Cardiometabolic Antecedents of Preeclampsia

Introduction

In this chapter, we first cover some of the data consistent with the hypothesis that both placental and maternal factors are important determinants of preeclampsia (“Placental and maternal aspects of preeclampsia”). The next section, “Pregnancy profile-an early informer of cardiometabolic risk,” highlights data suggesting that the “stress test” of pregnancy can unmask and amplify latent cardiometabolic abnormalities that contribute to endothelial dysfunction and preeclampsia. In the following section, “Do prepregnancy cardiometabolic risk factors foreshadow preeclampsia?,” we review the growing body of literature on prepregnancy cardiometabolic antecedents of preeclampsia, including metabolic syndrome antecedents, which may predispose to both preeclampsia and later-life CVD. We then highlight some of the “Potential pathways by which cardiometabolic antecedents contribute to preeclampsia.” In the final section, “Summary thoughts on cardiometabolic antecedents,” we propose that the metabolic syndrome actually contributes to placental dysfunction, with maternal and placental processes then cooperating in a vicious cycle of inflammation and endothelial dysfunction. We review two drugs under investigation, metformin and pravastatin, which hold promise for prevention or treatment of preeclampsia and later-life cardiovascular sequelae possibly by intervening in these pathways.

Placental and Maternal Aspects of Preeclampsia

In normal pregnancy, cytotrophoblast cells invade into the maternal spiral arteries that perfuse the placental intervillous space, remodeling these arteries into dilated conduits with expanded vascular capacity necessary to support fetal growth and development. Evidence suggests that this physiologic remodeling, with its characteristic distal funnel-shaped vascular dilatation, slows the inflow of blood, which, in turn, optimizes mixing of the blood in the intervillous space (avoiding hypoxia/reperfusion damage due to large variations in oxygen concentration). Preeclampsia, particularly early-onset preeclampsia, is characterized by insufficient physiological remodeling of the spiral arteries (to varying degrees between placentas and nonuniformly across a given placental bed). Decidual vasculopathy and related lesions in the placenta are collectively termed maternal vascular malperfusion lesions. Data are consistent with malperfusion being a manifestation of ischemia-reperfusion-type injury. The higher-speed jets from suboptimally remodeled vessels are predicted to damage placental structures (reviewed in Parks-2015). The malperfusion-stressed preeclampsia placenta is thought to release factors, including trophoblast-derived microparticles and antiangiogenic soluble receptors, into the maternal circulation that adversely affect the maternal vascular endothelium and activate inflammatory pathways, setting the stage for the maternal manifestations of preeclampsia.

The poorly perfused placenta is likely not solely responsible for the clinical manifestations of preeclampsia. The preeclampsia syndrome often occurs with minimal evidence of failed spiral artery transformation or other evidence of malperfusion. Furthermore, uteroplacental vascular lesions including failed spiral arterial remodeling, acute atherosis, and syncytial knots are found in excess with preeclampsia but also in patients with fetal growth restriction or preterm birth without preeclampsia and also (less frequently) in uncomplicated pregnancies. ^{, ,} Placental vascular lesions are thus a continuum across pregnancy outcomes. Preeclampsia when superimposed on chronic hypertension or diabetes mellitus confers a higher risk for poor perinatal outcome compared to preeclampsia alone suggesting a role for maternal factors. Gestational diabetes and prepregnancy obesity are often associated with larger babies yet predispose to preeclampsia. Preeclampsia and CVD share obesity, dyslipidemia, insulin resistance, diabetes, chronic hypertension, and inflammation as underlying risk factors. Furthermore, there is an overrepresentation of CVD in women with a history of preeclampsia. These data are consistent with both placental and maternal factors as important determinants of preeclampsia.

Pregnancy Profile—an Early Informer of Cardiometabolic Risk

In addition to spiral artery transformation, several other striking cardiovascular and metabolic changes occur during normal pregnancy as part of a complex adaptive response to ensure adequate uterine blood flow and adequate oxygen and nutrient delivery to the fetus. Systemic vasodilation (reduced total vascular resistance) during first trimester is accompanied by an increase in global arterial compliance (reduced vascular stiffness), changes that accommodate the greater intravascular volume, stroke volume, and heart rate that accompany pregnancy without increasing mean arterial pressure. ^, The high-output, low-resistance systemic circulation facilitates uteroplacental perfusion and allows the mother to function optimally during the physiologic state of pregnancy. Failure or reversal of these pregnancy-related maternal cardiovascular changes (i.e., low-output, high-resistance state) is thought to characterize preeclampsia. ^,

Metabolic adaptations occur especially during the latter half of normal pregnancy to meet the demands of the rapidly developing fetus; these include relative insulin resistance, elevations in cholesterol, triglycerides and free fatty acids, and inflammation/innate immune system activation. ^, Physiologic responses to pregnancy, including inflammatory response, are thought to be a continuum with preeclampsia representing an extreme. Exaggerated gestational insulin resistance, dyslipidemia, and inflammation characteristically develop before and during preeclampsia. ^, Women with dyslipidemia during the first or second trimester are at significantly heightened risk of developing preeclampsia. The cardiometabolic profile of preeclampsia, with vascular endothelial dysfunction central to maternal pathophysiology (see Chapter 10 for more details of vascular endothelial dysfunction in preeclampsia), is strikingly similar to that associated with CVD generally.

Pregnancy can unmask latent cardiometabolic abnormalities. Approximately 2%–3% of seemingly healthy women undergo a deterioration of glucose homeostasis under the metabolic stress of pregnancy, becoming less able to increase insulin secretion to overcome peripheral insulin resistance—but appear to revert to normal after delivery. This abnormality, gestational diabetes, is a form of “prediabetes” because it predicts later-life progression to overt diabetes and attendant health risks. Pregnancy also challenges the lipolytic system; this can cause women previously harboring clinically occult deficiencies of lipoprotein lipase to become severely hypertriglyceridemic during pregnancy. In women with a gestational triglyceride rise above the 95th percentile, HDL cholesterol was concurrently low and did not normalize postpartum even when triglycerides reverted, suggesting a chronic disorder. Nonpregnant family members of those same women evidenced dyslipidemia. These data suggest that a gestational supraphysiologic rise in maternal plasma lipids is a marker of an atherogenic “prelipemia.” Pregnancy may thus be considered as a cardiometabolic “stress test,” similar to a treadmill test for occult CVD. A “metabolic syndrome of pregnancy” may represent a failed stress test unmasking preexisting metabolic disease and vascular endothelial dysfunction.

The Generation R Study, an ongoing population-based birth cohort, showed that an early pregnancy atherogenic lipid profile of excess circulating triglyceride-rich lipoproteins is independently associated with both preeclampsia and later-life hypertension (but not gestational hypertension). The study included 5690 women with live-born singletons and nonfasting lipid measurements at 13.4 (range 10.5–17.2) weeks of gestation. Women who developed preeclampsia (2.4% of cohort) had significantly higher early pregnancy concentration of total triglycerides and remnant (atherogenic) cholesterol ([total cholesterol – LDL cholesterol] – HDL cholesterol) compared with women with normal pregnancy. Women with higher early pregnancy triglycerides and remnant cholesterol were also more at risk of developing hypertension 6 and 9 years after the pregnancy. Adjustment for prepregnancy body mass index (BMI) (higher in the preeclampsia group) attenuated but did not eliminate the associations of early pregnancy triglycerides with preeclampsia and future hypertension. The authors posit a causal pathway by which adiposity promotes dyslipidemia in early pregnancy leading to endothelial dysfunction and preeclampsia. As they noted, a hypertriglyceridemic profile has been associated with insulin resistance and abnormal free fatty acid composition as well as dysregulated lipoprotein lipase-regulating enzymes. These findings are also in keeping with previous reports of associations of mid- and late-pregnancy triglycerides and risk of preeclampsia. ^{, ,} Of note, numerous studies suggest that nonfasting triglycerides better or at least similarly predict CVD events compared to fasting levels, which could relate to postprandial overexposure of the vascular endothelium to atherogenic (triglyceride-rich) remnant lipoproteins.

Many of the vascular and metabolic alterations of preeclampsia, which in the nonpregnant state are predictors of CVD (e.g., elevated C-reactive protein, hypertriglyceridemia, hyperinsulinemia), are evident months and decades postpartum more frequently in women with history of preeclampsia compared to women with history of uncomplicated pregnancy and may be drivers of CVD. Women with a history of preeclampsia are at two- to threefold increased risk of developing hypertension, coronary artery disease, or stroke in later life, and the association strengthens to three- to eightfold with early onset (by 34 weeks) preeclampsia or preeclampsia with small-for-gestational-age delivery or recurrent preeclampsia. Early-onset preeclampsia is associated very high CVD mortality by age 60. Other pregnancy complications, likewise related to placental vascular disease, but without a hypertensive pregnancy syndrome—placental abruption, preterm birth, or fetal growth restriction—are also associated with later CVD. ^, These data, from women who were not exposed to the vascular hypertensive insults of an established hypertensive pregnancy syndrome, suggest that the pregnancy syndromes unmask CVD risk that was present before the pregnancy. This, however, does not preclude long-lasting adverse effects of abnormal pregnancy itself.

Do Prepregnancy Cardiometabolic Risk Factors Foreshadow Preeclampsia?

The vast majority of studies investigating maternal metabolic differences between women who develop preeclampsia and those who do not have relied on measurements conducted during pregnancy or months to years after pregnancy. As reviewed by Barden in 2006, these approaches indirectly point to preexisting, maternal constitutional factors as underlying the development of preeclampsia. Cardiometabolic differences between women who develop preeclampsia and those who do not are ideally interrogated longitudinally, including measurements before pregnancy. This has been difficult because baseline blood pressure, lipid, or glucose tolerance measurements are infrequent in women of child-bearing age and because of the large enrollment numbers needed for a sufficiently powered, prospective preeclampsia study. Despite these challenges, a considerable body of literature on prepregnancy cardiometabolic antecedents of preeclampsia has emerged. Unless otherwise noted, the studies cited used widely accepted criteria for preeclampsia at the time (e.g., hypertension arising after the 20th week of pregnancy and new-onset proteinuria of at least 2+ by urine dipstick or at least 300 mg of urine protein per 24 h).

The available published studies of metabolic syndrome and risk of preeclampsia have used differing criteria or do not always exactly define their threshold criteria, for the metabolic syndrome components of abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Over time, various health care organizations have proposed somewhat differing clinical definitions and categorical cut points for component conditions of the metabolic syndrome. ^, In 2009, a consortium of the National Heart, Lung, and Blood Institute, the American Heart Association, the World Heart Federation, the International Atherosclerosis Society, and the International Association for the Study of Obesity proposed an overarching list of criteria for metabolic syndrome diagnosis, in which at least three of the following must be met: ^,

• 1.

  A waist circumference >88 cm for women and >102 cm inches for men (in the United States, variable criteria for other countries);

• 2.

  Circulating triglyceride levels above 150 mg/dL (or drug treatment to lower triglyceride levels);

• 3.

  Circulating HDL-C cholesterol below 50 mg/dL for women and 40 mg/dL for men (or drug treatment to elevate HDL-C levels);

• 4.

  Blood pressure above 130/85 mmHg (or drug treatment to reduce elevated blood pressure);

• 5.

  Fasting blood glucose above 100 mg/dL (or drug treatment to reduce glycemia).