Pre-eclampsia is a multisystem disorder that affects approximately 3 to 5% of all pregnancies worldwide.1 Due to the non-specificity of signs and symptoms, it remains a serious clinical challenge that presents significant risks to both mother and child. There is no other pregnancy complication that is both so common and dangerous for mother and child alike, since it can lead to maternal death, stillbirth, and preterm delivery.
Better knowledge of the disease’s origin2 has led to the development of a simple blood test that detects a hormone, Placental Growth Factor (PlGF), measured on the Alere Triage® System. PlGF is produced by the placenta and falls to very low levels in women with the early onset and severe forms of pre-eclampsia. The use of PlGF alongside the traditional markers of disease, increased blood pressure (at or above 140/90 mmHg) and appearance of protein in the urine (>300 mg in a 24-hour collection) provides the clinician with objective information on the origin of the observed signs.
As long ago as 2000, the NIH (National Institutes of Health) working group on high blood pressure in pregnancy reported that, while 15 to 20% of pregnant women will become hypertensive, only a small proportion of them will actually develop pre-eclampsia.3 Similarly, proteinuria is not always indicative of pre-eclampsia,4 and its absence is increasingly recognized as not necessarily excluding pre-eclampsia-like syndromes. Thus, at the point-of-care, there is a clinical tendency for “over-diagnosis” and unnecessary monitoring, with decisions based on non-specific signs with arbitrary cut-off values. Women with non-classically defined symptoms are still at risk for adverse outcomes and present a particularly challenging subset of women to diagnose.5
In addition to the poor specificity of current diagnostic markers of the disease, the tools available to measure these signs of pre-eclampsia are unreliable and non-specific. The cut-off levels set for hypertension are dependent more on historical acceptability than specificity and will inevitably lead to over-diagnosis and misaligned risk stratification. Measurement of excreted protein cannot be reliably confirmed in a one-off ambulatory or even acute care setting; 24-hour (or an appropriately timed) urine collection is necessary, but often not performed. Nevertheless, it is the outcome of these initial assessments which defines the level of risk and the extent of future surveillance. Those patients perceived as at high risk will require close monitoring as in-patients or with frequent clinic visits. Patients will be monitored for signs of deterioration by measuring maternal blood pressure and blood markers for signs of maternal organ failure. The fetus will also be monitored to identify evidence of fetal growth restriction and fetal distress secondary to hypoxia and acidosis. A decision to deliver the fetus will be based upon both maternal and fetal well-being, as well as gestational age.
A key contributor to the development of the early and more severe form of pre-eclampsia is poor placental development. Placentation occurs from about weeks 6 to 18 of pregnancy and involves remodeling of the uterine spiral arteries, which supply the blood flow to the placenta. In early onset pre-eclampsia and in placentally-mediated fetal growth restriction, remodeling of the spiral arteries partially fails. This is associated with poor invasion of extravillous trophoblasts into the underlying placental bed, a pre-requisite for normal development of the placenta and its blood supply.6 Shallow placentation allows the pregnancy to continue but at the cost of problems with fetal and maternal health in the second and third trimesters of pregnancy.
As the pregnancy progresses, and the fetus increases the demand on the available blood supply, the placental oxidative stress leads to widespread activation and dysfunction of the maternal vascular endothelium.
This generalized maternal endothelial dysfunction is the cause of the downstream features of the disease which are characteristic of, but not specific to, the condition. For example, proteinuria in pre-eclampsia is associated with a specific endothelial renal lesion, glomerular endotheliosis, and the hypertension is thought to be a secondary effect to diffuse endothelial dysfunction. However, neither of these signs is specific to the underlying pathophysiology.
PlGF belongs to the vascular endothelial growth factor (VEGF) family and represents a key regulator of angiogenic events in pathological conditions.7 PlGF exerts its biological function through the binding and activation of the receptor Flt-1. In pre-eclampsia, it is thought that endothelial dysfunction leads to an increased level of a circulating decoy receptor, known as soluble Flt-1, (sFlt-1), a soluble receptor for both VEGF-A and PlGF.8
Circulating levels of sFlt-1 are increased in pre-eclampsia and particularly the early onset form of the disease, resulting in reduced levels of free VEGF-A and PlGF in the maternal circulation. Thus, the endothelial dysfunction observed in pre-eclampsia may be due to excess neutralization of VEGF-A and PlGF by circulating sFlt-1.
Levine et al showed that in a normal pregnancy PlGF levels track the development of the placenta, peaking at about 32 weeks when the placenta is fully developed and then declining until delivery. However, in pre-eclampsia, this rise and fall is considerably lower throughout the pregnancy, and levels are strikingly lower when the condition presents clinically.8
A newly published international study has confirmed that PlGF can be reliably and quickly measured within 15 minutes using the Alere Triage System.9 This evaluation found that the Alere Triage PLGF Test performed well in comparison to diagnoses made by Consultant Obstetric Clinicians involved in academic research in this area. It also established this new test for early onset pre-eclampsia as having a high clinical sensitivity and supported its reliability in identifying the disease.
“Alere Triage PLGF has the potential to remove the uncertainty in clinical decision-making at the point of care, without delay, in women presenting with signs and symptoms of pre-eclampsia before 35 weeks,” note the authors of this study. “It is in these pregnancies where a novel marker that directly correlates with the underlying pathology might have greatest clinical application.”9
These experts further conclude that because the test has “such a high sensitivity and specificity, its application in the diagnosis of early onset pre-eclampsia should significantly aid diagnosis alongside current methods.”9 Professor Christopher Redman, Emeritus Professor of Obstetrics at John Radcliffe Hospital, Oxford, concludes that “a reliable and specific test that aids in the diagnosis of those aspects of the pre-eclampsia syndrome that jeopardize the safety of mother and/or unborn baby would be invaluable.”
The Alere Triage® PlGF test is available only in certain locations and has not been approved by the FDA for commercialization in the U.S.
Louise Kenny, MBChB (hons), MRCOG, PhD, is Professor of Obstetrics at University College Cork and a consultant obstetrician and gynecologist at Cork University Maternity Hospital.
Dr. Kenny has a longstanding clinical and research interest in uteroplacental insufficiency, adverse pregnancy outcome, and pregnancy loss.
References
- World Health Organization. World health report: make every mother and child count. 2005.
- Maynard S, et al. Ann Rev Med. 2008;59:61-78.
- Roberts JM, et al. Hypertension. 2003;41:437-445.
- Douglas KA, Redman C. BMJ. 1997;309:1395-1400.
- Benton S, et al. AJOG. 2011;doi:10.1016/j.ajog.2011.06.058.
- Redman C, et al. Placenta. Supplement A, Trophoblast Research. 2003;Vol.17, S21-S27.
- Cao Y, et al. Science Signaling. 2009;Vol. 2, Issue 59 re1.
- Levine RJ, et al. New England Journal of Medicine. 2004;12:672-683.
- Knudsen UB, et al. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health. 2012;2:8-15.
