Maternal Angiogenic Profiles in Preeclampsia-Associated Versus Isolated Fetal Growth Restriction or Small-for-Gestational-Age Pregnancies: A Systematic Review and Meta-Analysis

Maternal angiogenic imbalance is a hallmark of preeclampsia (PE), but whether it differs between PE-associated and isolated fetal growth restriction (FGR)/small-for-gestational-age (SGA) pregnancies is unclear, particularly before clinical recognition. We searched PubMed, Embase, and CENTRAL for observational studies comparing maternal soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), or their ratio between these phenotypes. Analyses were stratified by sampling context and pooled as Hedges’ g using random-effects models. Twenty-three studies (630 PE-associated, 1476 isolated FGR/SGA pregnancies) were included. After clinical recognition, PE-associated FGR/SGA showed a higher sFlt-1/PlGF ratio (g = 1.04, 95% CI 0.51 to 1.57), higher sFlt-1 (1.05, 0.73 to 1.38), and lower PlGF (−0.60, −0.82 to −0.38) than isolated FGR/SGA; differences in the same directions were present before clinical recognition (ratio 0.86, 0.38 to 1.33; sFlt-1 0.38, 0.12 to 0.64; PlGF −0.46, −0.77 to −0.16). The sFlt-1 difference was larger after clinical recognition in the test for subgroup differences (p = 0.002) but not in meta-regression (p = 0.064), and this between-context contrast is therefore reported as exploratory; the PlGF difference was similar in both contexts. These group-level differences do not establish individual-level prediction, discrimination or threshold performance. PE-associated and isolated FGR/SGA should therefore be distinguished in biomarker research, and angiogenic thresholds derived in suspected PE require validation before application to normotensive FGR/SGA.