Examining the Evidence
Serum levels of 2 peptides help predict preeclampsia
To explore the role of angiogenic factors in preeclampsia—specifically, whether circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PIGF) and vascular endothelial growth factor (VEGF), plays a pathogenic role.
Increased levels of sFlt-1 and reduced levels of PIGF predicted the subsequent development of preeclampsia.
In this nested case-control study involving 120 pairs of women, researchers determined serum levels of 3 peptides known to be involved in modulating angiogenesis: sFlt-1, PIGF, and VEGF. They found that levels of sFLT-1 increased and PIGF decreased with advancing gestation in normotensive control pregnancies. These changes occurred earlier in gestation and to a more exaggerated extent among the cases that went on to develop preeclampsia. VEGF levels remained low throughout pregnancy, but did differ between cases and controls.
Levels of sFlt-1 increased 5 weeks prior to the development of clinical preeclampsia, while the decrease in PIGF could be noted in the middle trimester.
Strengths and weaknesses. The analytic, statistical, and methodological aspects of this study are sound. However, because of the nested, case-control design, it is impossible to calculate sensitivity, specificity, and positive and negative predictive values for any of these analytes. As an accompanying editorial notes, not all women with abnormal changes in sFlt-1 and PIGF went on to develop preeclampsia.1 A larger, prospective trial is needed to establish the clinical utility of these markers in predicting preeclampsia.
Endothelial dysfunction has long been a hallmark of preeclampsia, and various associations or explanations have been proposed (Savvidou2). Levine et al provide a framework that fits the symptoms of edema, hypertension, proteinuria, and resultant end-organ dysfunction into a paradigm that is useful in its organization, ability to generate testable hypotheses, and suggestion of potential therapy other than delivery.
Unanswered questions. This research adds to our understanding of how the pathology of preeclampsia propagates and becomes clinically recognizable. It offers less insight into the equally interesting question of what causes the initial perturbation that goes on to cause preeclampsia. Another important question is whether we should be developing a screening test for a condition that can as yet be cured only by delivery.
One might argue that knowing who is at increased risk would allow closer fetal testing, maternal observation, and an opportunity for earlier intervention in the form of antenatal steroid administration or delivery. However, these may be relatively small advantages over conventional prenatal screening, given the risks of increased maternal anxiety and the additional burden on a system of care that is already financially stressed and legally embattled.
This study is the latest of several publications3-5 that suggest we may finally be moving toward a more complete understanding of preeclampsia. It should be of interest to all obstetricians because it adds to general, specialty-specific background knowledge and holds promise as a source of therapy. These observations also raise the possibility of a predictive test for preeclampsia that might be applied before clinical symptomatology appears.
1. Solomon CG, Seely EW. Preeclampsia—searching for the cause. N Engl J Med. 2004;350:641-642.
2. Savvidou MD, Hingorani AD, Tsikas D, Frolich JC, Vallance P, Nicolaides KH. Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop preeclampsia. Lancet. 2003;361:1511-1517.
3. Maynard SE, Min J-Y, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649-658.
4. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest. 2003;111:707-716.
5. Koga K, Osuga Y, Yoshino O, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGEFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab. 2003;88:2348-2351.