Preeclampsia — Searching for the Cause
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《新英格兰医药杂志》
Three to 5 percent of pregnancies in the United States are complicated by preeclampsia, a multisystem disorder characterized by hypertension and proteinuria that occurs after 20 weeks of pregnancy. Preeclampsia is associated with substantial risks. For the fetus, these include intrauterine growth restriction, death, and prematurity with attendant complications, whereas the mother is at risk for seizures (eclampsia), renal failure, pulmonary edema, stroke, and death. Despite considerable research, the cause or causes of preeclampsia remain unclear, and there are no clinically useful screening tests to identify women in whom it will develop. Antihypertensive therapy lowers maternal blood pressure but does not improve fetal outcomes; the only "cure" is the delivery of the infant.
Preeclampsia has been dubbed the "disease of theories" because of the multiple hypotheses proposed to explain its occurrence. It is recognized that abnormal placentation and placental vascular insufficiency (see Figure) are core features of preeclampsia, but why these and associated systemic abnormalities occur remains uncertain. Among the many proposed causes are immunologic derangements (a maternal immune reaction to paternal antigen in the placenta), genetic factors, increased insulin resistance (and associated elevations in the levels of insulin, free fatty acids, and triglycerides), dietary calcium deficiency, increased oxidative stress, and prostaglandin imbalance (an increased ratio of thromboxane levels to prostacyclin levels). Preeclampsia is likely to be multifactorial in origin, and characteristics of the mother and the placenta may interact to lead to its development.
Figure. Placental Vascular Pathology in Preeclampsia (Hematoxylin and Eosin, x10).
Panel A shows normal term decidua capsularis with small spiral arterioles (arrow). Panel B shows decidual arterioles in preeclampsia with fibrinoid necrosis and atherosis, the presence of foamy cells in the necrotic vascular wall (arrow). Courtesy of Dr. Drucilla Roberts, Department of Pathology, Massachusetts General Hospital, Boston.
Recent research has focused on endothelial dysfunction as a central abnormality in preeclampsia. Abnormal pressor responsiveness in this disorder was recognized decades ago, when it was observed that women in whom preeclampsia was later diagnosed first lost the refractoriness to infused angiotensin II that is characteristic of normal pregnancy. More recent studies in preeclamptic women have demonstrated increased levels of factors associated with abnormal endothelial function, such as cytokines (e.g., tumor necrosis factor ) and endothelin-1.
Clinical research into factors that may cause preeclampsia has been complicated by the misclassification of study subjects, since not all hypertension in pregnancy is due to preeclampsia. Gestational hypertension — elevated blood pressure without proteinuria or other systemic manifestations — is frequently confused with preeclampsia but usually has a benign course. Other women who are labeled as having preeclampsia have unrecognized chronic hypertension. It is also unclear whether many abnormalities observed in women with preeclampsia are primary (causal) or are secondary to the disease process. At the same time, the lack of an animal model of preeclampsia has hampered laboratory research into this condition.
Given the uncertainty regarding the cause of preeclampsia, it is not surprising that effective interventions are lacking to prevent its occurrence. Despite encouraging preliminary observations, large studies of interventions based on hypothesized causes of preeclampsia have yielded inconsistent and often disappointing results. In randomized trials sponsored by the National Institutes of Health that were previously reported in the Journal, low-dose aspirin1 and calcium supplementation2 each failed to reduce significantly the risk of preeclampsia.
Currently, women who are at increased risk for preeclampsia are identified on the basis of epidemiologic factors. A first pregnancy, diabetes mellitus, preexisting hypertension or previous preeclampsia, multiple gestation, and higher body-mass index are among the recognized risk factors for the disorder, but they lack sensitivity and specificity. Although several markers have been proposed for the prediction of disease (including, for example, low urinary calcium levels and hyperinsulinemia), the substantial overlap with regard to these measures between women in whom preeclampsia later develops and women in whom it does not, as well as the low positive predictive values of these measures for disease, makes them of little use in practice.
In this issue of the Journal, Levine et al. (pages 672–683) report the results of a nested case–control study demonstrating the presence of increased levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and reduced levels of placental growth factor (PlGF) in women in whom preeclampsia develops. These changes were detected not only once disease was clinically apparent, but also several weeks earlier. The hypothesis is that high levels of sFlt-1 lead to placental vascular insufficiency and other systemic manifestations of preeclampsia by antagonizing the angiogenic and vasodilatory effects of vascular endothelial growth factor and PlGF. An earlier report by some of these authors and other investigators3 demonstrated that the infusion of sFlt-1 into pregnant rats resulted in findings consistent with preeclampsia (including hypertension, proteinuria, and glomerular endotheliosis — a characteristic renal lesion in preeclampsia). The current findings, coupled with the research in rats, suggest that these factors may have a role in the pathogenesis of preeclampsia.
These data are intriguing, but questions remain. In the current study, preeclampsia did not develop in all women with high sFlt-1 levels and low PlGF levels, and it did develop in some women with low sFlt-1 levels and high PlGF levels. This suggests that other maternal and placental factors are also likely to affect the occurrence and expression of disease. As Levine et al. note, large, longitudinal studies of pregnant women will be needed to define the clinical utility of high levels of sFlt-1 or low levels of PlGF for the identification of women in whom preeclampsia will develop. Prior experience with markers that ultimately turned out to lack sufficient predictive value, however, suggests the need for caution. Whether strategies for reducing the level of sFlt-1 or blocking its effects will have a therapeutic role is currently unknown.
The complications of preeclampsia have been recognized for centuries. Clinical and laboratory investigations over the years have better defined its pathophysiology but have failed to identify its "cause." Although more work is needed, the current report brings us one step closer.
Source Information
From the Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston (E.W.S).
References
Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med 1998;338:701-705.
Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69-76.
Maynard SE, Min J-Y, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649-658.(Caren G. Solomon, M.D., M)
Preeclampsia has been dubbed the "disease of theories" because of the multiple hypotheses proposed to explain its occurrence. It is recognized that abnormal placentation and placental vascular insufficiency (see Figure) are core features of preeclampsia, but why these and associated systemic abnormalities occur remains uncertain. Among the many proposed causes are immunologic derangements (a maternal immune reaction to paternal antigen in the placenta), genetic factors, increased insulin resistance (and associated elevations in the levels of insulin, free fatty acids, and triglycerides), dietary calcium deficiency, increased oxidative stress, and prostaglandin imbalance (an increased ratio of thromboxane levels to prostacyclin levels). Preeclampsia is likely to be multifactorial in origin, and characteristics of the mother and the placenta may interact to lead to its development.
Figure. Placental Vascular Pathology in Preeclampsia (Hematoxylin and Eosin, x10).
Panel A shows normal term decidua capsularis with small spiral arterioles (arrow). Panel B shows decidual arterioles in preeclampsia with fibrinoid necrosis and atherosis, the presence of foamy cells in the necrotic vascular wall (arrow). Courtesy of Dr. Drucilla Roberts, Department of Pathology, Massachusetts General Hospital, Boston.
Recent research has focused on endothelial dysfunction as a central abnormality in preeclampsia. Abnormal pressor responsiveness in this disorder was recognized decades ago, when it was observed that women in whom preeclampsia was later diagnosed first lost the refractoriness to infused angiotensin II that is characteristic of normal pregnancy. More recent studies in preeclamptic women have demonstrated increased levels of factors associated with abnormal endothelial function, such as cytokines (e.g., tumor necrosis factor ) and endothelin-1.
Clinical research into factors that may cause preeclampsia has been complicated by the misclassification of study subjects, since not all hypertension in pregnancy is due to preeclampsia. Gestational hypertension — elevated blood pressure without proteinuria or other systemic manifestations — is frequently confused with preeclampsia but usually has a benign course. Other women who are labeled as having preeclampsia have unrecognized chronic hypertension. It is also unclear whether many abnormalities observed in women with preeclampsia are primary (causal) or are secondary to the disease process. At the same time, the lack of an animal model of preeclampsia has hampered laboratory research into this condition.
Given the uncertainty regarding the cause of preeclampsia, it is not surprising that effective interventions are lacking to prevent its occurrence. Despite encouraging preliminary observations, large studies of interventions based on hypothesized causes of preeclampsia have yielded inconsistent and often disappointing results. In randomized trials sponsored by the National Institutes of Health that were previously reported in the Journal, low-dose aspirin1 and calcium supplementation2 each failed to reduce significantly the risk of preeclampsia.
Currently, women who are at increased risk for preeclampsia are identified on the basis of epidemiologic factors. A first pregnancy, diabetes mellitus, preexisting hypertension or previous preeclampsia, multiple gestation, and higher body-mass index are among the recognized risk factors for the disorder, but they lack sensitivity and specificity. Although several markers have been proposed for the prediction of disease (including, for example, low urinary calcium levels and hyperinsulinemia), the substantial overlap with regard to these measures between women in whom preeclampsia later develops and women in whom it does not, as well as the low positive predictive values of these measures for disease, makes them of little use in practice.
In this issue of the Journal, Levine et al. (pages 672–683) report the results of a nested case–control study demonstrating the presence of increased levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and reduced levels of placental growth factor (PlGF) in women in whom preeclampsia develops. These changes were detected not only once disease was clinically apparent, but also several weeks earlier. The hypothesis is that high levels of sFlt-1 lead to placental vascular insufficiency and other systemic manifestations of preeclampsia by antagonizing the angiogenic and vasodilatory effects of vascular endothelial growth factor and PlGF. An earlier report by some of these authors and other investigators3 demonstrated that the infusion of sFlt-1 into pregnant rats resulted in findings consistent with preeclampsia (including hypertension, proteinuria, and glomerular endotheliosis — a characteristic renal lesion in preeclampsia). The current findings, coupled with the research in rats, suggest that these factors may have a role in the pathogenesis of preeclampsia.
These data are intriguing, but questions remain. In the current study, preeclampsia did not develop in all women with high sFlt-1 levels and low PlGF levels, and it did develop in some women with low sFlt-1 levels and high PlGF levels. This suggests that other maternal and placental factors are also likely to affect the occurrence and expression of disease. As Levine et al. note, large, longitudinal studies of pregnant women will be needed to define the clinical utility of high levels of sFlt-1 or low levels of PlGF for the identification of women in whom preeclampsia will develop. Prior experience with markers that ultimately turned out to lack sufficient predictive value, however, suggests the need for caution. Whether strategies for reducing the level of sFlt-1 or blocking its effects will have a therapeutic role is currently unknown.
The complications of preeclampsia have been recognized for centuries. Clinical and laboratory investigations over the years have better defined its pathophysiology but have failed to identify its "cause." Although more work is needed, the current report brings us one step closer.
Source Information
From the Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Boston (E.W.S).
References
Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. N Engl J Med 1998;338:701-705.
Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69-76.
Maynard SE, Min J-Y, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 2003;111:649-658.(Caren G. Solomon, M.D., M)