Placental hormones, IGF-1, and early-life growth: endocrine links between birth size and infant metabolic programming-a systematic review

The purpose of this study is to systematically review human evidence linking placental hormones and IGF-1 with fetal growth, birth size, and early-life metabolic programming, and to identify disease-specific translational signals relevant to fetal growth restriction, metabolically complicated pregnancy, and extreme prematurity. A systematic review of PubMed and Scopus was performed for human studies published from January 2000 to March 2025. Eligible studies examined placental growth hormone, human placental lactogen, placental IGF-axis markers, or related stress-hormone pathways in relation to birth size, fetal or infant growth, or early metabolic outcomes. Reporting was aligned with PRISMA 2020. Risk of bias was assessed using RoB 2 for randomized trials and ROBINS-I principles for observational studies. Because of substantial clinical and methodological heterogeneity, findings were synthesized narratively. Thirty-seven included studies showed that mid-gestation placental growth hormone had the most consistent positive associations with fetal growth and birth size, whereas early placental growth hormone was less informative. Cord blood IGF-1 was the most reproducible endocrine correlate of birth length and weight. Reduced maternal or placental lactogen signals and lower placental 11β-HSD2 activity clustered with placental insufficiency and fetal growth restriction, while diabetic pregnancies showed a shift toward adiposity-related outcomes. In extreme prematurity, abrupt loss of placental endocrine support created a translational window in which rhIGF-1/rhIGFBP-3 replacement emerged as the clearest mechanism-based intervention, although current clinical evidence remains preliminary.

Placental endocrine markers should not be used as standalone screening tools. Their main value at present is mechanistic and translational: combined hormone patterns may refine biological understanding and risk stratification within defined maternal and neonatal disease frameworks, while IGF-1 replacement in extreme prematurity represents the most credible current therapeutic lead.

• Placental hormones and IGF-1 are linked with fetal growth, birth size, and neonatal metabolic adaptation, but 45 published evidence is heterogeneous and clinically fragmented.

• This systematic review organizes the human data within fetal growth restriction, diabetic/LGA pregnancy, and extreme prematurity frameworks and identifies translational signals-especially early IGF-1 replacement in extreme prematurity-rather than standalone diagnostic biomarkers.