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First Trimester Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 and Risk for Preeclampsia

Department of Medicine and Department of Obstetrics and Gynecology (R.T., M.W., J.E.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine and Department of Obstetrics and Gynecology (W.P.M., V.P.S., S.A.K.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215; National Institute of Child Health and Human Development (R.J.L.), Bethesda, Maryland 20892; and Department of Obstetrics, Gynecology, and Reproductive Sciences (R.N.T.), University of California, San Francisco, San Francisco, California 94143

Address all correspondence and requests for reprints to: Ravi Thadhani, M.D., M.P.H., Bullfinch 127, 55 Fruit Street, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: thadhani.r{at}mgh.harvard.edu.

An imbalance of pro- and antiangiogenic factors may lead to preeclampsia (PE). In this prospective nested case-control study, we investigated whether first trimester serum levels of placental growth factor (PlGF), a potent angiogenic factor, and its soluble inhibitor, soluble fms-like tyrosine kinase 1 (sFlt1), distinguished women who developed PE (n = 40) from those who developed gestational hypertension (n = 40), delivered a small for gestational age (SGA) newborn (n = 40), or completed a full term normal pregnancy (n = 80). Compared with controls, serum PlGF levels were lower among women who developed PE (23 ± 24 pg/ml vs. 63 ± 145 pg/ml; P < 0.01) or gestational hypertension (27 ± 19 pg/ml; P = 0.03), or who delivered a SGA newborn (21 ± 16 pg/ml; P < 0.01). In contrast, serum sFlt1 levels did not markedly differ between the groups: PE, 1048 ± 657 pg/ml; gestational hypertension, 942 ± 437 pg/ml; SGA newborns, 1011 ± 479 pg/ml; and normal controls, 973 ± 490 pg/ml. Multivariable analysis adjusting for potential confounders and serum sFlt1 levels demonstrated a 3.7-fold (95% confidence interval, 1.2–12.5) increase in risk for PE for every log unit decrease in serum levels of PlGF compared with controls. Analyses for gestational hypertension and SGA were not significant. Examined in tertiles, the risk for PE was increased 28.7-fold (95% confidence interval, 2.3–351.0) in the third (<12 pg/ml) compared with the first (>39 pg/ml) PlGF tertile. First trimester serum levels of PlGF and sFlt1 may identify women at high risk for PE.

This work was supported by National Institutes of Health Grants HD39223 (to R.T.), RR17376 (to M.W.), HL73469 (to R.N.T.), DK02825 and DK64255 (to S.A.K.); by grants from the American Heart Association (to M.W.) and the McGuirk Family Research Foundation (to R.T. and J.E.); and by the Carl Gottschalk Award from the American Society of Nephrology (to S.A.K.).

R.T., V.P.S., and S.A.K. were involved intellectually in the design of this study. R.T., M.W., and J.E. recruited all patients into the MOMS database and supervised the entire study. R.T., R.J.L., R.M.T., V.P.S., and S.A.K. performed all data analyses and interpretation of results. W.M. and S.A.K. performed all analyses of blood samples. All authors contributed to the writing of the manuscript.

Abbreviations: CI, Confidence interval; PE, preeclampsia; PlGF, placental growth factor; sFlt1, soluble fms-like tyrosine kinase 1; SGA, small for gestational age; VEGF, vascular endothelial growth factor.

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