Editor's Note: Commentary based on Henderson JT, Whitlock EP, O'Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2014;160:695-703.

Background

Preeclampsia is a multisystem disorder proposed to be secondary to abnormal development of placental vasculature, causing maternal endothelial dysfunction. Clinically, this appears as hypertension after 20 weeks gestation with either proteinuria or evidence of end organ dysfunction (elevated creatinine, abnormal liver function tests, low platelet count, pulmonary edema or cerebral or visual symptoms). Preeclampsia causes significant maternal and fetal mortality and morbidity. It accounts for 12% of maternal deaths in this country with the greatest disease burden occurring among African Americans. Other than delivery of the placenta, there is no effective therapy to prevent disease progression or to treat preeclampsia.

High-risk features for the development of preeclampsia include prior history of preeclampsia, diabetes, hypertension, kidney disease, autoimmune disease, as well as multifetal pregnancies. Maternal age over 35 years and elevated body mass index are considered moderate risk factors; however, with the rise in obesity across the U.S. and advancing maternal age, this likely contributes significantly to disease burden, as well.

Methods

This review was conducted for the purpose of updating the U.S. Preventative Services Task Force inactive 1996 recommendations on aspirin use for prevention of preeclampsia. In addition to including all studies from the prior review, the authors performed a comprehensive search for additional studies published between 2006 and 2013, yielding 544 citations. After rigorous study selection using predetermined inclusion criteria, 27 articles were included in this analysis. The goal was to address three key questions: 1) is low-dose aspirin effective for reducing adverse maternal and perinatal outcomes in women at high risk for preeclampsia; 2) is low-dose aspirin effective for preventing preeclampsia in women at increased risk; 3) is there any harm associated with aspirin use to the mother or fetus during pregnancy? The analysis included average risk study populations for the purpose of answering this last question.

Two investigators evaluated each study using rigorous methodology with a third available to resolve discrepancies via consensus.

Results

The mean age of participants ranged from 20-33 and assumed to be predominantly white based on country of origin and reported data. The daily aspirin dose varied from 60-150 mg. All trials initiated aspirin at 12 weeks gestation or beyond and most continued until delivery, though six trials stopped earlier.

The results based on the three key questions are as follows: firstly, there was no statistically significant benefit for prevention of perinatal death with aspirin use; there was a 14% risk reduction for preterm birth and 20% for intrauterine growth retardation. Treatment with aspirin was also associated with a higher average birth weight. Secondly, there was a 24% reduction in preeclampsia incidence with aspirin use. Thirdly, aspirin use did not demonstrate any evidence of increased perinatal mortality. There was a non-statistically significant increased risk of placental abruption with no difference in risk for postpartum hemorrhage, fetal intracranial hemorrhage or mean blood loss, with aspirin use. One study reported no differences in developmental outcomes up to 18 months of life with aspirin use.

Conclusion

Low-dose aspirin (60-150 mg) taken daily after the first trimester of pregnancy, in high-risk women for preeclampsia, reduces the risk for adverse outcomes with no evidence for increased risk.

Commentary

The results of this evidence analysis are comparable to prior reviews. Critics may say that despite this data, there are no recent supportive large randomized controlled trials, and this review was based on trials that were individually underwhelming. In addition, the benefits were modest. However, there does not appear to be any significant harm associated with aspirin use. Considering the lack of other treatment options, it appears reasonable to recommend aspirin to the highest-risk patients in an effort to reduce disease burden and improve outcomes. In its 2014 updated recommendations, the U.S. Preventative Services Task Force has recommended low-dose aspirin in high-risk women (prior history of preeclampsia, diabetes, multifetal gestation, hypertension, kidney disease, and autoimmune disease). Other groups including the American Congress of Obstetricians and Gynecologists and the American Heart and Stroke Associations have also recommended aspirin for certain higher-risk groups.

Mechanistically, preeclampsia is associated with increased platelet turnover and increased platelet-derived thromboxane levels. Low-dose aspirin reduces platelet thromboxane synthesis and maintains vascular wall prostacyclin synthesis, thereby providing a potential mechanism for improving the systemic endothelial dysfunction and maternal inflammation that occurs in preeclampsia.

From the cardiologist's standpoint, preeclampsia has been shown to increase the risk for future cardiovascular and cerebrovascular disease. The history of the so-called "failed stress test of pregnancy" should be elicited and considered by all cardiologists managing women. Whether this reflects a predisposition to underlying endothelial dysfunction or whether preeclampsia results in permanent arterial changes is unknown. It is not known whether prevention of preeclampsia with aspirin would improve the lifetime risk of cardiovascular disease for women. This raises interesting questions for future investigation and highlights the need for additional research.

References

1. LeFevre ML. Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161:819-26.
2. McDonald SD, Malinowski Z, Zhou Q, et al. Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review and meta-analysis. Am Heart J 2008;156 918-30.
3. Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol 1999;180(2 Pt 1):499-506.
4. Askie LM, Duley L, Henderson-Smart DJ, et al. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791-8.
5. Bushnell C, McCullough LD, Awad IA, et al. Guidelines for the prevention of stroke in women: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:1545-88.
6. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122-31.

Keywords: Abruptio Placentae, Aspirin, Autoimmune Diseases, Birth Weight, Blood Platelets, Body Mass Index, Consensus, Cost of Illness, Creatinine, Diabetes Mellitus, Disease Progression, Epoprostenol, Exercise Test, Female, Fetal Growth Retardation, Fetal Mortality, Fetus, Goals, Humans, Hypertension, Incidence, Infant, Newborn, Inflammation, Intracranial Hemorrhages, Kidney Diseases, Liver Function Tests, Maternal Age, Maternal Death, Mothers, Obesity, Perinatal Mortality, Placenta, Platelet Count, Postpartum Hemorrhage, Pre-Eclampsia, Pregnancy, Pregnancy Trimester, First, Premature Birth, Proteinuria, Pulmonary Edema, Research Personnel, Risk Factors, Risk Reduction Behavior, Stroke, Thromboxanes, United States

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