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Preeclampsia: Multiple Approaches for a Multifactorial Disease

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Preeclampsia: Multiple Approaches for a Multifactorial Disease Disease Models & Mechanisms 5, 9-18 (2012) doi:10.1242/dmm.008516 CLINICAL PUZZLE Preeclampsia: multiple approaches for a multifactorial disease Kathleen A. Pennington1,*, Jessica M. Schlitt1,*, Daniel L. Jackson1, Laura C. Schulz1 and Danny J. Schust1,‡ Preeclampsia is a pregnancy-specific disorder characterized by hypertension and dehydrogenase (LDH) levels >600 or total bilirubin >1.2 (indicative of significant excess protein excretion in the urine. It is an important cause of maternal and fetal hemolysis); and a platelet count <100,000 morbidity and mortality worldwide. The disease is almost exclusive to humans (Sibai, 2004). Other recommendations are and delivery of the pregnancy continues to be the only effective treatment. The less stringent and recognize the diagnosis of disorder is probably multifactorial, although most cases of preeclampsia are partial HELLP syndrome when some of the characterized by abnormal maternal uterine vascular remodeling by fetally derived above characteristics are absent. placental trophoblast cells. Numerous in vitro and animal models have been used The multiple criteria for the diagnosis of to study aspects of preeclampsia, the most common being models of placental severe preeclampsia illustrate the multifocal nature of the disease. Elevated proteinuria oxygen dysregulation, abnormal trophoblast invasion, inappropriate maternal and oliguria are indicative of renal vascular damage and anomalous maternal-fetal immune interactions. dysfunction. Headache and visual changes Investigations into the pathophysiology and treatment of preeclampsia continue are evidence of central nervous system DMM to move the field forward, albeit at a frustratingly slow pace. There remains a involvement. Impaired liver dysfunction is pressing need for novel approaches, new disease models and innovative typically defined as liver function tests [AST investigators to effectively tackle this complex and devastating disorder. or alanine aminotransferase (ALT) levels] that exceed twice the upper limit of normal (ACOG, 2002). Fetal growth restriction is Preeclampsia: the clinical syndrome with 300 mg of proteinuria over 24 hours. variously defined as an estimated fetal weight Preeclampsia is the most common Blood pressure elevations must be confirmed of less than the 10th, 5th or 3rd percentile hypertensive disease of pregnancy, affecting via two separate measurements taken at least (Figueras and Gardosi, 2011). 5-8% of pregnancies (Saftlas et al., 1990) and 6 hours apart. Severe preeclampsia is Management of preeclampsia consists of accounting for nearly 18% of maternal deaths diagnosed if there are more severe elevations two options: delivery or observation. (ACOG, 2002) in the United States. Little of blood pressure or evidence of other end- Management decisions depend on the change has been noted in the incidence of organ dysfunction. The specific criteria as gestational age at which preeclampsia is this disease in the United States during the defined by the American Congress of diagnosed. The only effective treatment for national data-collection periods of 1993- Obstetricians and Gynecologists (ACOG) preeclampsia is delivery of the fetus and 1997 and 2001-2005 (Berg et al., 2009). are shown in Box 1. Patients with severe placenta, and the decision to deliver involves Preeclampsia is also associated with adverse preeclampsia can also exhibit hemoconcen- Disease Models & Mechanisms fetal outcomes, including intrauterine growth tration due to intravascular volume depletion Box 1. American Congress of retardation (IUGR), placental abruption, and elevated serum uric acid levels (Wagner, Obstetrics and Gynecology oligohydramnios and non-reassuring fetal 2001). HELLP syndrome is a specific variant (ACOG) criteria for diagnosis of surveillance. It is clinically defined as of severe preeclampsia. HELLP is an severe preeclampsia hypertension and proteinuria with onset acronym for hemolysis, elevated liver Preeclampsia is considered severe if one or following the 20th week of pregnancy enzymes and low platelets. It has been more of the following criteria is present (ACOG, (Wagner, 2001). Preeclampsia can be further suggested that, to meet the criteria for 2002): differentiated into mild and severe forms. HELLP syndrome, a patient’s test results • Blood pressure of 160 mm Hg systolic or Mild preeclampsia is defined by a systolic must indicate: microangiopathic anemia on higher, or 110 mm Hg diastolic or higher on blood pressure of >140 mmHg or a diastolic a peripheral smear; liver aspartate amino- two occasions at least 6 hours apart while the blood pressure >90 mmHg in combination transferase (AST) levels >70; lactate patient is on bed rest • Proteinuria of 5 g or higher in a 24-hour urine specimen, or 3+ or greater in two random urine samples collected at least 4 hours apart 1 Department of Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Oliguria of less than 500 ml in 24 hours 500 North Keene Street, Columbia, MO 65201, USA • *These authors contributed equally to this work • Cerebral or visual disturbances ‡Author for correspondence ([email protected]) • Pulmonary edema or cyanosis © 2012. Published by The Company of Biologists Ltd • Epigastric or right upper-quadrant pain This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share • Impaired liver function Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, • Thrombocytopenia distribution and reproduction in any medium provided that the original work is properly cited and all further distributions Fetal growth restriction. of the work or adaptation are subject to the same Creative Commons License terms. • Disease Models & Mechanisms 9 CLINICAL PUZZLE Modeling preeclampsia balancing the potential benefit to the fetus Maternal-Fetal Medicine specialist. considering early- and late-onset preeclampsia of further in utero development with fetal Expectant management over this gestational separately). However, what is clear is that all and maternal risk of progressive disease, age range has been shown to have benefit to forms of the disease are characterized by a including the development of eclampsia, the fetus, but should only be done if the disruption of vascular remodeling and a which is preeclampsia complicated by disease process can be managed to minimize systemic anti-angiogenic response. The maternal seizures. The decision can be the risk to the mother (Sibai, 2004). underlying mechanisms contributing to these difficult for the clinician because expectantly The multifocal nature of preeclampsia is changes remain unclear and might overlap. managed (actively surveyed) preeclampsia related to its pathogenesis. Although the Among the possible mechanisms that have can progress and threaten the life of both the exact pathway leading to preeclampsia been most studied are alterations in the mother and the fetus. However, premature continues to be poorly defined, many maternal immune response to the allogenic birth remains a leading cause of neonatal promising insights are discovered every year. fetus and placental oxygen dysregulation morbidity and mortality worldwide (Fonseca Continued interest in this disease process, as (including inappropriate placental hypoxia et al., 2007). Mild preeclampsia at 37 0/7 evidenced by over 25,000 published articles and hypoxia-reoxygenation injury). weeks gestation or greater should be treated on preeclampsia, has led to a variety of useful In normal pregnancy, cytotrophoblast with expeditious delivery (Wagner, 2001). but imperfect in vitro and animal models for cells originating in the anchoring villi of the Women diagnosed with mild preeclampsia a disorder that is fairly restricted, albeit not fetal portion of the placenta attach to and prior to 37 weeks of gestation can be exclusive, to humans. In this Clinical Puzzle invade the maternal endometrium (a process managed expectantly until they reach 37 article, we discuss the multiple pathological known as interstitial invasion). A subset of weeks provided they undergo regular factors and processes that contribute to these extravillous trophoblast cells acquires antenatal testing and maternal evaluation to preeclampsia and the existing experimental endothelial characteristics and invades monitor for fetal deterioration and/or models used to study them, and highlight maternal spiral arteries (known as progression to severe preeclampsia. It is outstanding research questions in the field. endovascular invasion). During early DMM generally recommended that patients with pregnancy, these trophoblast cells plug the severe preeclampsia deliver once they reach Pathophysiology of preeclampsia spiral arteries, maintaining a hypoxic uterine 32-34 0/7 weeks of gestation. The onset of The clinical manifestations of hypertension environment. They ultimately replace some severe preeclampsia prior to fetal viability and proteinuria that define preeclampsia of the endothelial cells in the vessel wall and (23-25 weeks of gestation) is also generally probably represent the late stage of a disease alter vessel compliance so that it becomes treated by delivering the fetus. Management that begins very early in pregnancy. There are ‘leaky’ and allows maternal blood to fill the of severe preeclampsia when onset is multiple theories, and little agreement, about intervillous spaces of the placenta (Fig. 1) detected between 24 and 34 weeks of the ultimate
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