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Insulin Resistance and Its Potential Role in Pregnancy-Induced Hypertension

Endocrinology, Diabetes and Hypertension Division (E.W.S.) and Divisions of General Medicine and Women’s Health (C.G.S.), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Ellen W. Seely, M.D., Endocrine, Diabetes, and Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, Massachusetts 02115.

	Abstract

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
New-onset hypertension (which includes preeclampsia and gestational hypertension) is a common and morbid complication of pregnancy. Many features of the insulin resistance syndrome have been associated with this condition. These include hypertension, hyperinsulinemia, glucose intolerance, obesity, and lipid abnormalities. Other accompanying abnormalities may include elevated levels of leptin, TNF, tissue plasminogen activator, plasminogen activator inhibitor-1, and testosterone. The documentation of these features before the onset of hypertension in pregnancy suggests that insulin resistance or associated abnormalities may have a role in this disorder. Furthermore, the recognition that features of the insulin resistance syndrome persist many years after pregnancy among women with this condition raises the possibility that these women may have increased risk for future cardiovascular disease. These observations suggest that interventions to reduce insulin resistance may reduce the risk of both hypertension in pregnancy and later life cardiovascular complications, and warrant further study.

	Introduction

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
PREGNANCY-INDUCED HYPERTENSION complicates 5–10% of pregnancies in the United States and is a major cause of maternal, fetal, and neonatal morbidity and mortality. Although complications of hypertensive disorders of pregnancy have been recognized for centuries, the cause(s) of these disorders remains poorly understood. Accumulating research indicating associations of features of the insulin resistance syndrome and these disorders suggests that additional data are needed to elucidate their potential role in pathogenesis, utility for risk stratification, and implications for intervention strategies.

	Classification of hypertensive disorders of pregnancy

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Hypertensive disorders of pregnancy include 1) new onset in pregnancy (preeclampsia or gestational hypertension), 2) preexisting hypertension, and 3) exacerbation of preexisting hypertension (superimposed preeclampsia; Table 1) (1). New-onset hypertension develops during the second half of pregnancy (usually in the third trimester) in 3–5% of women who were previously normotensive. In these women, hypertension typically resolves within 6 wk postpartum, although they may be predisposed to later essential hypertension. Preeclampsia is a systemic syndrome whose hallmark is proteinuria (300 mg protein or more over 24 h). Other systemic manifestations include disseminated intravascular coagulation, hemolysis, elevated liver function tests, and, rarely, seizures (eclampsia); delivery is the only definitive treatment. Gestational hypertension, a generally more benign disorder, is diagnosed when blood pressure is elevated in the absence of these findings. When other systemic manifestations of disease are absent, the distinction between preeclampsia and gestational hypertension is made by the presence and magnitude of proteinuria; thus, misclassification is possible. It remains uncertain whether preeclampsia and gestational hypertension represent different disease entities or different manifestations of the same disease process; it is possible that insulin resistance may play an important role in both. The majority of women with preexisting hypertension do well in pregnancy. However, about 20% develop superimposed preeclampsia, with its attendant risks.

	Potential causes

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
The cause(s) of hypertensive pregnancy is uncertain and include immune, genetic, and placental abnormalities. All may contribute to endothelial dysfunction characteristic of preeclampsia. Endothelial dysfunction may, in turn, underlie several critical features of preeclampsia, including vasoconstriction, hypertension, loss of the usual pregnancy-associated refractoriness to pressor effects of angiotensin II, increased platelet aggregation, and proteinuria (1).

Some data have suggested that abnormalities of the placenta are the primary cause of preeclampsia. However, the observations that several metabolic abnormalities predispose to the development of preeclampsia, and that these abnormalities are also observed in the nonpregnant state in women who have had preeclampsia, suggest that features of the mother must also be considered.

All cases of de novo hypertension in pregnancy are unlikely to be attributable to a single cause. Rather, different etiologies may lead to the same phenotype in different women. Here we focus on the potential role of insulin resistance and associated abnormalities as pathogenic factors for the development of hypertensive pregnancy and its complications. The insulin resistance syndrome provides a plausible link between hypertensive pregnancy and many of its risk factors and sequelae in both pregnancy and later life.

	Insulin resistance and cardiovascular risk outside of pregnancy

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Although the relationship between diabetes and cardiovascular risk has long been recognized, it is increasingly clear that even in the absence of diabetes, insulin resistance is associated with a higher risk of cardiovascular disease. The metabolic syndrome (also called syndrome X) describes the coexistence of hyperinsulinemia, obesity (particularly central), glucose intolerance, hypertension, and dyslipidemia (including elevated triglyceride levels). More recently, associations have been appreciated between these abnormalities and other potential contributors to cardiovascular risk, including increased proportion of small dense low density lipoprotein (LDL) particles, increased plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen (TPA Ag), TNF, C-reactive protein (CRP), and cellular adhesion molecules (2, 3). Other endocrine correlates of insulin resistance in women include elevated androgen levels and reduced levels of SHBG (4).

	Insulin resistance and normal pregnancy

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Insulin resistance and resultant hyperinsulinemia are characteristic of normal pregnancy and are maximal in the third trimester. This is probably mediated by several hormonal changes, including elevations in levels of human placental lactogen, progesterone, cortisol, and estradiol (5). Many of the markers noted above to correlate with insulin resistance likewise vary over the course of pregnancy. For example, levels of triglycerides, small dense LDL particles, free fatty acids, PAI-1, TPA Ag, vascular cell adhesion molecule (VCAM), leptin, and TNF increase as normal pregnancy and associated insulin resistance progress (6, 7, 8). Levels of CRP are slightly elevated in normal pregnancy, but unlike the other markers noted, do not increase serially with advancing gestation (9).

	Hypertensive pregnancy

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Insulin resistance.

In women whose pregnancies are complicated by hypertension, there appears to be an exaggeration of insulin resistance and associated metabolic changes (Table 2). Although it remains uncertain to what extent these factors are pathogenic in hypertensive pregnancy, the available data suggest that some may play a role in disease evolution, whereas others may be markers of the underlying disease process. Exaggerated hyperinsulinemia relative to normal pregnancy is well described in women with established preeclampsia (10, 11) or gestational hypertension (10). Studies more directly assessing insulin resistance have also suggested differences between women with de novo hypertension in pregnancy and normotensive women. In a small study using the euglycemic clamp technique, insulin resistance was greatest in women with gestational hypertension, whereas results were similar in women with normotensive pregnancy and women with preeclampsia (12). A recent study using minimal model analysis (13) yielded comparable results, although in another report using this method, women with preeclampsia were more insulin resistant than normotensive controls (14). These seemingly discrepant observations may be explained by small sample sizes, diagnostic misclassification, and/or the likely multifactorial nature of this condition.

Obesity and physical inactivity, two factors closely associated with insulin resistance, are also predictive of hypertensive pregnancy. A higher body mass index before pregnancy or early in pregnancy is associated with increased risk for both preeclampsia and gestational hypertension (17, 18, 21, 22, 23). Furthermore, greater gestational weight gain has also predicted risk for preeclampsia (17) or gestational hypertension (23), as has higher waist circumference (a measure of central adiposity) between 6 and 16 wk (22). In contrast, increased participation in leisure time physical activity in the first 20 wk of pregnancy has been associated with reduced risk (24). Although these observations are consistent with a role for insulin resistance in hypertensive pregnancy, it is also possible that other factors, such as diet composition, may explain the observed associations.

Furthermore, some studies (16, 25) suggest that gestational diabetes (which itself is associated with underlying insulin resistance) is a risk factor for the development of hypertensive pregnancy. This association persists even after adjusting for obesity and maternal age (26).

Lipids.

In women with established preeclampsia, triglyceride (6, 13, 14) and free fatty acid levels (14, 27) have been reported to be higher and high density lipoprotein cholesterol levels lower (6, 14) than those in women with normotensive pregnancy. Other investigators have documented these abnormalities only in women with gestational hypertension (12). Studies have reported an increased proportion of small dense LDL particles in women with established preeclampsia (6, 7).

Similar to hyperinsulinemia, elevated total cholesterol levels (18, 28) have been reported to antedate the development of either preeclampsia or gestational hypertension. Elevated triglyceride (29, 30) and free fatty acid levels (29) during pregnancy have similarly preceded the development of preeclampsia specifically, as have lower levels of high density lipoprotein cholesterol (30).

Oxidized lipids may impair endothelial function directly or indirectly by effects on prostaglandins, including increasing synthesis of thromboxane and inhibiting synthesis of prostacyclin (31). Increases in small dense LDL and triglycerides may also contribute to impaired endothelial function.

Leptin.

Some data suggest that leptin levels are elevated in women with established preeclampsia (32, 33, 34), although not in women with gestational hypertension (34) Leptin levels as early as 20 wk gestation were reported to predict the development of preeclampsia in a high risk population (30).

Increased leptin levels may in part reflect maternal adiposity and have also been hypothesized to reflect placental insufficiency. Leptin might also contribute to endothelial dysfunction by increasing free fatty acid oxidation (35).

TNF, CRP, and VCAM.

Elevations in TNF (36, 37, 38) or its receptor (38) have been reported in women with established preeclampsia compared with normotensive controls in several studies, although some data are inconsistent (39). Elevated TNF levels in the early third trimester (40) may predict the development of preeclampsia, although levels measured earlier have generally not been predictive (40, 41). In small studies polymorphisms in the TNF gene have been associated with preeclampsia (42, 43). Another inflammatory marker, CRP, was not predictive of preeclampsia (41).

TNF may promote hypercoagulability and increased lipolysis, with resulting impairment of endothelial relaxation. TNF also causes the release of VCAM-1, elevations of which have been reported in established preeclampsia (38, 44), although not before its development (45).

PAI-1 and TPA Ag.

Women with established preeclampsia have higher levels of TPA Ag than normotensive pregnant women, and elevations are proportional to the magnitude of proteinuria (46). PAI-1 is likewise elevated in established preeclampsia and is higher in more severe disease (47). Among women at high risk for preeclampsia, the ratio of PAI-1 to PAI-2 (the latter primarily produced by the placenta) was increased before the development of disease (30). Increased PAI-1 may reflect impaired fibrinolytic function, which might predispose to the coagulopathy associated with preeclampsia.

Testosterone and SHBG.

Cross-sectional data indicate higher levels of total and free testosterone, but comparable levels of SHBG, in women with established preeclampsia compared with normotensive women; differences were not explained by body mass index (48). In a prospective study, although neither total nor free testosterone in the first trimester predicted later development of preeclampsia, lower levels of SHBG were predictive (4). Polycystic ovary syndrome, which is associated with insulin resistance, elevated testosterone, and low SHBG levels, has been linked to increased risk for pregnancy-induced hypertension even in the absence of associated obesity (49). Elevated androgen levels may be explained at least in part by increases in inhibin A, which have also been described in women with preeclampsia (50).

In animal models, androgens increase vasoconstriction in response to pressors (51). Androgens also affect the prostaglandin balance to decrease the synthesis of prostacyclin (52), leading to increased platelet aggregation. Both of these abnormalities are characteristic of preeclampsia.

	Postpartum findings in women with a history of new-onset hypertension in pregnancy

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Because several measures associated with insulin resistance antedate the development of hypertension in pregnancy, a logical question is whether such abnormalities persist postpartum. Persistence of these abnormalities after delivery would support the hypothesis that underlying insulin resistance (i.e. predating pregnancy) may predispose not only to hypertension during pregnancy, but also to other cardiovascular disorders later in life.

In several studies conducted postpartum, women with a history of preeclampsia have been shown to be insulin resistant, as demonstrated by elevated fasting insulin and glucose levels (53) (at 6 months to 2 yr postpartum), greater insulin response to oral glucose tolerance testing (54, 55) (at 8 wk and as late as 17 yr postpartum), or decreased glucose disposal by minimal model analysis (14) (on average at 12 wk postpartum) compared with women with normotensive pregnancy. Other components of the metabolic syndrome that have been reported postpartum among women with prior preeclampsia include elevated triglyceride levels and higher uric acid levels (53). Total cholesterol and very low density lipoprotein levels were also demonstrated to be elevated 2–5 yr after preeclamptic pregnancy (56), and elevated testosterone levels were found 17 yr after preeclamptic pregnancy (57), compared with levels after uncomplicated pregnancy. Abnormal brachial artery flow mediated (endothelium-dependent) dilatation has also been described in women studied a median of 3 yr after a pregnancy complicated by preeclampsia as compared to women with normotensive pregnancy, even after adjustment for body mass index and other potential confounders (58). These and other similar findings (56) suggest that endothelial dysfunction in preeclampsia is an underlying characteristic of affected women.

	Later life risks

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
The persistence of abnormalities of the metabolic syndrome postpartum suggests that women who have had a hypertensive pregnancy may be at increased risk for cardiovascular complications later in life. Assessment of later risks among women with a history of hypertensive pregnancy is limited by the long lag time between the age of child bearing and that when cardiovascular events become more likely. Remote diagnoses of new-onset hypertension in pregnancy cannot readily be confirmed by chart review, and a distinction between de novo hypertension in pregnancy and underlying essential hypertension may be impossible.

Although some earlier studies suggested no increase in future risk of hypertension among women who had preeclampsia or eclampsia (59, 60), the recognition that hypertensive pregnancy is associated with features of the insulin resistance syndrome has resulted in renewed interest in long-term sequelae of this condition. In a large study comparing women with severe preeclampsia or eclampsia to women with uncomplicated pregnancy, the risk for hypertension was increased almost 3-fold at 2–24 yr of follow-up; the magnitude of risk was correlated with the length of follow-up and was higher among women who had recurrent preeclampsia in their second pregnancy (61). Likewise, blood pressure was higher in women with preeclampsia on average 17 yr after pregnancy than among women who had uncomplicated pregnancy, despite similar body mass indexes in the two groups (55).

Similar to hypertension, the risk of other cardiovascular diseases may also be increased in women with prior preeclampsia, although studies of cardiovascular risk are likewise limited by the difficulty in ruling out essential hypertension misdiagnosed as preeclampsia. In a study of Norwegian women (62), mortality due to cardiovascular causes was increased among women who had preeclampsia and preterm delivery (considered a proxy for severity of preeclampsia) compared with preeclamptic women who delivered at term or women with preterm delivery alone. In another report, women who had a prior discharge diagnosis of preeclampsia were twice as likely as women with uncomplicated pregnancy to be admitted to the hospital for or die from ischemic heart disease (63).

	Clinical implications

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Although available data do not prove a cause and effect relationship between the insulin resistance syndrome and new-onset hypertension in pregnancy, the associations between these conditions raise the possibility that interventions that improve insulin sensitivity may reduce the likelihood of this pregnancy complication. Because obesity is both a major contributor to insulin resistance and a recognized risk factor for preeclampsia, interventions geared to weight reduction before pregnancy and/or avoidance of excessive weight gain during pregnancy may have merit. Similarly, increased exercise, which likewise improves insulin sensitivity, may also reduce risk. Given the well recognized adverse effects of obesity on many pregnancy outcomes, including gestational diabetes, these approaches make sense generally, but warrant explicit study in women at high risk of hypertensive pregnancy. Studies of pharmacological interventions, such as the use of the insulin sensitizer metformin, may also warrant study in women at high risk for preeclampsia.

Women who have had preeclampsia in one pregnancy are at increased risk in subsequent pregnancies. Thus, lifestyle interventions may be particularly relevant to reducing future preeclamptic pregnancy among these women, and studies are particularly warranted in this population.

Even beyond reproductive years, a history of hypertensive pregnancy may have important implications for medical care. The observations of increased prevalence of hypertension and other cardiovascular disease many years after a pregnancy complicated by de novo hypertension suggests that this pregnancy complication might reasonably be viewed as another cardiovascular risk factor in women. In other words, the hormonal milieu of normal pregnancy may cause women with underlying insulin resistance to manifest transient hypertension, which would otherwise not be evident until later in life (64).

Asking women about a history of hypertension in pregnancy may be useful in stratifying future cardiovascular risk, although more data are needed to assess to what extent the risk associated with this condition is independent of obesity and other well established predictors of cardiovascular disease. In women who have had hypertensive pregnancy, attention to cardiovascular risk factors and counseling regarding weight control, diet, and exercise may be particularly important.

	Future directions

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 
Multiple studies have demonstrated associations between markers of insulin resistance and hypertensive pregnancy. Findings consistent with the insulin resistance syndrome have been observed before, during, and after this pregnancy complication. However, further work is indicated in several areas. More data are needed to determine whether insulin resistance plays a causal role in the development of preeclampsia, gestational hypertension, or both. To improve our ability to identify women at risk for hypertensive pregnancy who might benefit from closer monitoring and intervention, large prospective longitudinal studies are needed to determine whether there are markers of insulin resistance with sufficient sensitivity and specificity to be clinically relevant. Studies should be undertaken to assess the effects of specific interventions directed at the insulin resistance syndrome on the risk of developing hypertensive pregnancy. Finally, the impact of a history of preeclampsia or gestational hypertension on future cardiovascular risk, and the potential relevance of targeted interventions, requires further investigation.

	Footnotes

 
E.W.S. is supported by NIH Grants R01HL67332 and SCOR(H) P50HL55000.

Abbreviations: CRP, C-reactive protein; LDL, low density lipoprotein; PAI-1, plasminogen activator inhibitor-1; TPA Ag, tissue plasminogen activator antigen; VCAM, vascular cell adhesion molecule.

Received February 13, 2003.

Accepted March 18, 2003.

	References

Top Abstract Introduction Classification of hypertensive... Potential causes Insulin resistance and... Insulin resistance and normal... Hypertensive pregnancy Postpartum findings in women... Later life risks Clinical implications Future directions References

 

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