Circulating angiogenic factors and the risk of preeclampsia.

BACKGROUND The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascular endothelial growth factor (VEGF), may have a pathogenic role. METHODS We performed a nested case-control study within the Calcium for Preeclampsia Prevention trial, which involved healthy nulliparous women. Each woman with preeclampsia was matched to one normotensive control. A total of 120 pairs of women were randomly chosen. Serum concentrations of angiogenic factors (total sFlt-1, free PlGF, and free VEGF) were measured throughout pregnancy; there were a total of 655 serum specimens. The data were analyzed cross-sectionally within intervals of gestational age and according to the time before the onset of preeclampsia. RESULTS During the last two months of pregnancy in the normotensive controls, the level of sFlt-1 increased and the level of PlGF decreased. These changes occurred earlier and were more pronounced in the women in whom preeclampsia later developed. The sFlt-1 level increased beginning approximately five weeks before the onset of preeclampsia. At the onset of clinical disease, the mean serum level in the women with preeclampsia was 4382 pg per milliliter, as compared with 1643 pg per milliliter in controls with fetuses of similar gestational age (P<0.001). The PlGF levels were significantly lower in the women who later had preeclampsia than in the controls beginning at 13 to 16 weeks of gestation (mean, 90 pg per milliliter vs. 142 pg per milliliter, P=0.01), with the greatest difference occurring during the weeks before the onset of preeclampsia, coincident with the increase in the sFlt-1 level. Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeclampsia was associated with a small-for-gestational-age infant. CONCLUSIONS Increased levels of sFlt-1 and reduced levels of PlGF predict the subsequent development of preeclampsia.

[1]  M. Paech,et al.  Postcesarean Analgesia with Spinal Morphine, Clonidine, or Their Combination , 2004, Anesthesia and analgesia.

[2]  Robert N. Taylor,et al.  First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. , 2004, The Journal of clinical endocrinology and metabolism.

[3]  J. Foidart,et al.  Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. , 2003, The Journal of clinical endocrinology and metabolism.

[4]  I. Ingemarsson,et al.  Glomerular endotheliosis in normal pregnancy and pre‐eclampsia , 2003, BJOG : an international journal of obstetrics and gynaecology.

[5]  Seth M Steinberg,et al.  A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. , 2003, The New England journal of medicine.

[6]  D. Saller,et al.  Second‐Trimester Maternal Serum Placental Growth Factor and Vascular Endothelial Growth Factor for Predicting Severe, Early‐Onset Preeclampsia , 2003, Obstetrics and gynecology.

[7]  Y. Taketani,et al.  Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. , 2003, The Journal of clinical endocrinology and metabolism.

[8]  D. Mukherjea,et al.  Expression and Function of Placenta Growth Factor: Implications for Abnormal Placentation , 2003, The Journal of the Society for Gynecologic Investigation: JSGI.

[9]  T. Libermann,et al.  Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia , 2003 .

[10]  J. Haigh,et al.  Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. , 2003, The Journal of clinical investigation.

[11]  Robert N. Taylor,et al.  Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies. , 2003, American journal of obstetrics and gynecology.

[12]  F. Kabbinavar,et al.  Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  K. Alitalo,et al.  Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. , 2002, The American journal of pathology.

[14]  C. Oudejans,et al.  Plasma Placenta Growth Factor Levels in Midtrimester Pregnancies , 2001, Obstetrics and gynecology.

[15]  S. Chow,et al.  Decreased Maternal Serum Placenta Growth Factor in Early Second Trimester and Preeclampsia , 2001, Obstetrics and gynecology.

[16]  H. Ho,et al.  Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. , 2001, American journal of obstetrics and gynecology.

[17]  Jm Roberts,et al.  Pathogenesis and genetics of pre-eclampsia , 2001, The Lancet.

[18]  James J. Walker,et al.  Pre-eclampsia , 2000, The Lancet.

[19]  S. Gardiner,et al.  Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia , 2000, Nature.

[20]  T. H. Wang,et al.  Preeclampsia is associated with reduced serum levels of placenta growth factor. , 1998, American journal of obstetrics and gynecology.

[21]  F. Ghezzi,et al.  Disturbed Feto‐Maternal Cell Traffic in Preeclampsia , 1998, Obstetrics and gynecology.

[22]  J. Cutler,et al.  Trial of calcium to prevent preeclampsia. , 1997, The New England journal of medicine.

[23]  C. Damsky,et al.  Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular adhesion phenotype. One cause of defective endovascular invasion in this syndrome? , 1997, The Journal of clinical investigation.

[24]  L. Poston,et al.  Human placental syncytiotrophoblast microvillous membranes impair maternal vascular endothelial function , 1997, British journal of obstetrics and gynaecology.

[25]  R. Dersimonian,et al.  Trial of Calcium for Preeclampsia Prevention (CPEP): rationale, design, and methods. , 1996, Controlled clinical trials.

[26]  W. Bowes,et al.  Birth‐Weight‐for‐Gestational‐Age Patterns by Race, Sex, and Parity in the United States Population , 1995, Obstetrics and gynecology.