Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia
Richard J. Levine, M.D., M.P.H., Chun Lam, M.D., Cong Qian, M.S., Kai F. Yu, Ph.D., Sharon E. Maynard, M.D., Benjamin P. Sachs, M.B., B.S., D.P.H., Baha M. Sibai, M.D., Franklin H. Epstein, M.D., Roberto Romero, M.D., Ravi Thadhani, M.D., M.P.H., S. Ananth Karumanchi, M.D., for the CPEP Study Group
Background Alterations in circulating soluble fms-like tyrosinekinase 1 (sFlt1), an antiangiogenic protein, and placental growthfactor (PlGF), a proangiogenic protein, appear to be involvedin the pathogenesis of preeclampsia. Since soluble endoglin,another antiangiogenic protein, acts together with sFlt1 toinduce a severe preeclampsia-like syndrome in pregnant rats,we examined whether it is associated with preeclampsia in women.
Methods We performed a nested case–control study of healthynulliparous women within the Calcium for Preeclampsia Preventiontrial. The study included all 72 women who had preterm preeclampsia(<37 weeks), as well as 480 randomly selected women —120 women with preeclampsia at term (at 37 weeks), 120 womenwith gestational hypertension, 120 normotensive women who deliveredinfants who were small for gestational age, and 120 normotensivecontrols who delivered infants who were not small for gestationalage.
Results Circulating soluble endoglin levels increased markedlybeginning 2 to 3 months before the onset of preeclampsia. Afterthe onset of clinical disease, the mean serum level in womenwith preterm preeclampsia was 46.4 ng per milliliter, as comparedwith 9.8 ng per milliliter in controls (P<0.001). The meanserum level in women with preeclampsia at term was 31.0 ng permilliliter, as compared with 13.3 ng per milliliter in controls(P<0.001). Beginning at 17 weeks through 20 weeks of gestation,soluble endoglin levels were significantly higher in women inwhom preterm preeclampsia later developed than in controls (10.2ng per milliliter vs. 5.8 ng per milliliter, P<0.001), andat 25 through 28 weeks of gestation, the levels were significantlyhigher in women in whom term preeclampsia developed than incontrols (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001).An increased level of soluble endoglin was usually accompaniedby an increased ratio of sFlt1:PlGF. The risk of preeclampsiawas greatest among women in the highest quartile of the controldistributions for both biomarkers but not for either biomarkeralone.
Conclusions Rising circulating levels of soluble endoglin andratios of sFlt1:PlGF herald the onset of preeclampsia.
Source Information
From the Division of Epidemiology, Statistics, and Prevention Research (R.J.L., K.F.Y.) and the Perinatology Research Branch (R.R.), National Institute of Child Health and Human Development, Department of Health and Human Services, Bethesda, MD; the Center for Vascular Biology, Renal and Molecular and Vascular Medicine Divisions, Departments of Medicine and Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston (C.L., B.P.S., F.H.E., S.A.K.); Allied Technology Group, Rockville, MD (C.Q.); the Department of Medicine, George Washington University School of Medicine, Washington, DC (S.E.M.); the Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati (B.M.S.); Wayne State University School of Medicine, Detroit (R.R.); and the Departments of Medicine and Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston (R.T.).
Address reprint requests to Dr. Levine at the NIH/NICHD, Bldg. 6100, Rm. 7B03, Bethesda, MD 20892, or at levinerj{at}mail.nih.gov or to Dr. Karumanchi at Beth Israel Deaconess Medical Center, 330 Brookline Ave., RW 663B, Boston, MA 02215, or at sananth{at}bidmc.harvard.edu.
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A correction has been published: N Engl J Med 2006;355(17):1840.
37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age. 
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