Editorial: Incremental progress in predicting preeclampsia
Preeclampsia has been called the “great masquerader” and the “disease of exceptions” because of its complex, varied, and often insidious presentation.1 The disorder can evolve slowly during the course of the third trimester or present with sudden, catastrophic ferocity when puerperal eclampsia strikes a previously asymptomatic woman following an uncomplicated pregnancy. It can be associated with fetal growth restriction and macrosomia, and with small placentas and large ones. It can strike obese, older, hypertensive multiparas and athletic, young, healthy nulliparas.
In a bow to preeclampsia’s protean manifestations, the American College of Obstetricians and Gynecologists recently offered a new definition of the disorder that dropped the requirement for proteinuria.2 Of note, while our century-old schedule of prenatal visits was designed for early detection of this potentially lethal condition, many patients we suspect of developing the disorder never meet the definition, while others can have fulminant presentations a week after a normal prenatal visit.
What is needed is a highly predictive, anticipatory, and inexpensive diagnostic test to guide management. Despite a flurry of candidates including blood pressure “roll-over” tests, measurements of circulating prostacyclin, nitric oxide, endothelin and fibronectin levels, and more recent efforts to exploit proteomic and metabolomic analyses, none has proven reliable and/or practical.
The pathogenesis of preeclampsia
Despite decades of study, we are still searching for the exact cause of preeclampsia. However, this etiological fog is beginning to lift. The anatomic sine qua non of the disorder is impairment of the normal remodeling of uterine spiral arteries that occurs during the first 20 weeks of pregnancy.3 Recent evidence suggests that this phenomenon may be linked to reduction in specialized uterine natural killer (NK) cells and an increase in activated macrophages mediated by periconceptional endometrial and/or uterine vascular inflammation.4,5
The cause(s) of this inflammation remain conjectural but likely accompany the collection of clinical settings and conditions long associated with the disease. These include aberrant maternal immune responses to paternal antigens (in younger nulliparas), chronic hypertension with or without concomitant vascular or renal disease (in generally older multiparas), severe obesity, and autoimmune diseases.
Regardless of the trigger, the net effect of this impaired vascular remodeling is a progressive relative or absolute reduction in uteroplacental blood flow. But how is this placental “problem” linked to maternal manifestations of the disease that can include hypertension, vasospasm, endothelial cell damage, increased platelet turnover, and hemolysis, as well as renal, hepatic, pulmonary, cardiac, and cerebral dysfunction?
For decades, the link between uteroplacental vascular insufficiency and these maternal sequelae remained undiscovered. Then in 1998, Clark and colleagues first demonstrated that placental trophoblast cells released a soluble form of the receptor for vascular endothelial growth factor (VEGF), known as sFlt-1.6 A couple years later, Vuorela and associates detected elevated levels of sFlt-1 in the amniotic fluid of preeclamptic women.7 In 2003, Sugimoto et al. observed that intravenous injections of anti-VEGF antibodies or sFlt-1 in a murine model caused proteinuria and glomerular changes reminiscent of the glomerular endotheliosis seen in human preeclampsia.8