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Urinary Placental Growth Factor and Risk of Preeclampsia
Richard J. Levine, MD, MPH;
Ravi Thadhani, MD, MPH;
Cong Qian, MS;
Chun Lam, MD;
Kee-Hak Lim, MD;
Kai F. Yu, PhD;
Anastasia L. Blink, MPH;
Benjamin P. Sachs, MD, DPH;
Franklin H. Epstein, MD;
Baha M. Sibai, MD;
Vikas P. Sukhatme, MD, PhD;
S. Ananth Karumanchi, MD
JAMA. 2005;293:77-85.
Context Preeclampsia may be caused by an imbalance of angiogenic factors. We previously demonstrated that high serum levels of soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and low levels of placental growth factor (PlGF), a proangiogenic protein, predict subsequent development of preeclampsia. In the absence of glomerular disease leading to proteinuria, sFlt1 is too large a molecule to be filtered into the urine, while PlGF is readily filtered.
Objective To test the hypothesis that urinary PlGF is reduced prior to onset of hypertension and proteinuria and that this reduction predicts preeclampsia.
Design, Setting, and Patients Nested case-control study within the Calcium for Preeclampsia Prevention trial of healthy nulliparous women enrolled at 5 US university medical centers during 1992-1995. Each woman with preeclampsia was matched to 1 normotensive control by enrollment site, gestational age at collection of the first serum specimen, and sample storage time at –70°C. One hundred twenty pairs of women were randomly chosen for analysis of serum and urine specimens obtained before labor.
Main Outcome Measure Cross-sectional urinary PlGF concentrations, before and after normalization for urinary creatinine.
Results Among normotensive controls, urinary PlGF increased during the first 2 trimesters, peaked at 29 to 32 weeks, and decreased thereafter. Among cases, before onset of preeclampsia the pattern of urinary PlGF was similar, but levels were significantly reduced beginning at 25 to 28 weeks. There were particularly large differences between controls and cases of preeclampsia with subsequent early onset of the disease or small-for-gestational-age infants. After onset of clinical disease, mean urinary PlGF in women with preeclampsia was 32 pg/mL, compared with 234 pg/mL in controls with fetuses of similar gestational age (P<.001). The adjusted odds ratio for the risk of preeclampsia to begin before 37 weeks of gestation for specimens obtained at 21 to 32 weeks, which were in the lowest quartile of control PlGF concentrations (<118 pg/mL), compared with all other quartiles, was 22.5 (95% confidence interval, 7.4-67.8).
Conclusion Decreased urinary PlGF at mid gestation is strongly associated with subsequent early development of preeclampsia.
Author Affiliations: Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Department of Health and Human Services, Bethesda, Md (Drs Levine and Yu and Ms Blink); Departments of Medicine and Obstetrics, Massachusetts General Hospital, and Harvard Medical School (Dr Thadhani), Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School (Drs Lam, Epstein, Sukhatme, and Karumanchi), and Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, and Harvard School of Public Health (Drs Lim, Sachs, and Karumanchi), Boston, Mass; Allied Technology Group, Rockville, Md (Mr Qian); and Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio (Dr Sibai).
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