Hypertension Disorders in Pregnancy: The Potential of Prophylactic Aspirin

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Coordination between OB/GYN and primary care providers or cardiologists is also needed for long-term CVD risk prevention in patients after delivery.
Coordination between OB/GYN and primary care providers or cardiologists is also needed for long-term CVD risk prevention in patients after delivery.

Hypertensive disorders affect an estimated 6% to 8% of pregnancies in the United States and represent a top global cause of maternal and fetal morbidity and mortality.1 Preeclampsia has been linked to higher rates of preterm delivery, low birth weight, and postdelivery complications.2 Other findings have shown higher subsequent rates of cardiovascular (CV) risk factors such as hypertension, increased body mass index, and stroke in the offspring of women who had developed preeclampsia while pregnant with them.3

"Preeclampsia is a multisystem disease that occurs after 20 weeks of gestation, characterized by new-onset hypertension and proteinuria, mediated by abnormalities in the vasculature of the placenta," Erin D. Michos, MD, MHS, associate professor of medicine and epidemiology at Johns Hopkins School of Medicine, and associate director of preventive cardiology at the Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland, told Cardiology Advisor. "This leads to uteroplacental insufficiency, inappropriate vasoconstriction in multiple vascular beds, and both short-term and long-term endothelial dysfunction."

Various studies have identified a greater likelihood of developing metabolic disorders and CVD later in life in women with preeclampsia. A meta-analysis published in 2017, which included >6.4 million women, demonstrated a 4-fold increased risk for future heart failure and a 2-fold increase in the risk for coronary heart disease, stroke, and death resulting from CV disease (CVD) in women with vs without a history of preeclampsia.4

Low-Dose Aspirin Prophylaxis

To aid in the prevention of preeclampsia, the American College of Obstetricians and Gynecologists and the US Preventive Services Task Force recommend low-dose aspirin (81 mg/d) prophylaxis in patients with 1 or more high-risk factors; these include previous preeclampsia, chronic hypertension, type 1 or 2 diabetes, autoimmune or renal disease, and multifetal gestation.5 In addition, this approach should be considered for women with more than 1 moderate risk factor, including maternal age ≥35 years, first pregnancy, body mass index >30 kg/m2, and family history of preeclampsia.

In a randomized clinical trial published in 2017, daily low-dose aspirin led to a lower incidence of preeclampsia in high-risk women compared with placebo (odds ratio, 0.38; 95% CI, 0.20-0.74; P =.004).6 A 2014 systematic review found that low-dose aspirin use was associated with reductions in the risk for preterm birth, intrauterine growth retardation, and preeclampsia by 14%, 20%, and 24%, respectively.7 No significant harms to mother or fetus were observed, and professional guidelines state that this strategy is considered safe.

"The pathologic vascular lesion of the placenta found in preeclampsia is called 'acute atherosis,' and is similar to that observed in atherosclerosis, including lipid-laden foam cells," Dr Michos explained. The placental insufficiency, vasoconstriction, and endothelial dysfunction associated with preeclampsia "can lead to placental ischemia, which in turn may worsen oxidative stress and inflammation, a vicious cycle which does not end well and can become a pregnancy emergency." Aspirin may be useful in this setting because of its anti-inflammatory effects and antiplatelet effects.

Although it is recommended that this regimen begin at 12 to 28 weeks of gestation, some study findings suggest optimal results with treatment initiation before 16 weeks. A meta-analysis of randomized trials found significant reductions in severe preeclampsia (relative risk, 0.47; 95% CI, 0.26-0.83) and fetal growth restriction (relative risk, 0.56; 95% CI, 0.44-0.70) with initiation of aspirin before 16 weeks, but only modest reduction in preeclampsia when aspirin was initiated after 16 weeks (relative risk, 0.81; 95% CI, 0.66-0.99).8 However, other results have been inconsistent regarding this timing.

The guidelines further point out that the evidence to date does not support the use of low-dose aspirin to prevent stillbirth, early pregnancy loss, preterm birth, or fetal growth restriction.5

Treatment Implications and Future Directions

Clinicians should "reinforce current guidelines from the American Heart Association, which recognizes these adverse pregnancy outcomes as a major CVD risk factor for women, on par with smoking," said Dr Michos. "These women need encouragement for healthy lifestyle changes after delivery to mitigate their long-term CVD risk, as well as close monitoring of CVD risk factors," such as blood pressure and glucose tolerance, as well as pharmacologic therapies when indicated. Coordination between obstetrician/gynecologists and primary care providers or cardiologists is also needed for long-term CVD risk prevention in these patients after delivery.

Dr Michos noted that it is still unknown whether hypertensive disorders in pregnancy actually mediate future CVD pathogenesis via direct vascular damage, or whether they simply reveal the patient's preexisting susceptibility to CVD. "There is definitely a possibility that preeclampsia directly generates lasting endothelial dysfunction, with endothelial dysfunction in women with preeclampsia persisting into the postpartum period, which leads to their heightened CVD risk." However, it is unclear how these patients should be managed or monitored after pregnancy, especially if their blood pressure returns to normal.

Research is needed to address these issues, as well the potential role of aspirin or statins to reduce CVD risk in these women. "We usually do not treat young women with aspirin in primary CVD prevention, as the bleeding risks usually outweigh the benefits," Dr Michos stated. "This is where I think screening for subclinical atherosclerosis with coronary artery calcium scores after the age of 40 can help refine risk assessment to guide the risk discussion and help patients make informed choices."

References

1. Gillon TER, Pels A, von Dadelszen P, MacDonell K, Magee LA. Hypertensive disorders of pregnancy: a systematic review of international clinical practice guidelines. PLoS ONE. 2014;9(12):e113715.

2. Hoffman K, Patel A, Tang A, Poornima I. A case-control study of preeclampsia and the future development of cardiovascular risk factors. J Am Coll Card. 2018;71(11 Supplement):A1861.

3. Thoulass JC, Robertson L, Denadai L, et al. Hypertensive disorders of pregnancy and adult offspring cardiometabolic outcomes: a systematic review of the literature and meta-analysis. J Epidemiol Community Health. 2016;70(4):414-422.

4. Wu P, Haththotuwa R, Kwok CS, et al. Preeclampsia and future cardiovascular health: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2017;10(2).

5. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 743: Low-dose aspirin use during pregnancy. Obstet Gynecol. 2018;132(1):e44-e52.

6. Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-622.

7. 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(10):695-703.

8. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017;216(2):110-120.     

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