Abstract
Background: Preeclampsia remains a leading contributor to maternal and perinatal morbidity and mortality, with a disproportionate burden in low- and middle-income countries. Conventional antenatal surveillance identifies the disorder only once hypertension and proteinuria are established. Placental growth factor (PlGF), a pro-angiogenic mediator, and soluble fms-like tyrosine kinase-1 (sFlt-1), its anti-angiogenic antagonist, diverge several weeks before clinical presentation. This study evaluated maternal serum PlGF, sFlt-1 and the sFlt-1/PlGF ratio, measured in the Antenatal period, as predictors of subsequent preeclampsia. Methods: A Multicenter prospective observational study was conducted over 18 months with a common study format. In total, 135 women with singleton pregnancies were recruited consecutively, 87 at 11-13 weeks and 48 at 20-24 weeks of gestation, and followed to delivery. PlGF and sFlt-1 were measured by automated electrochemiluminescence immunoassay and the ratio derived for each participant. Clinical risk stratification was performed using maternal age, body mass index, previous history of preeclampsia, mean arterial pressure (MAP), PlGF MoM, serum sFlt-1 concentration and the sFlt-1/PlGF ratio. The primary outcome was preeclampsia diagnosed according to the American College of Obstetricians and Gynecologists (ACOG) criteria. Diagnostic indices were calculated from contingency tables with Wilson binomial confidence intervals, and the area under the receiver operating characteristic (ROC) curve (AUC) was calculated using the trapezoidal method for PlGF, sFlt-1, and the sFlt-1/PlGF ratio. Results: Preeclampsia developed in 18 of 135 women (13.3%); 5 (3.7%) early-onset and 13 (9.6%) late-onset. Affected women had lower mean PlGF (102.6 ± 34.5 vs 268.8 ± 62.4 pg/mL), higher sFlt-1 (3248 ± 642 vs 1462 ± 385 pg/mL) and a higher
ratio (39.8 ± 11.6 vs 8.9 ± 3.5); all p < 0.001. At a cut-off of ≥ 38 the ratio gave a sensitivity of 94.4% (95% CI 74.2-99.0), specificity 91.5% (95% CI 85.0-95.3), positive predictive value 63.0%, negative predictive value 99.1% and accuracy 91.9%, exceeding either analyte alone (both 88.9% sensitivity). The clinical risk stratification yielded an AUC of 0.903 (95% CI 0.807-0.999); classifying only the high-risk stratum as test-positive gave a sensitivity of 77.8% and specificity of 92.3%, with preeclampsia in 14 of 23 high-risk (60.9%) and 1 of 83 low-risk women (1.2%). Conclusion: Maternal serum PlGF, sFlt-1, and particularly the sFlt-1/PlGF ratio were effective in identifying women at risk of developing preeclampsia during early pregnancy. The sFlt-1/PlGF ratio demonstrated the highest diagnostic performance, with a negative predictive value of 99.1%, making it especially useful for confidently identifying women who are unlikely to develop preeclampsia. This may help clinicians focus closer surveillance and preventive interventions, including aspirin prophylaxis, on women at higher risk.