Second-Trimester Maternal Serum Placental Growth Factor and Vascular Endothelial Growth Factor for Predicting Severe, Early-Onset Preeclampsia Bruno M. Polliotti, PhD, A. Gordon Fry, MD, Devereux N. Saller, Jr, MD, Robert A. Mooney, PhD, Christopher Cox, PhD, and Richard K. Miller, PhD OBJECTIVE: To determine whether alterations in second- trimester maternal serum cytokine concentrations can identify women at risk for developing severe, early-onset preeclampsia. METHODS: Patients with severe preeclampsia requiring de- livery prior to 34 weeks (n  20) were each matched by gestational age, gravidity, parity, and sample freezing time with three healthy controls who delivered at term (n  60). By using second-trimester maternal sera originally col- lected for fetal aneuploidy screening, the concentrations of placental growth factor, vascular endothelial growth fac- tor, granulocyte colony-stimulating factor, endothelin-1, and human chorionic gonadotropin were compared be- tween patients and controls. Logistic regression analysis was used to estimate odds ratios for high versus low (me- dian split) cytokine concentrations with respect to the de- velopment of severe, early-onset preeclampsia. Receiver operating characteristic (ROC) curves based on a second logistic regression, using actual cytokine values, were plot- ted to illustrate reciprocal impact on sensitivity and speci- ficity. RESULTS: Placental growth factor and vascular endothelial growth factor levels were significantly lower in patients than in controls. No significant differences were observed for the other cytokines. The odds ratios (with 95% confi- dence intervals) were 15.54 (3.29, 73.40) for vascular endo- thelial growth factor and 4.20 (1.35, 13.06) for placental growth factor. Receiver operating characteristic analysis of placental growth factor and vascular endothelial growth factor confirmed that both were useful in discriminating between patients and controls. Models combining both vascular endothelial growth factor and placental growth factor provided the best performance for identifying pa- tients at risk for developing severe, early-onset preeclamp- sia, according to both odds ratios and ROC analyses. CONCLUSION: Combined analysis of placental growth fac- tor and vascular endothelial growth factor is potentially useful as a tool for early identification of patients at risk for developing severe, early-onset preeclampsia. (Obstet Gy- necol 2003;101:1266 –74. © 2003 by The American Col- lege of Obstetricians and Gynecologists.) Despite decades of research, the pathogenesis of pre- eclampsia remains poorly understood, and attempts to identify early markers of the disorder have been disap- pointing. Biochemical markers that could predict the subsequent onset of preeclampsia before maternal clini- cal manifestations become apparent would be advanta- geous because they may elucidate the pathophysiologic mechanisms of the disorder and identify specific patients early in pregnancy who are at high risk for developing preeclampsia. 1,2 Once identified, these women may ben- efit from targeted therapy that could prevent or diminish the effects of the disease. Because the preponderance of maternal and perinatal morbidity and mortality occurs when disease develops at an early gestational age, 3,4 early prediction of preeclampsia would have the greatest potential to favorably impact maternal and perinatal outcome if it can identify the subset of women destined to develop severe, early-onset disease. The association between abnormal placentation and preeclampsia is well known and is thought to involve inadequate trophoblast invasion of maternal spiral arter- ies during early gestation. 5 Evidence of placental de- rangement may be reflected in maternal circulation by alterations in the concentration of biochemical markers involved in the process of normal placental develop- ment. Placental growth factor and vascular endothelial growth factor, members of the platelet-derived growth factor family, are both important local mediators of angiogenesis in the human placenta 6 and can be isolated from the maternal circulation. Changes in the circulating concentrations of these factors may represent abnormal From the Departments of Obstetrics and Gynecology, Pathology, and Biostatistics, University of Rochester Medical Center, Rochester, New York. DNS is currently affiliated with the Department of Obstetrics and Gynecology, University of West Virginia, Robert C. Byrd Health Science Center, Morgantown, West Virginia. 1266 VOL. 101, NO. 6, JUNE 2003 0029-7844/03/$30.00 © 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier. doi:10.1016/S0029-7844(03)00338-7