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.
Levine
Richard J
RJ
Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Department of Health and Human Services, Bethesda, MD 20892, USA. levinerj@mail.nih.gov
Maynard
Sharon E
SE
Qian
Cong
C
Lim
Kee-Hak
KH
England
Lucinda J
LJ
Yu
Kai F
KF
Schisterman
Enrique F
EF
Thadhani
Ravi
R
Sachs
Benjamin P
BP
Epstein
Franklin H
FH
Sibai
Baha M
BM
Sukhatme
Vikas P
VP
Karumanchi
S Ananth
SA
D000328:Adult; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D005260:Female; D005865:Gestational Age; D006801:Humans; D016015:Logistic Models; D016017:Odds Ratio; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood* / Q000175:diagnosis; D011247:Pregnancy / Q000097:blood*; D011257:Pregnancy Proteins / Q000097:blood*; D012307:Risk Factors; D018709:Statistics, Nonparametric; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
D015415:Biomarkers; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1