Maternal Circulating Angiogenic Biomarkers for Predicting Fetal Growth Restriction and Small-for-Gestational-Age Birth Without Preeclampsia

Maternal circulating angiogenic factors are established biomarkers in preeclampsia, but their early profiles in fetal growth impairment without preeclampsia remain unclear. We quantitatively synthesized data from observational studies measuring maternal serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), or their ratio before 29 weeks and before clinical recognition of growth impairment in singleton pregnancies without preeclampsia, subsequently classified as fetal growth restriction (FGR), small for gestational age (SGA), or unaffected. PubMed, Embase, and the Cochrane Library were searched through April 2026; 22 studies were included. In random-effects meta-analysis, PlGF was lower in affected pregnancies (standardized mean difference [SMD] −0.38; 95% CI −0.63 to −0.13; I2 = 92.0%; 19 studies), whereas sFlt-1 did not differ (SMD 0.03; 95% CI −0.27 to 0.34; I2 = 79.5%; 12 studies) and the ratio was higher in the primary analysis (SMD 0.39; 95% CI 0.08 to 0.70; I2 = 80.0%; seven studies). This pattern suggests that the ratio signal was influenced largely by lower PlGF. Bivariate analysis of five PlGF accuracy studies yielded a summary sensitivity of 0.29 and specificity of 0.86. Despite substantial heterogeneity, reduced PlGF was the most consistent early angiogenic feature in pregnancies subsequently classified as FGR/SGA without preeclampsia. Its low sensitivity does not support its use as a stand-alone screening test, but these findings warrant further evaluation of PlGF within multimarker prediction models.