, C/S, fetal intraventricular hemorrhage or neonatal bleeding

Duley et al. 2007

Cochrane Meta-analysis 2007

• Small trials mostly positive

• Publication bias?

• Exact GA to start aspirin

• Noted higher efficacy with higher doses aspirin – need a study to compare doses

Limitations: Key areas of future study:

Duley et al. 2007

A closer look at aspirin…• What gestational age to start aspirin?

• Which guidelines to use to determine preeclampsia risk?

What gestational age to start aspirin? Roberg et al. 2016

• Meta-analysis of RCTs looking at benefits of aspirin in pregnancy

• 6 studies, 3 sent data

• Had to have at least 350 people

• 11949 participants total; 3293 recruited before 17 wk

• 60mg aspirin dose, started before or after 17wk gestation

• Outcomes: preeclampsia, preeclampsia with SF, SGA

Roberg et al. 2016

What gestational age to start aspirin?

No difference between starting aspirin before or after 17wk GA

• RR preeclampsia before 17 wk 0.93 (CI 0.75-1.15)

• RR preeclampsia at or after 17wk 0.93 (CI 0.7-1.23)

• Difference between groups p=0.99, not significant

Future study implications:

• Need a large RCT to study further

• Need to study a dose larger than 60mg

Roberg et al. 2016

Which guidelines to use? Werner et al. 2015

• Attempted to create a decision model based on cost

• Compared 4 protocols of preeclampsia aspirin prevention:

• No aspirin

• ACOG guidelines

• USPSTF guidelines

• Universal aspirin

• Included cost of aspirin, preeclampsia, preterm birth and adverse outcome of aspirin

• Aspirin started at first prenatal visit and continued until delivery

Werner et al. 2015

Which guidelines to use?

Approach Rate of Preeclampsia

% getting Aspirin $ saved compared to no Aspirin *

No Aspirin 4.18% 0%

ACOG 4.17% 0.35% $12 million

USPSTF 3.83% 23.5% $377 million

Universal Aspirin 3.81% 100% $365 million

Werner et al. 2015

*Assumes 4 million births per year.

USPSTF guidelines: Similar cost savings to universal aspirin use, ¼ women treated.

Which guidelines to use? • USPSTF criteria or universal aspirin prophylaxis – both pragmatic

and cost effective

• Recommended USPSTF criteria

• Similar cost benefit but only ¼ women treated -> less risk

• Adverse event of GI bleed, abruption, aspirin exacerbated respiratory disease

Werner et al. 2015

New Areas of Research• Statins

• Metformin

• Enoxaparin

• Exercise

• Vitamin D

• Screening algorithms

Statins in Pregnancy?Costantine et al. 2016

•Pravastatin – cat X due to lack of indication rather than documented risk

•Animal preeclampsia models: statins help angiogenic balance and endothelial function.

Costantine et al. 2016

Statins in Pregnancy?• Pilot study, first of a series of studies

• FDA-approved investigational new drug study

• Collaborated with NICHD

• Double blind placebo controlled RCT focused on safety and pharmakineticsof 10mg pravastatin

• 20 women 12.0-16.6 wk at high preeclampsia risk

• Randomized to daily pravastatin 10mg vs placebo

• Took statin until delivery or a condition developed that required the drug be discontinued

Costantine et al. 2016

Statins in Pregnancy?• Side Effects: musculoskeletal pain and heartburn

• No myopathy, rhabdo or liver injury

• Reduced maternal cholesterol but not fetal

Costantine et al. 2016

Statins in Pregnancy?• No maternal, fetal or infant deaths

• No identified safety risks associated with 10mg pravastatin

Pravastatin Placebo

Preeclampsia 0 4 (3 with SF)

Preterm del (<37) 1 5

Small for GA 0 1

NICU 2 5

Fetal anomalies Hypospadias Polydactyly

Coarctation of the aorta

Ventriculomegaly

Maternal compl. none Postpartum hysterectomy 2/2 to placenta previaand atony

Costantine et al. 2016

Statins in Pregnancy?• Promising findings – justifies larger study, dose evaluation

• Potential to be more effective than aspirin

• Follow up with infants planned at 5 yr of age

Costantine et al. 2016

Public Health SignificanceMain et al. 2015

•207 pregnancy related deaths over 2002-2005 in CA

•Preeclampsia/ecclampsia is 2nd leading cause – 17% cases (second to cardiovascular)

•Concluded 60% preeclampsia deaths could have been prevented

•Aspirin prophylaxis can influence maternal death rate (Norton 2016)

Main et al. 2015

Objectives1. Understand current guidelines for preeclampsia prevention.

2. Review studies on the efficacy of low dose aspirin use for preeclampsia prevention.

3. Discuss new areas of research in preeclampsia prevention.

Conclusions• Aspirin 81mg daily starting at 12-16wk gestation in high risk patients

• Aspirin is safe

• Need further study on long-term impact on childhood development

Conclusions continued• Calcium supplement benefit in calcium deficient women in

developing countries

• New areas of research: statins, metformin, enoxaparin, exercise, vitamin D and screening algorithms.

Why prevent preeclampsia?

Conclusions continued• Preeclampsia prevention clinical and public health impact: can

greatly benefit maternal and infant morbidity and mortality

QUESTIONS?

References• American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Report of the American College of Obstetricia ns and Gynecologists’ Task

Force on Hypertension in Pregnancy. 2013. 1- 11, 27-30. http://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy. Accessed 2/6/17.

• Brownfoot FC, Hastie R, Hannan NJ, et al. Metformin as a prevention and treatment for pre -eclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. American Journal of Obstetrics & Gynecology 2016;214:356.e1 -15.

• Costantine MM, Cleary K, Hebert MF, et al. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. American Journal of Obstetrics & Gynecology 2016;214:720.e1 -17.

• Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD004659. DOI: 10.1002/14651858.CD004659.pub2.

• Final Recommendation Statement: Low-Dose Aspirin Use for the Prevention of Morbidity and Mortality From Preeclampsia: Preventive Medication . U.S. Preventive Services Task Force. 2014. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFina l/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication. Accessed 2/6/17.

• First-trimester risk assessment for early-onset preeclampsia. Committee Opinion No. 638. American College of Obstetricians and G ynecologists. Obstetrics & Gynecology 2015;126:e25–7.

• Groom KM, McCowan LM, Stone PR, et al. Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in w omen with a prior history -an open-label randomised trial (the EPPI trial): study protocol. BMC Pregnancy Childbirth 2016; 16:367.

• Grotegut CA. Prevention of Preeclampsia. The Journal of Clinical Investigation 2016;126:4396 -4398.

• Main EK, McCain CL, Morton CH, et al. Pregnancy-related mortality in California: causes, characteristics, and improvement opport unities. Obstetrics & Gynecology 2015;125:938–47.

• Norton, Mary. What Is New in the Prevention of Preeclampsia?: Best Articles From the Past Year. Obstetrics & Gynecology 2016; 128:651-2.

• Park F, Russo K, Williams P, et al. Prediction and prevention of early -onset pre-eclampsia: impact of aspirin after first-trimester screening. Ultrasound in Obstetrics & Gynecology 2015;46:419–23.

• Physical activity and exercise during pregnancy and the postpartum period. Committee Opinion No. 650. American College of Obs tetricians and Gynecologists. Obstetrics & Gynecology 2015;126:e135–42.

• Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592 -4.

• Roberge S, Sibai B, McCaw-Binns A, Bujold E. Low-dose aspirin in early gestation for prevention of preeclampsia and small -for-gestational-age neonates: meta-analysis of large randomized trials. American Journal of Perinatology 2016;33:781 –5.

• Shramm AM and Clowse ME. Aspirin for prevention of preeclampsia in lupus pregnancy. Autoimmune Diseases 2014;2014:Article ID 920467, 8 pages. http://dx.doi.org/10.1155/2014/920467.

• Vitamin D: screening and supplementation during pregnancy. Committee Opinion No. 495. American College of Obstetricians and G ynecologists. Obstetrics & Gynecology 2011;118:197–8.

• Werner EF, Hauspurg AK, Rouse DJ. A cost-benefit analysis of low-dose aspirin prophylaxis for the prevention of preeclampsia in the United States. Obstetrics & Gynecology 2015;126:1242–50.

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