Editorial: Incremental progress in predicting preeclampsia

March 21, 2016

A look at the latest science on preeclampsia and the reliability of predicting the condition.

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.

More: Obstetric history and CVD risk

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

NEXT: Can the ratio of sFlt-1 and PIGF predict preeclampsia?


The major breakthrough occurred in 2004, when Levine and colleagues conducted a nested case-control study and reported that circulating sFlt-1 levels normally increased across gestation while levels of a placental pro-angiogenic growth factor, PlGF, decreased during the last 2 months of pregnancy and that these physiological changes occurred earlier in women destined to develop preeclampsia.9  Hypoxia was subsequently shown to be the driver of these antiangiogenic placental changes.10  Thus, increased levels of sFlt-1, and perhaps decreased PlGF levels, appear to provide a crucial link between the pathognomonic placental lesion in preeclampsia and its maternal manifestations.

Recommended: How the Perinatal Episode of Care Mode will effect your care of high-risk patients?

Direct support for the connection then came from an unlikely source: the fundamental maternal features of the disorder-hypertension, proteinuria, renal dysfunction, increased platelet turnover, and hemolysis-are commonly elicited in nonpregnant women and men undergoing treatment for cancer with inhibitors of VEGF.11 Despite this robust pathogenic relationship, studies of maternal sFLT1 and PlGF levels have shown them to be only modestly predictive of preeclampsia and, although their ratio adds to predictive accuracy, the precise clinical utility of the sFlt-1/PlGF ratio remained to be established.12,13

Can the ratio of sFlt-1 to PlGF predict preeclampsia?

Given the absence of preventative treatments beyond minimally effective low-dose aspirin therapy, the greatest practical utility of a marker of preeclampsia would be its ability to differentiate impending preeclampsia from nonprogressive or less-pathological conditions such as chronic and gestational hypertension. For example, it is often difficult to decide how to triage a woman found to have increased blood pressure or minimal proteinuria. Should she be delivered if at term or given corticosteroids and hospitalized if preterm? A test that predicted risk for maternal or perinatal morbidity or who did or did not require medical intervention would be very helpful.

A recent prospective, multicenter, international observational study (PROGNOSIS) sought to help answer these questions by deriving and validating a serum sFlt-1/PlGF ratio that was predictive of the absence of preeclampsia within 1 week or its presence within 4 weeks in women with signs and symptoms suggestive but not diagnostic of the disorder.14  Suggestive signs included having a singleton pregnancies between 24 to 37 weeks with 1 or more of the following: new elevation in blood pressure < 140/90 mmHg, new proteinuria but < 2+ on dipstick, and preeclampsia-related laboratory findings not meeting strict criteria for HELLP syndrome. Suggestive symptoms included edema, headache, visual changes, and sudden weight gain.

In a development cohort of 500 women, the authors identified a sFlt-1/PlGF ratio of 38 as the optimal predictive cut-off value. They then performed a validation study with another 550 women and found that a cut-off ≤ 38 was associated with the absence of preeclampsia or HELLP syndrome in the next week (ie, a negative predictive value) in 99.3% (95% CI: 97.9–99.9) of such women, while values above 38 were associated with the diagnosis of preeclampsia or HELLP syndrome within 4 weeks with a positive predictive value of 36.7% (95% CI: 28.4–45.7), a sensitivity of 66.2% (95% CI: 54.0–77.0), and a specificity of 83.1% (95% CI: 79.4–86.3). Strengths of this study included the use of both discovery and validation cohorts and its large size.

NEXT: How increasing knowledge will help answer questions.


However, as an accompanying editorial notes, these findings apply only to a high-risk, mostly white population with singleton gestations and cannot be extended to the general population of mixed racial composition or patients with multifetal gestations.15 In addition, the study was sponsored by the maker of the diagnostic platform. We also have no idea whether use of sFlt-1/PlGF would actually improve maternal and perinatal outcomes or reduce costs (ie, add value to obstetrical care). Nonetheless, this approach represents the first practical application of our improved understanding of the pathogenesis of the disease.

Take-home message

Our understanding of the etiology and pathogenesis of preeclampsia is increasing. As we continue to unravel the pathogenesis of this ancient obstetrical nemesis unique to humans, additional markers will no doubt be discovered. For example, we have recently reported that high concentrations of the NK cell chemokine interferon-gamma-inducible protein 10 (IP-10) may paradoxically impede uterine NK cell recruitment and that first-trimester elevations in maternal serum IP-10 may predict subsequent development of preeclampsia.4  This study suggests that agents that facilitate uterine NK cell recruitment could prove a powerful approach to preventing the disease.

I predict that an intensive study of the pathogenesis of the disorder will permit development of a battery of such markers and allow us not only to identify women at risk early but also to bring to bear novel preventative agents.

Next: How much does it cost to have a baby in the US?



Redman C. Pre-eclampsia: A complex and variable disease. Pregnancy Hypertens. 2014;4(3):241–242.

Preeclampsia Foundation. New Guidelines in Preeclampsia Diagnosis and Care Include Revised Definition of Preeclampsia. December 4, 2013. http://www.preeclampsia.org/the-news/1-latest-news/299-new-guidelines-in-preeclampsia-diagnosis-and-care-include-revised-definition-of-preeclampsia. Accessed March 14, 2016.

Brosens I, Pijnenborg R, Vercruysse L, Romero R. The "Great Obstetrical Syndromes" are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193–201 Review.

Lockwood CJ, Huang SJ, Chen CP, et al. Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am J Pathol. 2013;183(3):841–856.

Lockwood CJ, Matta P, Krikun G, et al. Regulation of monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha and interleukin-1beta in first trimester human decidual cells: implications for preeclampsia. Am J Pathol. 2006;168(2):445–452.

Clark DE, Smith SK, He Y, et al. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol Reprod. 1998;59(6):1540–1548.

Vuorela P, Helske S, Hornig C, Alitalo K, Weich H, Halmesmäki E. Amniotic fluid--soluble vascular endothelial growth factor receptor-1 in preeclampsia. Obstet Gynecol. 2000;95(3):353–357.

Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran M, Sudhakar A, Kalluri R. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003;278(15):12605–12608.

Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–683.

Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the "chicken-and-egg" question. Endocrinology. 2004;145(11):4835–4837.

Brinda BJ, Viganego F, Vo T, Dolan D, Fradley MG. Anti-VEGF-induced hypertension: a review of pathophysiology and treatment options. Curr Treat Options Cardiovasc Med. 2016;18(5):33.

Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, et al; EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis. BJOG. 2012;119(7):778–787.

Leaños-Miranda A, Campos-Galicia I, Isordia-Salas I, et al. Changes in circulating concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor measured by automated electrochemiluminescence immunoassays methods are predictors of preeclampsia. J Hypertens. 2012;30(11):2173–2181.

Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(1):13–22.

Seely EW, Solomon CG. Improving the prediction of preeclampsia. N Engl J Med. 2016;374(1):83–84.