Preeclampsia: What we know and what we do not know
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Preeelampsia: What We Know and What We Do Not Know
James M. Roberts
Preeclampsia remains a major health problem for mothers and infants. Studying the entire patho- physiology of preeclampsia rather than "pregnancy-induced hypertension" has greatly expanded our knowledge of the disorder. Current thinking approaches preeclampsia as a 2 stage disorder: reduced placental perfusion usually secondary to abnormal implantation and a consequent maternal disorder characterized by endothelial dysfunction and subsequent pathophysiological changes. We know much about the 2 stages and less about their linkage. It is evident that reduced placental perfusion is not sufficient to account for the pathophysiology. Reduced perfusion and abnormal implantation occur in other conditions (intrauterine growth restriction and preterm labor) without the maternal syn- drome. This leads to the hypothesis that reduced placental perfusion must interact with maternal constitutional factors to generate the systemic pathophysiology of preeclampsia. The similarities of these risk factors and metabolic alterations between preeclampsia and atherosclerosis suggest a common pathophysiology. Oxidative stress is postulated as the genesis of endothelial dysfunction in atherosclerosis. The author proposes that oxidative stress secondary to reduced placental perfusion leads to endothelial dysfunction, linking the 2 stages of the syndrome. Copyright 9 2000 by W.B. Saunders Company
E clampsia was first described 2,000 years ago as seizures associated with pregnancy
and resolving with delivery. 1 It was not until the end of the 19th century that the associa- tion with proteinuria and increased blood pressure ted to the conclusion that this preg- nancy abnormality was more than a seizure disorder. Rather, the occurrence of new onset increased blood pressure, especially in associ- ation with proteinuria, identified a clinical state in which the maternal condit ion could rapidly deteriorate and in which the fetus was at increased risk independent of seizures. Since that time, the 2 markers have been used in several classification schemes to define this syndrome. There are several variations cur- rently in use likely reflecting the fact that the findings by which the syndrome is defined were selected for historical reasons rather
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pitts- burgh, Pittsburgh, PA. Supported by National Institutes of Health (NIH) Grant: PO1 HD 30367. Address reprint requests to James M. Roberts, MD, Director, Magee- Womens Research Institute, 204 Craft Ave, Suite 610, Pittsburgh, PA 15213; e-mail: email@example.com Copyright 9 2000 by W.B. Saunders Company O146-0005/00/2401-0007510. 00/0
than because of a close association with patho- physiology or adverse outcome. It is abun- dantly clear that preeclampsia is not simply pregnancy-induced hypertension and protein- uria. 2 Appreciation of this fact has led to an enormous increase in our understanding of the disorder in the last 15 years. There are many things we now understand about the disorder but likewise many we do not.
Preeclampsia: What We Know
Preeclampsia is a leading cause of maternal mor- tality and increases perinatal mortality 5-fold. The increase in perinatal mortality is due, at least, in part to a management strategy which is now, as it was 100 years ago, delivery to termi- nate the pregnancy specific disease. While deliv- ery is always beneficial to the mother, it may result in the transition of a sick fetus in utero to a sick premature neonate in the nursery. Nearly 15% of preterm births are indicated preterm births for preeclampsia. Advances in therapy must target both maternal and neonatal well being.
24 Seminars in Perinatology, Vol 24, No 1 (February), 2000: pp 24-28
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Pathology and Pathophysiology
The pathological changes of preeclampsia are most consistent with reduced perfusion rather than mechanical disruption of blood vessels. 3 In the liver, for example, the characteristic hemor- rhage and necrosis are most consistent with pro- found vasoconstriction leading to infarction with bleeding into the necrotic area. In addition, subendocardial necrosis, a characteristic change in hypovolemic shock, is also present in women dying with eclampsia. These pathological evi- dences of reduced organ blood flow are sup- ported by the pathophysiological findings of re- duced perfusion to virtually any organ in the preeclamptic woman. 3
Certain pathological and pathophysiological changes are especially revealing. The kidney of the woman with preeclampsia manifests a char- acteristic morphological change present in no other form of hypertension. This change, termed glomerular endotheliosis, consists of oc- clusion of the glomerular capillary lumen by swollen endothelial and mesangial cells with in- clusions in the basement membrane. Interest- ingly, despite the proteinuria, the renal podo- cytes are completely normal. ~ In addition to showing that preeclampsia is not merely a vari- ant of essential hypertension, the profound changes in the glomerular endothelial cells sug- gest that vascular endothelium may be an impor- tant target in this disorder. Another finding pro- viding special insight is the abnormality of the spiral arteries that perfuse the intervillous space. Ordinarily these vessels undergo striking modi- fication in pregnancy. 4 Their diameter increases dramatically and the smooth muscle and inner elastic lamina of the vessel wall are lost. Endo- thelium no longer lines these cells but rather trophoblast cells that express endothelial anti- gens. 5 These changes do not take place in the vessels that supply the placenta of the pre- eclamptic woman. 6 They may occur in some su- perficial decidual vessels but never extend to the inner third of the myometrium as is characteris- tic of normal pregnancy. These findings illus- trate 2 important points. The first is that a char- acteristic finding in preeclampsia and one which is likely pathophysiologically important, is re- duced placental perfusion. Second, the physio- logical modification that occurs, at least, in part secondary to trophoblastic invasion, is ordinarily
completed by 20 to 22 weeks gestation. Thus, although preeclampsia characteristically pre- sents in late gestation, the root causes are present much earlier.
The pathophysiological changes of pre- eclampsia further support the presence of the disorder from earlier gestation than its clinical presentation. 3 The reduced organ perfusion of preeclampsia is secondary to profound vasocon- striction. Rather than an increase in either usual or unique pressors, vasoconstriction is secondary to an increased sensitivity to all pressors. Quite importantly this can be shown in groups of women destined to develop preeclampsia weeks to months before clinically evident disease. Ac- tivation of the coagulation cascade, especially platelets, likely further reduces organ perfusion by the formation of microthrombi. As with vas- cular sensitivity, increased platelet turnover is present months before clinical preeclampsia. Fi- nally, fluid is lost from the vascular compart- ment secondary to vasoconstriction and and to an endothelial leak. These changes further re- duce organ perfusion. Again the consequent re- duction in plasma volume antedates the diagnos- tic findings of preeclampsia. ~
Endothelial Dysfunction in Preeelampsia
Normal endothelium buffers response to circu- lating pressors, prevents activation of platelets, activates circulating anticoagulants, and main- tains fluids in the intravascular compartment. 7 Thus, the earliest pathophysiological changes of preeclampsia are all consistent with abnormali- ties of endothelial function. This is further sup- ported hy the morphological changes in the glo- merular capillary endothelium. In addition, biochemical markers of endothelial activation, increased cellular fibronecton, von Willebrand Factor, vascular cell adhesion molecule, and thrombomodulin amongst others, are increased in the circulation of women with preeclampsia. Many of these markers, as well as other indica- tors of endothelial dysfunction, are present weeks to months prior to clinical preeclampsia. Endothelial dysfunction is posited to be a central feature leading to the other pathophysiological changes of preeclampsia explaining the multior- gan involvement and protean manifestations.
26 James M. Robe~r
The Stages of Preeclampsia
Preeclampsia is a 2 stage disorder, s Preeclampsia is a pregnancy specific disease that begins to abate with delivery of the placenta. Sixty years ago Page 9 proposed that the placenta was tile important pregnancy component and that the feature that resulted in preeclampsia was re- duced placental perfusion. The abnormal im- plantation, typical of preeclampsia, the associa- tion of preeclampsia with medical disorders characterized by microvascular disease and with obstetrical conditions with large placentas sup- ported this hypothesis. Subsequently, further support was provided by direct measurements of intervillous blood flow and animal experiments. The reduced pertiasion of the intervillous space is the first stage that culminates in stage 2: en- dothelial dysfunction and systemic maternal dis- ease.
Preeclampsia: What We Do Not Know
What is the l inkage between the 2 stages of preeclampsia: maternal feta l /p lacental inter- actions. As we begin to explore the l inkage between reduced placental perfusion and the maternal systemic manifestations of pre- eclampsia, it is evident that a l though reduced perfusion seems necessary for preeclampsia it is clearly not sufficient. Not all mothers with growth restricted infants have preeclampsia. Some condit ions that predispose to pre- eclampsia (obesity and insulin resistance) are associated with large infants. Perhaps, most importantly, the abnormal implantat ion char- acteristic of preeclampsia is present in women with growth restricted infants and in one third of women delivering preterm. 6,1~ This suggests that the reduced perfusion must interact with maternal factors to result in preeclampsia. It is quite likely that these risk factors may be dif- ferent for different women. For example, sev- eral genetic polymorphisms are associated with preec lamps ia - -but not in all populations. An angiotensinogen variant is associated with preeclampsia in Utah and Japan II but not En- gland ~2 and Pittsburgh and a variant of the homocysteine related gene methylene tetrahy- drofolate reductase is present in preeclamptic women in Japan and Italy but not in 2 US populat ions) ~ The existence of different risk factors for different women indicates that
there will not likely be any 1 preeclampsia gene and also suggests that preventive therapy may need to be tailored to individual popula- tions.
Preeclampsia and Atherosclerosis
As we begin to look at the risk factors that could predispose to preeclampsia, the similarity of these risk factors to those for atherosclerosis is striking. Similar risks include obesity, diabetes, hypertension, black race, and hyperhomocys- teinemia. Further support for common risk fac- tors comes from the relationship of preeclamp- sia to cardiovascular disease in later life. The classic work of Chesley et a114 indicates that women with eclampsia in their first pregnancy have no excess of cardiovascular disease in later life compared with appropriately matched women with unknown pregnancy history. How- ever, if pregnancy history is known, women who have been pregnant and never developed pre- eclampsia have a lower risk of cardiovascular disease than the general female population. 15 In addition to the commonality of risk factors indi- cated by this relationship, there are other inter- esting similarities between the disorders. The endothel ium is target in both and the character- istic dyslipidemia predisposing to atherosclerosis in women, elevated triglycerides, reduced high density lipoprotein, and increased low density l ipoprotein (LDL) cholesterol in association with small dense LDL, are also present in women with preeclampsia./6,17
Oxidative Stress: The Linkage Between Reduced Placental Perfusion and Preeclampsia
Information on the pathogenesis of atherosclero- sis may provide clues as to the linkage of reduced placental perfusion to endothelial dysfunction in preeclampsia. Oxidative stress, with the formation of oxidized LDL from small dense LDL in the subendothelial space, has been postulated as the initiator of endothelial damage in atherosclero- sis. is There is also abundant evidence of oxidative stress in preeclampsia.19 Markers of oxidative stress are increased in blood and tissues of women with the disorder and there are reports of increased concentration of antibodies directed against oxi- dized LDL. Perhaps alteration of endothelial func- tion by reactive oxygen species generated in the
Preeclampsia 2 7
intervillous space can link reduced placental per- fusion to systemic maternal disease in preeclamp- sia. How might oxidative stress arise in preeclamp- sia? One of the primary sources of oxidative stress is reduced organ perfusion with subsequent return of normal oxygenation. A secondary wave of injury due to the formation of reactive oxygen species with reperfusion accounts for much of the tis- sue damage with coronary occlusion or stroke. With reduced peffusion, adenosine triphosphate cannot be fully oxidized and breaks down to aden- osine providing increased substrate for the bi- functional enzyme, xanthine oxidase/dehydroge- naseY ~ The enzyme is increased in response to hypoxia and preferentially functions as its oxidase form to produce uric acid and superoxide radical. With reinstitution of oxygen delivery, there is an abundant production of this radical. Uterine blood flow decreases with many normal activities. Changes in posture strikingly alter uterine blood flow. Increased requirements for nutrient and ox- ygen delivery to other organs (eg with exercise) reduces uterine blood flow. In labor, the blood flow to the placenta is transiently reduced with every uterine contraction. Adaptive mechanisms appear to prevent the formation of reactive oxygen species in the normal pregnant woman. However, in a setting of reduced placental perfusion, as is present in preeclampsia, might these normal re- ductions of uterine blood flow result in hypoxia sufficient to generate oxidative stress? In support of this hypothesis we have demonstrated increased xanthine oxidase/dehydrogenase and increased oxidase activity in the invasive cytotrophobtasts of preeclamptic women, z: Reactive oxygen species in general are quite labile; nonetheless, there are several possibilities for transfer of their effects to endothelium. The simplest would be oxidative in- jury by stable products of lipid oxidation such as malondialdehyde, known to be...