Distinguishing Constitutionally Small Fetuses from True Fetal Growth Restriction: A Guided Systematic Review of Precision Diagnostic Frameworks Integrating Growth Trajectories

Distinguishing constitutionally small fetuses from true fetal growth restriction (FGR) remains one of the most persistent diagnostic challenges in perinatal medicine, with major implications for surveillance intensity, timing of delivery, and long-term outcomes. Although traditional definitions rely heavily on population-based percentiles, emerging evidence suggests that static size thresholds cannot reliably capture the complex biological divergence between healthy small fetuses and those affected by placental insufficiency. This systematic review synthesizes contemporary literature on precision diagnostic strategies, following PRISMA 2020 guidelines. Comprehensive searches of major databases and registers identified 1,326 records, of which 47 met criteria for full qualitative synthesis. Studies were appraised for methodological quality, risk of bias, and relevance to growth trajectory-based classification. Across the evidence base, several consistent themes emerged. Growth velocity, rather than absolute size, provides more accurate prediction of fetal compromise. Abnormal Doppler hemodynamics—particularly elevated umbilical artery pulsatility, reduced cerebroplacental ratio, and ductus venosus waveform changes—represent robust indicators of placental dysfunction. Molecular signatures, including angiogenic imbalance, oxidative stress markers, and proteomic/metabolomic alterations, further differentiate pathological FGR from constitutionally small but healthy fetuses. Integrated assessment combining serial biometry, Doppler indices, placental imaging, and biomarkers demonstrates the highest discriminatory power. The review highlights a clear shift in the field toward multimodal, precision-based diagnosis that moves beyond percentile cut-offs. Current clinical practice remains anchored to outdated definitions, despite evidence supporting dynamic, individualized growth assessment. Advancing perinatal care will require updated guidelines, broader adoption of trajectory-based tools, and coordinated research to validate multimodal diagnostic frameworks capable of earlier, more accurate identification of true FGR.