Preeclampsia is a serious maternal-fetal disease that affects 2–7% of pregnancies in healthy nulliparous women (21,28). This condition is diagnosed after 20 wk of gestation on the basis of persistent hypertension (blood pressure > 140/90 mm Hg) (1) and proteinuria (24-h urinary protein level of at least 0.3 g·d−1) (1). Preeclampsia should also be suspected without proteinuria if the patient presents with hypertension and other symptoms of major organ dysfunction, including thrombocytopenia, elevated liver enzyme activities, persistent headaches or visual disturbances, or epigastric pain (2,46).
A diagnosis of preeclampsia can have serious implications for both mother and fetus. Preeclampsia accounts for 15% of preterm births and their associated morbidities and mortality (34), and can also lead to intrauterine growth restriction and death (48). Maternal complications include an increased risk of abruptio placentae, renal failure, pulmonary edema, cerebral hemorrhage, stroke, and circulatory collapse (9,48). Careful management has led to a decrease in maternal mortality resulting from preeclampsia in developed countries (53); however, the associated maternal mortality rate in the developing world remains high (18).
Preeclampsia is often called the “disease of theories,” as many factors are believed to contribute to its development (48). These include abnormal placental development, predisposing maternal constitutional factors, oxidative stress, immune maladaptation, and genetic susceptibility (40,42,54). Each of these factors contributes to systemic maternal endothelial dysfunction, which leads to vasoconstriction and reduced perfusion of critical organs and tissues. Although the pathophysiological processes that lead to preeclampsia begin in early pregnancy, maternal symptoms do not appear until mid- to late gestation (42). The severity of symptoms can accelerate rapidly, leading to life-threatening seizures (eclampsia) or the necessity for immediate delivery regardless of gestational age (42).
Other than appropriately timed delivery, there are no proven interventions to treat preeclampsia or prolong gestation. However, epidemiological evidence suggests that women who participate in regular physical activity have a reduced risk of developing the disease (24,33,49). We propose that regular physical activity may protect against preeclampsia by intervening at three key stages in the disease process: 1) enhanced placental growth and vascularity (protection against abnormal placental development), 2) reduction of oxidative stress, and 3) reversal of endothelial dysfunction. This review describes current theories on the pathophysiology of preeclampsia, demonstrates how regular physical activity may act as a preventative intervention at early stages in the disease process, and discusses methodological issues for future research on this topic.
Hypothetical underlying causes of preeclampsia can be divided into five main categories: abnormal placental development, predisposing maternal constitutional factors, oxidative stress, immune maladaptation, and genetic susceptibility (40,42,54). Each of these hypothetical causes contributes to the development of endothelial dysfunction, which then leads to late-stage symptoms of preeclampsia. These hypothetical causes are not mutually exclusive, and probably interact to produce the symptoms associated with preeclampsia (54). The proposed mechanisms may also be sequential events in the pathenogenesis of preeclampsia. Abnormal placental development and predisposing maternal constitutional factors, for example, both cause oxidative stress, which would contribute to the development of endothelial dysfunction and preeclampsia. Each of these five theories has been reviewed extensively elsewhere (40,42,54), and will be described briefly here.
Abnormal placental development.
Abnormal development of the placental blood supply may cause persistent placental hypoxia (42) or repeated episodes of hypoxia and reperfusion (22). The underperfused placenta may produce toxins, such as cytokines, lipid peroxides (41), or placental villous tissue fragments (27). When released into the maternal circulation, these substances could contribute to oxidative stress, which leads to systemic endothelial dysfunction (22).
Predisposing maternal constitutional factors.
Several maternal constitutional factors that increase the risk of preeclampsia (diabetes, hypertension, obesity, hyperlipidemia) are also risk factors for atherosclerosis (42). These conditions may cause oxidative stress and endothelial dysfunction before pregnancy (41), increasing maternal susceptibility to preeclampsia.
Excessive pro-oxidant accumulation may contribute to systemic endothelial dysfunction in preeclamptic women (7,8). The underlying causes of oxidative stress are believed to include abnormal placental development and predisposing maternal constitutional factors (42). It is therefore unclear whether oxidative stress is a stage in the disease process or a distinct cause of preeclampsia.
Foreign genetic material in the developing embryo may activate the maternal immune system, triggering a widespread nonspecific inflammatory response (40). The endothelial activation and dysfunction observed in preeclampsia are consistent with vascular inflammation (40).
The genetic component of preeclampsia risk may result from independent contributions of maternal and fetal genes, or an interaction between maternal and fetal genotypes (54). Inheritance of preeclampsia is probably mediated by multiple genes that increase maternal susceptibility to conditions implicated in the etiology of preeclampsia (abnormal placental development, predisposing maternal constitutional factors, oxidative stress, and immune maladaptation) (54).
Multiple underlying causes may explain the heterogeneity of patient symptoms. Preeclampsia, for example, is associated with an increased incidence of both small (56) and large for gestational-age infants (55). Abnormal placentation is probably an important etiological factor in women who deliver small infants, as hypoperfusion would restrict fetal growth (56). Conversely, inadequate placental development probably is not involved in the disease process among women who deliver large babies (55).
Each of the five causes of preeclampsia may contribute to endothelial dysfunction (42). Evidence for endothelial dysfunction in preeclamptic patients includes increased production of vasoconstrictors (29) and coagulants (36,51), decreased production of vasodilators (35), and reduced endothelium-dependent dilation (12). This dysfunction is exacerbated by increased vascular sensitivity to vasoconstrictors, such as angiotensin II (20). The autonomic nervous system adaptations that facilitate reduced peripheral vascular resistance in normal pregnancy are absent in preeclampsia (45). Preeclamptic women demonstrate resting sympathetic hyperactivity (45), which may contribute to excessive vasoconstriction and elevated blood pressure.
Many symptoms of preeclampsia are attributable to vascular endothelial dysfunction (Table 1). Hypertension results from excessive vasoconstriction and failure to reduce peripheral vascular resistance during pregnancy (2). Convulsions result from cerebral hemorrhaging, vasospasm and focal ischemia (2,53). Proteinuria reflects increased renal endothelial permeability to large proteins. Increased endothelial permeability also causes edema (54). Peripheral edema leads to weight gain and swelling of the extremities, whereas cerebral edema can cause headaches and blurred vision (54). Dyspnea results from pulmonary edema (54). Abdominal pain occurs when fluids and inflammatory substances leak into the liver (54). In some cases, maternal endothelial dysfunction reduces utero-placental blood flow and persistent ischemia can cause intrauterine growth restriction (42).
PREVENTION AND TREATMENT
The primary method of preventing maternal and fetal mortality and morbidity is via appropriately timed delivery, balancing the maternal and fetal risks against the consequences of premature birth (42). There are no proven interventions to reduce the incidence of preeclampsia or to prolong gestation.
Recent efforts to prevent preeclampsia have focused on attenuating the development of oxidative stress. In a controlled randomized trial, Chappell et al. (8) demonstrated that nutritional antioxidant supplementation lowered the incidence of preeclampsia in women at risk for the disease. Measurement of plasminogen activator inhibitor-1 to plasminogen activator inhibitor-2 revealed that endothelial dysfunction was reduced among women who consumed antioxidant supplements. They postulated that reducing oxidative stress in early pregnancy might prevent the resulting endothelial dysfunction and late-stage symptoms of preeclampsia (8). Larger studies are needed to confirm these results.
EARLY DETECTION OF PREECLAMPSIA: RECENT PROGRESS
Although there are currently no proven interventions to prevent preeclampsia (47), early identification of women at risk is essential to the development of preventive measures. A large body of research has focused on the identification of biochemical predictors of preeclampsia. These markers are early indicators of disease progression (placental dysfunction, oxidative stress, altered antioxidant status, and endothelial activation) that eventually lead to the systemic, second-stage symptoms of preeclampsia.
Unfortunately, methodological problems have limited the usefulness of many biochemical tests. Many studies have failed to report sensitivity and specificity of specific markers, which are essential to determine the potential value of proposed markers for early prediction of preeclampsia. In addition, some proposed markers often fail to distinguish between preeclampsia and intrauterine growth restriction (IUGR), as both conditions are characterized by shallow tropoblastic invasion and increased uteroplacental resistance (7). For example, an abnormal uterine artery Doppler wave form and elevated ascorbic acid concentrations are sensitive indicators of preeclampsia, but they are not specific enough to screen out pregnancies complicated by IUGR.
Elevated levels of leptin and placental growth factor (PlGF), which reflect placental insufficiency, successfully distinguish between preeclampsia and IUGR at 20 wk of gestation. Increases in the ratio of PAI-1 to PAI-2, an indicator of endothelial activation and placental dysfunction, and in the concentrations of the antioxidant uric acid, were also effective predictors of preeclampsia. Levels of the cellular adhesion molecule fibronectin are elevated by mid-gestation in women who later develop preeclampsia, and the magnitude of this elevation reflects the severity of the disease (37). Elevated thrombomodulin levels have been shown to predict the development of preeclampsia with >80% sensitivity and specificity; however, a control group of women with IUGR was not examined (4). In the second half of pregnancy, impaired flow-mediated dilation (<3.0%) in the brachial artery correctly predicted future development of preeclampsia in 90% of cases (50). Flow-mediated vasodilation exceeded this cutoff value in all pregnant women who did not develop preeclampsia, resulting in a negative predictive value of 100% (50). Unfortunately, trials of thrombomodulin and flow-mediated dilation did not include a control group of women with IUGR (4,50).
These results suggest that no single marker is currently adequate to predict the development of preeclampsia and that a combination of indices would be most effective. Abnormal uterine artery Doppler waveforms at 20 and 24 wk are sensitive predictors but should be combined with biochemical markers that are specific for the development of preeclampsia. The most promising markers include fibronectin and the three combination indices recently identified by Chappell et al. (7) (Loge PlGF − 3.0(PAI-1/PAI-2 ratio), PAI-2·PlGF, and leptin/PlGF ratio). The adequate specificity of these combination indices (>88%) should improve predictive value (percent of patients with the condition that are correctly identified) when combined with the sensitive abnormal uterine artery Doppler waveforms.
EVIDENCE FOR A PROTECTIVE EFFECT OF PRENATAL EXERCISE AGAINST PREECLAMPSIA
There are currently no large-scale clinical trials testing the hypothesis that regular prenatal exercise is beneficial to prevent or delay the onset of preeclampsia. Epidemiologic studies, however, indicate that the incidence of preeclampsia is reduced among physically active nulliparous women (24,33,49).
In a recent case-control study, Sorenson et al. (49) tested the hypothesis that regular exercise and physical activity reduce the risk of preeclampsia. Recreational exercise and physical activity habits of 201 preeclamptic and 383 normotensive pregnant women were evaluated by postpartum questionnaire. Each subject’s average weekly recreational energy expenditure was calculated for the year before conception and the first 20 wk of gestation. Indexes of daily physical activity, including the average distance walked and number of flights of stairs climbed, were also assessed. After controlling for confounding variables, including parity, moderate-intensity recreational activity in the first 20 wk of pregnancy reduced the risk of preeclampsia by 24%. Vigorous physical activity during this time period was associated with a 54% reduction in risk, suggesting a dose–response relationship. A 60% reduction in risk was reported among women who engaged in vigorous recreational activity in the year before conception. An inverse relationship between stairs climbed and the incidence of preeclampsia was also observed. These results indicate that physical activity before and during the first 20 wk of pregnancy reduce the risk of preeclampsia.
Marcoux et al. (33) studied the relationship between leisure-time physical activity (LTPA) during the first 20 wk of pregnancy and the risk of developing preeclampsia and gestational hypertension. Subjects were primiparous hospital patients that included 172 women with preeclampsia, 254 women with gestational hypertension, and 505 healthy pregnant controls. LTPA was evaluated by postpartum questionnaire. Regular LTPA in early pregnancy significantly reduced the risk of preeclampsia, and the relative risk decreased with the time spent on activity. Women with the highest weekly energy expenditure were 43% less likely to develop preeclampsia than sedentary women. Frequent walking during the workday was also associated with a significantly lower risk of preeclampsia.
Irwin et al. (24) examined the relationship between occupational physical activity and the incidence of pregnancy-induced hypertension, gestational hypertension, and preeclampsia in military personnel. A panel of experts evaluated medical records of 5605 active-duty women in the U.S. Navy and classified subjects’ job descriptions by physical activity exposure. High levels of occupational activity were associated with a significantly reduced risk of pregnancy-induced hypertension in nulliparous women. Frequent lifting was associated with a significantly reduced risk of preeclampsia in nulliparous women. A nonsignificant trend toward reduced risk was reported for jobs that required more lifting, standing, physical exertion, or operating industrial machinery. Conversely, preeclampsia risk was slightly increased in parous women with physically demanding jobs. The reason for differing effects of occupational activity in nulliparous and parous women is unclear.
Studies indicate that regular physical activity protects against preeclampsia in nulliparous women. As suggested by Sorenson et al. (49), the similarity of findings despite differing study populations, methodologies, and imprecise quantification of physical activity suggests that this protective effect is robust.
POSTULATED MECHANISMS OF PROTECTIVE EFFECT OF PRENATAL EXERCISE AGAINST PREECLAMPSIA
As illustrated in Table 2, physical conditioning positively effects key physiological variables that are adversely effected in preeclampsia. If physical conditioning produces similar results in women at risk for preeclampsia, regular physical activity may attenuate the progression of the disease. We hypothesize that three separate but potentially interactive mechanisms could explain a protective effect of prenatal exercise against preeclampsia (Fig. 1).
Enhanced placental growth and vascularity.
Abnormal placental development is believed to be an underlying cause of preeclampsia in a small percentage of preeclamptic women whose fetuses demonstrate intrauterine growth restriction (42). Among these women, inadequate trophoblastic invasion of the uterine spiral arteries in early pregnancy leads to reduced perfusion and placental hypoxia (42). The resulting oxidative stress then causes systemic vascular endothelial dysfunction and late-stage symptoms of preeclampsia (42). Thus, interventions that promote early placental growth and vascular development may attenuate pathophysiological placental changes in this subset of women.
Several studies suggest that regular maternal exercise during early to mid-pregnancy stimulates placental growth. As summarized by Clapp (11), maternal exercise beginning in early gestation was associated with increased placental volumes and growth rates. The fraction of nonfunctional tissue was reduced, and the volume of villous tissue increased in the placentas of exercising women (25). Early pregnancy appears to be an important time for the stimulation of placental growth, as these adaptations were observed in term placentas of mothers who stopped exercising after 20 wk of gestation (25). Modest additional increases in placental volume and surface area were reported among women who continued to exercise until term (25).
Enhanced placental growth and vascularity may be an adaptive response to intermittent reductions in placental blood flow during exercise (11). These adaptations improve placental perfusion and transport capacity, and may prevent reductions in fetal substrate and oxygen supplies (25). Regular exercise in early pregnancy may therefore protect against the abnormal placental development that contributes to preeclampsia. This contrasts with the traditional interpretation that women with larger placentas are more likely to develop preeclampsia (42). In this regard, conditions that dramatically increase trophoblastic tissue (hydatidiform mole) (42) or placental area (i.e., multiple gestation) (14) result in an increased incidence of preeclampsia. This may reflect relative underperfusion of the large placenta secondary to insufficient placental vasculature, or inadequate uterine blood flow to supply the additional placental tissue (42). The hypoxic placenta releases substances into the maternal circulation that are believed to cause immune activation, oxidative stress, and endothelial dysfunction (42).
In contrast to multiple gestation and placentas with increased trophoblastic tissue, the placentas of exercising mothers have an enhanced vascular supply and reduced volume of nonfunctional tissue. In addition, all of the epidemiological studies that have adequately quantified physical activity have demonstrated a reduced rather than increased risk of preeclampsia with physical activity in nulliparous women (24,33,49).
Intermittent reductions in fetal and placental oxygen supplies are believed to be the stimulus for exercise-induced increases in placental growth and vascularity (11,25). This suggests that placental size will increase only to the extent that is necessary to meet fetal and placental demands. We therefore hypothesize that exercise-induced stimulation of placental growth and vascularity may correct inadequate placental development and slightly enhance normal placental development.
Prevention/reduction of oxidative stress.
Regular exercise training reduces oxidative stress by enhancing antioxidant defense systems (39). Acute exercise increases production of pro-oxidants, and a corresponding depletion of antioxidants is required to restore oxidative balance (39). When training is repeated regularly, the body adapts by enhancing antioxidant defense systems to limit cellular damage from exercise-induced oxidative stress (39).
Antioxidant upregulation by chronic exercise has been confirmed in skeletal muscle (38,39), liver, heart (52), and blood (5,15). Augmented activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxide, have also been demonstrated (5,39). Vigorous or prolonged exercise is most effective in promoting enzymatic adaptation in rats (38); however, increased energy expenditure for low-intensity physical activity was associated with high SOD activity in erythrocytes of Spanish women (15). Conversely, increased energy expenditure for high-intensity physical activity is associated with elevated whole-blood glutathione peroxidase activity (a nonenzymatic antioxidant), which is also increased in active skeletal muscle after training (39). Increases in total antioxidant capacity, plasma concentrations of antioxidants uric and ascorbic acid, and plasma SOD activity have been reported in male soccer players compared with sedentary controls (5). Therefore, regular exercise upregulates antioxidant capacity, and may reduce the oxidative stress that leads to endothelial dysfunction in preeclampsia.
Correction of vascular endothelial dysfunction.
Existing research indicates that aerobic conditioning reverses endothelial dysfunction. Research consistently demonstrates that exercise training improves endothelium-dependent dilation in patients with impaired endothelial responses resulting from a variety of conditions, including aging (17), Type 2 diabetes (31), and heart failure (32). Although most studies have examined the local effects of arm or leg exercise, systemic improvements in endothelial function have recently been demonstrated with large muscle mass exercise in heart failure patients (32).
Systemic elevations in vascular shear stress during large muscle mass exercise have been proposed as the stimulus for training-induced improvements in endothelial function (23). Exercise increases blood viscosity and flow, pulse pressure, and heart rate, all of which contribute to elevated shear stress (26). Aerobic training produces short-term improvements in endothelial function to compensate for high levels of shear stress during exercise (30), and repeated shear stress exposure leads to structural remodeling of the vascular system. These structural adaptations reduce shear stress, and endothelial function returns to pretraining levels. This model explains results obtained in healthy human subjects in whom endothelial function is not improved by training (26). Improvements in endothelial function, however, are maintained in patients with disease-related endothelial dysfunction (31,32) despite increases in functional capacity. Therefore, exercise training may not alter endothelial function in subjects with normal endothelial responses, but may attenuate or correct disease-related endothelial dysfunction.
By reversing endothelial dysfunction, exercise may prevent the progressive deterioration of endothelial responses that occurs in preeclampsia and attenuate subsequent maternal symptoms. Regular exercise may also correct postnatal dysfunction, as impaired endothelial-dependent dilation has been demonstrated 3 yr after delivery in women with preeclamptic pregnancies (6).
RECOMMENDATIONS FOR FUTURE STUDY
Current research provides both epidemiological evidence and a theoretical basis for the use of exercise to prevent or delay the onset of preeclampsia. Future research should continue both approaches to rigorously test this hypothesis. Important factors to consider include parity, and the timing (prepartum, early pregnancy, mid- to late gestation), amount, and intensity of the exercise stimulus.
Regular physical activity has been linked to a reduced risk of preeclampsia (24,33,49). However, existing studies did not adequately control for physical fitness of subjects, occupational and leisure-time physical activity, and preconceptual and/or prenatal exercise. Future studies should use a prospective case-control design that controls for these confounding variables.
To accurately assess the relationship between physical activity and preeclampsia, physical activity should be quantified by calculating each subject’s weekly energy expenditure for leisure and occupational activity. This should also be done regularly during pregnancy to avoid inaccuracies in subject recall at the time of delivery. Future studies should also control for both leisure-time and occupational physical activity levels using individualized activity records.
Prospective, randomized trials.
A recent summary from the National Heart, Lung, and Blood Institute Working Group on Research on Hypertension during Pregnancy (43) recommended clinical trials to assess whether antioxidant vitamin supplementation could prevent preeclampsia by reducing oxidative stress. Regular exercise also has well-documented antioxidant effects (5,15,39), and should similarly be examined as a potential preventive measure.
Prospective, randomized trials are necessary to test the hypothesis that prenatal exercise may prevent preeclampsia or prolong gestation in women at risk for premature delivery. If the incidence of preeclampsia was reduced in women randomly assigned to an exercising group when compared with nonexercising controls, this would suggest that exercise has a clinically significant preventative effect. Several design considerations must be taken into account when developing a study to assess the potential preventative role of prenatal exercise. Primiparous and nulliparous women should be examined separately, as one epidemiological study has indicated that the relationship between exercise and preeclampsia differs between these two groups (24). Because only 2–7% of women develop the disease, numerous women would need to be tested to show significant differences in the incidence of preeclampsia between exercising and nonexercising women. Targeting women at risk for preeclampsia (family history of preeclampsia or gestational diabetes, high prepregnancy BMI) is more cost-effective, and increases the likelihood that the disease will develop in members of the study population.
Selecting outcome measures that predict the future development of preeclampsia may further reduce the sample size needed to detect a preventative effect of prenatal exercise (Fig. 2). These outcome measures provide information about the progression of the disease and its effects on physiological systems before the diagnosis of preeclampsia. Inadequate placental development, for example, can often be detected both by changes in biochemical markers and by persistent abnormalities in the uterine artery Doppler waveform in mid-gestation (7). Altered levels of antioxidants indicate oxidative stress (7), whereas abnormal levels of biochemical markers (7) and impaired flow-mediated vasodilation (12) result from endothelial dysfunction. Endothelial dysfunction may also be reflected in measures of cardiac autonomic control (10,44). In addition, preliminary evidence indicates that the combination indices proposed by Chappell et al. (7) are sensitive and specific predictors of preeclampsia in high-risk women. These physiological markers can therefore be used to detect pathological changes preceding preeclampsia in smaller groups of women, and to evaluate the effects of prenatal exercise on early stages in the disease process.
This work was supported by the Physician’s Serviced Incorporated Foundation, Garfield Kelly Cardiovascular Research and Development Fund (Queen’s University), and Advisory Research Committee (Queen’s University).
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Keywords:©2004The American College of Sports Medicine
HYPERTENSION; PREGNANCY; AEROBIC CONDITIONING; OXIDATIVE STRESS; ENDOTHELIUM