Rx

PAbstract Preeclampsia is a hypertensive disorder specific to pregnancy that remains a significant cause of maternal and neonatal morbidity and mortality. Identification of women who are most at risk for preeclampsia is imprecise. Because of the potential negative health consequences of preeclampsia for women and newborns and the lack of effective screening mecha-nisms preventing preeclampsia is an important component of prenatal care. Researchers have documented that low-dose aspirin, taken daily after the first trimester, can decrease the development of preeclampsia and reduce the incidence of pre-term birth and birth of small-for-gestational-age infants. This column includes an overview of low-dose aspirin in pregnancy and a review of current recommendations from leading national organizations. https://doi.org/ 10.1016/j.nwh.2017.12.002

Keywords aspirin | hypertension | preeclampsia | pregnancy

the potential adverse effects of preeclampsia for women and newborns, preventing preeclampsia, especially among women at greatest risk, is an important component of prenatal care.

Overview of Preeclampsia Preeclampsia is estimated to affect between 5% and 10% of pregnancies in the United States, with recurrence in up to 25% of subsequent

Preeclampsia is a systemic hypertensive disor-der specific to pregnancy that involves multiple organ systems. It remains a significant cause of maternal morbidity and mortality in the United States and globally. Because the only resolu-tion of preeclampsia is delivery of the placenta, the disease is also a leading causative factor in medically necessary preterm birth (Amaral, Wallace, Owens, & LaMarca, 2017). Because of

Low-Dose Aspirin for the Prevention of Preeclampsia

HEIDI COLLINS FANTASIA

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Heidi Collins Fantasia, PhD, RN, WHNP-BC, is an associate professor in the Zuckerberg College of Health Sciences, Susan and Alan Solomont School of Nursing, at the University of Massachusetts Lowell in Lowell, MA. The author reports no conflicts of interest or relevant finan-cial relationships. Address correspondence to: Heidi_Fantasia@uml.edu.

risk factors, which makes screening and preven-tion more challenging.

Researchers have investigated different screening mechanisms to identify women at risk for preeclampsia, including maternal serum markers and first trimester ultrasonographic findings (including uterine artery Doppler flow and resistance), but these additional screening tests have not resulted in the accurate prediction of preeclampsia (Halscott, Ramsey, & Reddy, 2014). To date, an effective screening algorithm for the identification of women at risk for pre-eclampsia does not exist.

Pathophysiology of PreeclampsiaThe etiology and underlying pathophysiol-ogy of primary and recurrent preeclampsia are not completely understood. However, certain characteristics have been identified, and the placenta is involved in the development of the disease. Hallmarks of preeclampsia include pla-cental ischemia, maternal immune activation, increased arterial resistance, decreased produc-tion of vasodilators, and maternal endothelial dysfunction. This causes decreased blood flow to major organs. These factors, combined with the maternal hypertension, often result in intra-uterine fetal growth restriction (IUGR) and small-for-gestational-age infants (Amaral et al., 2017; Grotegut, 2016; Tolcher et al., 2017).

pregnancies (Grotegut, 2016; Tolcher et al., 2017). Preeclampsia is recognized as a new onset of hypertension in the second half of preg-nancy, often with blood pressure at greater than 140/90 mm Hg and co-occurring proteinuria. Multiorgan system complications can occur such as renal failure, elevated liver enzymes and low platelets (HELLP syndrome), edema, hemolysis, and progression to eclamptic seizures (Amaral et al., 2017).

Risk factors for preeclampsia include preg-nancy at the extremes of maternal age (adoles-cents and women older than 40 years of age), obesity, preexisting hypertension, diagnosis of preeclampsia in a previous pregnancy, diabetes or renal disease, nulliparity, multiple gestation, and preexisting autoimmune diseases such as antiphospholipid antibody syndrome and sys-temic lupus erythematosus (Grotegut, 2016). However, not all women with these risk factors develop preeclampsia, and the condition can occur in women who do not have any known

Preeclampsia is estimated to

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pregnancies in the United States,

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of subsequent pregnancies

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Role of Low-Dose AspirinThe pathophysiology of preeclampsia is not fully understood, and neither is the mecha-nism by which low-dose aspirin works to pre-vent preeclampsia. However, aspirin has anti-coagulant and anti-inflammatory properties that contribute to the mechanism of action in preventing preeclampsia. When given at the beginning of the second trimester (<16 weeks gestation) low-dose aspirin works to inhibit platelet aggregation and promote vasodila-tion. This pharmacologic mechanism results in increased blood flow to the uterus and placenta (Mone, Mulcahy, McParland, & McAuliffe, 2017; Tolcher et al., 2017).

Safety of Low-Dose Aspirin in PregnancyLow-dose aspirin is generally considered to be safe during pregnancy. There is no evidence that low-dose aspirin is associated with acute risks to the fetus, but data on long-term effects are lacking (American College of Obstetricians and Gynecologists [ACOG], 2013). Although the use of nonsteroidal anti-inflammatory drugs such as aspirin has been associated with increased maternal and neonatal bleeding risk and ante-natal closure of the fetal ductus arteriosus, those adverse effects have not been observed in large, clinical trials of low-dose aspirin and

pregnancy, and the risk of overall harm is small (LeFevre, 2014). One reason may be the lower dose (81 mg) that is used for the prevention of preeclampsia. There is also no link between low-dose aspirin and fetal anomalies, and low-dose aspirin is typically initiated at the end of the first trimester, when organogenesis is com-plete (Henderson et al., 2014; Mone et al., 2017). Aspirin is excreted in breast milk (Bayer, n.d.), but low-dose aspirin is discontinued at child-birth, and women who have taken low-dose aspirin during pregnancy have no restrictions on initiation of breastfeeding.

Current RecommendationsIn 2014, the U.S. Preventive Services Task Force (USPSTF) issued an update recom-mending the use of low-dose aspirin to pre-vent preeclampsia among women who are at risk of developing the disease (LeFevre, 2014). This is a Grade B recommendation, indicat-ing that clinicians should offer this service to women (see Box 1). ACOG (2016) also sup-ports this recommendation. According to ACOG, the use of low-dose aspirin, at a dos-age of 81 mg per day, should be initiated between 12 and 28 weeks of gestation for the prevention of preeclampsia among women with significant risk factors that were identi-fied by the USPSTF (see Box 2).

Box 1. USPSTF Grade Definitions

Grade Definition Implications for Practice

A Recommended, high certainty Offer to women of substantial benefit

B Recommended, high certainty Offer to women of moderate to substantial benefit

C Recommend based on Offer to selected women based individual women’s characteristics on individualized assessment and clinical judgment, benefit small

D Do not recommend, moderate Discourage to high certainty of no benefit or harms outweigh benefits

I Insufficient evidence to assess Discuss uncertainty of benefits benefits and harms; current and harms with women evidence is poor, lacking, or conflicting

Source: U.S. Preventive Services Task Force (2016).

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Implications for Nursing PracticeResearchers have documented that the use of low-dose aspirin among pregnant women at risk for preeclampsia has multiple benefits, includ-ing reduced risk of preeclampsia, preterm birth, and IUGR (Henderson, et al., 2014; LeFevre, 2014; Roberge et al., 2017; Rolnik et al., 2017). During clinical trials, researchers have used doses of aspirin ranging from 60 mg to 150 mg; however, there is no consensus on whether any one dose in that range is ideal. In the United States, low-dose aspirin is inexpensive and read-ily available without a prescription in a stan-dard dose of 81 mg, which is why this is the

dose recommended by the USPSTF and ACOG (ACOG, 2016; LeFevre, 2014).

There are no current recommendations for the use of low-dose aspirin for all women dur-ing pregnancy, and nurses should clarify this point when working with pregnant women. For women without any risk factors for preeclamp-sia, there is no benefit to daily low-dose aspirin therapy (see Box 2). However, for women at risk for preeclampsia, early identification is impor-tant. Although the current recommendation from ACOG and the USPSTF (ACOG, 2016; LeFevre, 2014) states that low-dose aspirin can be implemented at any time during the second trimester, other researchers have documented that low-dose aspirin appears to be less effective

Box 2. Summary of USPSTF Recommendations for Use of Low-Dose Aspirin in Pregnancy

Risk Level Risk Factors for Preeclampsia USPSTF Recommendation

High risk History of preeclampsia

Chronic hypertension

Preexisting type 1 or type 2 diabetes

Renal disease

Multiple gestation

Autoimmune disease

Recommend low-dose aspirin if one or more factors present

Moderate risk Nulliparity

BMI > 30 kg/m2

Age > 35 years

Family history of preeclampsia

Previous small-for-gestational-age or low-birth-weight infant

African American race

Low socioeconomic status

10 years since previous pregnancy

Consider low-dose aspirin if several factors present

Low risk No risk factors listed above

Previous uncomplicated full-term birth

Do not recommend low-dose aspirin

Note. BMI = body mass index; USPSTF = U.S. Preventive Services Task Force.

Source: LeFevre (2014).

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overt upper and lower gastrointestinal bleeding from ulceration. Additionally, aspirin has been associated with severe allergic reactions includ-ing hives, respiratory distress, and angioedema, even among women who report previously tak-ing aspirin without incident (Bayer, n.d.).

ConclusionPreeclampsia is a significant cause of mater-nal and neonatal morbidity and mortality, and identification of women who are most at risk for developing the disease is imprecise. For women at risk, daily low-dose aspirin can reduce the incidence of preeclampsia and, therefore, decrease the risk for fetal IUGR and for medi-cally necessary preterm birth. Early identifica-tion of women who would benefit most from low-dose aspirin will allow for the initiation of therapy at the beginning of the second trimester and potentially improve maternal and neonatal health outcomes. NWH

ReferencesAmaral, L. M., Wallace, K., Owens, M., &

LaMarca, B. (2017). Pathophysiology and current clinical management of preeclampsia. Current Hypertension Reports, 19(8), 61. doi:10.1007/s11906-017-0757-7

American College of Obstetricians and Gyne- cologists. (2013). Hypertension in pregnancy. Retrieved from https://www.acog.org/Resources -And-Publications/Task-Force-and-Work- Group-Reports/Hypertension-in-Pregnancy

American College of Obstetricians and Gynecolo-gists. (2016). Practice Advisory on Low-Dose Aspirin and Prevention of Preeclampsia: Updated Recommendations. Retrieved from https://www.acog.org/About-ACOG/News-Room/Practice-Advisories/Practice-Advisory-Low-Dose-Aspirin-and-Prevention-of-Preeclampsia-Updated-Recommendations

Bayer. (n.d.). Aspirin: Comprehensive prescrib-ing information. Silver Spring, MD: U.S. Food and Drug Administration. Retrieved from https://www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-Profes-sional%20Labeling.pdf

Grotegut, C. A. (2016). Prevention of preeclamp-sia. The Journal of Clinical Investigation, 126(12), 4396–4398. doi:10.1172/JCI91300

Halscott, T. L., Ramsey, P. S., & Reddy, U. M. (2014). First trimester screening cannot predict

for the prevention of preeclampsia if initiated after 16 weeks gestation (Roberge et al., 2017). A careful and thorough review of personal and family history will identify women who are most

at risk for preeclampsia and for whom low-dose aspirin therapy would provide the most ben-efit. Early identification of risk factors will allow time to discuss whether low-dose aspirin is an appropriate choice and if so, when to begin tak-ing the medication.

Additionally, it is not known if the use of low-dose aspirin during pregnancy has any pro-tective effect on women’s cardiovascular health after the pregnancy has ended. Daily use of low-dose aspirin has been investigated as a pharma-cologic therapy for the primary prevention of cardiovascular disease in women, but this rec-ommendation is age dependent. According to the USPSTF, daily low-dose aspirin is not rec-ommended for primary prevention of cardio-vascular disease in women younger than 50 or older than 70 years. For women between the ages of 50 and 59 years who have a greater than 10% risk of developing cardiovascular disease in the next decade, it is a Grade B recommenda-tion (see Box 1). For women between the ages of 60 and 69 years, the use of low-dose aspirin is a Grade C recommendation and should be an individualized decision because adverse events such as bleeding risk increase with age (Sarma & Scott, 2016).

Although use of low-dose aspirin dur-ing pregnancy has not been associated with an increased risk for bleeding that can occur with the use of nonsteroidal anti-inflammatory drugs at greater doses (LeFevre, 2014), preg-nant women should still be educated to report any side effects they think might be related to the low-dose aspirin. These could range from mild gastrointestinal events such dyspepsia to

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meta-analysis. American Journal of Obstetrics and Gynecology, 216(2), 110–120. doi:10.1016/j.ajog.2016.09.076

Rolnik, D. L., Wright, D., Poon, L. C., O’Gorman, N., Syngelaki, A., de Paco Matallana, C., . . . Molina, F. S. (2017). Aspirin versus placebo in pregnancies at high risk for preterm preeclamp-sia. New England Journal of Medicine, 377, 613–622. doi:10.1056/NEJMoa1704559

Sarma, A., & Scott, N. S. (2016). Aspirin use in women: Current perspectives and future direc-tions. Current Atherosclerosis Reports, 18(17), 1–8. doi:10.1007/s11883-016-0630-1

Tolcher, M. C., Chu, D. M., Hollier, L. M., Mas-trobattista, J. M., Racusin, D. A., Ramin, S. M., . . . Aagaard, K. M. (2017). Impact of USPSTF recommendations for aspirin for prevention of recurrent preeclampsia. American Journal of Obstetrics and Gynecology, 217(3), 365.e1–365.e8. doi:10.1016/j.ajog.2017.04.035

U.S. Preventive Services Task Force. (2016). Grade definitions. Retrieved from https://www .uspreventiveservicestaskforce.org/Page/Name/grade-definitions

adverse outcomes yet. Prenatal Diagnosis, 34(7), 668–676. doi:10.1002/pd.4407

Henderson, J. T., Whitlock, E. P., O’Connor, E., Senger, C. A., Thompson, J. H., & Rowland, M. G. (2014). Low-dose aspirin for the prevention of morbidity and mortality from preeclampsia: A systematic evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 112. AHRQ Publication No. 14-05207-EF-1. Rock-ville, MD: Agency for Healthcare Research and Quality. Retrieved from https://www.ncbi .nlm.nih.gov/books/NBK196392/pdf/Book-shelf_NBK196392.pdf

LeFevre, M. L. (2014). Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: US Preventive Services Task Force recommendation statement. Annals of Internal Medicine, 161(11), 819–826. doi:10.7326/M14-1884

Mone, F., Mulcahy, C., McParland, P., & McAuliffe, F. M. (2017). Should we recommend universal as-pirin for all pregnant women? American Journal of Obstetrics and Gynecology, 216(2), 141.e1– 141.e5. doi:10.1016/j.ajog.2016.09.086

Roberge, S., Nicolaides, K., Demers, S., Hyett, J., Chaillet, N., & Bujold, E. (2017). The role of as-pirin dose on the prevention of preeclampsia and fetal growth restriction: Systematic review and

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