PHYSICAL ACTIVITY DURING PREGNANCY MAY REDUCE THE OCCURRENCE OF PREECLAMPSIA.

In this communication we provide a brief overview of the clinical and public health significance of preeclampsia, and highlight evidence regarding whether physical activity may play a role in its prevention. We will also discuss available data regarding specific details (e.g., duration, type and intensity) of physical activity associated with clinically relevant reductions in the preeclampsia occurrence.

What is Preeclampsia and Why is it Important?

Hypertensive disorders during pregnancy are the second leading cause, after embolism, of maternal mortality in the United States, accounting for approximately 15% of such deaths. Hypertension in pregnancy is associated with potentially lethal complications including abruptio placentae, disseminated intravascular coagulation, cerebral hemorrhage, hepatic failure, and acute renal failure. Preeclampsia, one of the hypertensive disorders of pregnancy, has an incidence of 3-7%.

Preeclampsia is characterized clinically by maternal high blood pressure, proteinuria and edema. Preeclamptics are more likely than normotensive pregnant women to experience metabolic disturbances similar to those seen in nonpregnant patients with coronary heart disease. Metabolic disturbances consistently associated with preeclampsia include hypertriglyceridemia, excessive lipid peroxidation, antioxidant deficiency, insulin resistance, sympathetic nervous system over-reactivity, plasma elevations of pro-inflammatory cytokines and C-reactive protein, hyper-homocystinemia, hyperleptinemia, and a thromboxane-prostacyclin imbalance that favors vasoconstriction. Moreover, pathologic lesions found in preeclamptic placentas are similar to those seen in atherosclerosis. There is considerable overlap between the epidemiology of preeclampsia, essential hypertension and coronary heart disease. Risk factors for the respective disorders include obesity, sedentary lifestyle, history of diabetes, familial history of essential hypertension, depression and anxiety. Women with a history of preeclampsia have increased risk of developing essential hypertension in the years following such pregnancies. For example, Nisell et. al. reported that after seven years of follow-up, women with a history of gestational hypertension or preeclampsia experienced an increased risk of developing essential hypertension compared to normotensive controls (37% and 20% vs. 2%, respectively).

Overall, available evidence suggests that the pathophysiological and epidemiological characteristics of preeclamptics are remarkably similar to those seen among men and nonpregnant women with essential hypertension. However, relatively little research has been conducted to assess the occurrence of the former condition in relation to modifiable risk factors such as physical activity. This is an important area that should be explored further in future studies.

What is the Evidence of Reduced Risk of Preeclampsia with Physical Activity?

To date there are only three published studies that have assessed the occurrence of preeclampsia in relation to maternal recreational physical activity. Over a decade ago, Marcoux et al. performed a case-control study of previously pregnant Canadian women. Women who participated regularly in recreational physical activity during the first 20 weeks of pregnancy experienced a 43% reduction in risk of preeclampsia as compared to sedentary women. The investigators also noted that the relative risk of preeclampsia decreased as average time spent performing physical activities increased. Sorensen et al. found that regular participation in recreational physical activity during the first 20 weeks of pregnancy was associated with a 35% reduced risk of preeclampsia. The risk of preeclampsia decreased in proportion to exercise intensity and total energy expended during the activities. The authors also documented a possible reduction in risk of preeclampsia in relation to walking and stair climbing, activities that pregnant women perform routinely. Women who climbed stairs regularly experienced a 44% to 69% reduction in risk of preeclampsia, and the reduction was evident among all women, irrespective of their participation in recreational physical activities. In 2004, Saftlas et al. reported results from a nested case-control study of New Haven, CT women that corroborated the previous reports from Montreal and Seattle.

What Mechanisms are Likely to Account for the Observed Reductions in Preeclampsia Risk in Relation to Maternal Participation in Recreational Physical Activity during Pregnancy?

Evidence from epidemiological, controlled clinical metabolic, and animal studies suggests that physical activity may impact preeclampsia occurrence through a number of biological pathways. Potential intermediate effects include reduced blood pressure, decreased concentrations of pro-inflammatory cytokines and leptin in peripheral circulation, reduced oxidative stress, and improved plasma lipid and lipoprotein concentrations. The following paragraphs include a brief review of the literature, which documents metabolic and other physiologic changes associated with habitual physical activity. Where possible, specific indication is provided regarding whether studies included pregnant women.

Results from observational epidemiological studies and randomized trials have consistently demonstrated an inverse relation between recreational physical activity and blood pressure in nonpregnant and pregnant women. In a meta-analysis of randomized controlled trials, investigators observed that aerobic exercise performed by nonpregnant women significantly reduced resting systolic and diastolic blood pressures. Exercise therapy has also been shown to result in reduced diastolic blood pressures in pregnant women with a history of mild hypertension, gestational hypertension or family history of hypertensive disorders.

Recreational physical activity is also associated with improvements in lipid concentrations in men and nonpregnant women. Specific improvements include reduced plasma triglycerides and increased high-density lipoproteins. Every aspect of lipid metabolism is dramatically altered during pregnancy. Maternal serum or plasma cholesterol and triglyceride concentrations increase 1.5- and 3-fold, respectively, above nonpregnant levels by the mid-third trimester. Pregnancy-associated hyperlipidemia is further exaggerated in women with preeclampsia. Recently, Butler et al. reported that mean triglyceride concentrations were lower among women in the highest tertiles of time performing physical activity compared to inactive women. Similar reductions were seen in total cholesterol. Linear relationships were observed across levels of physical activity measures for triglyceride and total cholesterol. There was no association between physical activity and HDL-cholesterol. These data suggest that habitual physical activity performed during pregnancy may mitigate the pregnancy-associated dyslipidemia commonly noted in preeclampsia.

Moderate intensity physical activity results in decreased concentrations of proinflammatory cytokines and C-reactive protein in peripheral circulation. Clapp and Kiess reported that regular weight-bearing exercise during pregnancy influences alterations in plasma tumor necrosis factor-[alpha] during pregnancy. Women randomized to the physical activity group experienced a greater attenuation of the pro-inflammatory cytokine concentrations during pregnancy compared to sedentary women. As late pregnancy is characterized by both an increase in insulin resistance and elevated circulating TNF-[alpha] levels, regular weight-bearing exercise during pregnancy may moderate insulin resistance, which is characteristic of preeclampsia.

Results from studies of the relationship between physical activity and increased risk of oxidative stress are equivocal. Evidence suggests that physical activity also results in increased antioxidant enzyme activity. This increase compensates for greater oxidative stress that may be attributable to vigorous physical activity. Given the central role of oxidative stress in the pathophysiology of preeclampsia, more studies are needed to clarify the relationship between maternal and fetal enzymatic and non-enzymatic antioxidant response to physical activity during pregnancy.

Hyperleptinemia has emerged as a promising clinical risk factor for preeclampsia. As noted previously, preeclampsia risk is inversely associated with maternal physical activity before and/or during pregnancy. In a study of 879 normotensive, non-diabetic pregnant women, Ning et al. reported that maternal leptin concentration in early pregnancy was inversely related with multiple measures of maternal physical activity (e.g., duration, intensity and total energy expenditure). The authors reported that mean leptin was 5.8 ng·mL-1 lower among active vs. inactive women. Mean leptin was approximately 8 ng·mL-1 lower among women in the highest levels of time performing physical activity and energy expenditure, compared with inactive women. These findings are consistent with previously published observational studies that have evaluated the impact of habitual physical activity on leptin concentrations in men and nonpregnant women. Physical activity may influence plasma leptin concentrations via several postulated biological mechanisms. Some investigators have noted that exercise-induced sympathetic nervous system modifications result in increased catecholamine concentration, which may attenuate leptin synthesis and release. Alternatively, physical activity may influence plasma leptin concentrations directly through its impact on synthesis. Results from animal and human studies support this thesis. Lastly, some investigators postulate that improved insulin sensitivity, secondary to physical activity, may influence leptin synthesis and concentrations, independent of adipose tissue mass. Whatever the mechanism, results from animal and human studies using diverse methodologies suggest that physical activity is an independent determinant of leptin concentration in the peripheral circulation.

Finally, recreational physical activity has been linked to improvements in emotional well-being and reductions in stress and anxiety. Investigators have shown that pregnant women experiencing anxiety and/or depression are at a 3-fold increased risk of preeclampsia. It is reasonable to speculate that the risk of preeclampsia, particularly those cases attributable to maternal psychosocial stress, may be impacted by the psychophysiological benefits of regular physical activity.

Should PA be Evaluated as a Nonpharmacological Therapy for Women with Hypertension in Pregnancy?

Questions remain unanswered concerning contraindications for recreational physical activity during pregnancy. For instance, although physical activity is often prescribed as a nonpharmacological therapy for mild hypertension in nonpregnant individuals, pregnant women presenting with mild hypertension may be directed to go on bed-rest. The question of whether women with high-normal or slightly elevated blood pressures in early pregnancy should be encouraged to begin a supervised moderate-intensity physical activity regimen, is a good one. Prospective studies, conducted in diverse populations, are needed to address this question.

Summary

Physical activity may reduce the risk of preeclampsia through several relevant physiological and metabolic pathways. Emerging results from small clinical and epidemiological studies in pregnant women offer compelling evidence of both short and long-term benefits of physical activity in pregnancy. These data provide evidence to support the biological plausibility of using recreational physical activity to help prevent preeclampsia in pregnant women. Future studies in this area should also explore the link between physical activity and risk of developing chronic hypertension.