Background Impaired fetal cranial growth trajectories, diverging < 20 weeks’ gestation, are associated with growth, vision and neurodevelopment deficits at age 2 years. We aimed to understand the maternal-fetal pathophysiological processes underlying childhood developmental deficiencies. Methods Between 2012 and 2019, the INTERBIO-21st Fetal Study enrolled 3598 pregnant women who initiated antenatal care before 14 weeks’ gestation. We prospectively measured fetal cranial and linear growth, and brain volume, and monitored the infants’ health, growth and development from birth to age 2 years to identify growth and development phenotypes. We also prospectively and concomitantly obtained early pregnancy maternal blood samples, measured maternal-fetal placental blood flow, and collected placental tissue and umbilical cord blood samples at birth. We conducted placental histopathology, genetic, epigenetic and metabolomic wide association studies to better understand the pathophysiology of fetal phenotypes that manifest distinct characteristics in childhood. Findings We identified five phenotypes using fetal cranial size, femur length and brain volume data complemented with childhood growth, vision and development data. The most severe growth and development deficiency was observed in the cranial early faltering growth phenotype (EFG) that demonstrated fetal growth restriction <25 weeks’ gestation associated with reduced umbilical cord blood flow and an increased maternal vascular malperfusion as compared with the other four phenotypes. The EFG phenotype had a phospholipid signature with odds ratios for phosphatidylcholine (PC) and ether lipids PC (O-) species associated with the EFG group in maternal samples at <16 weeks’ gestation; there were also positive odds ratios for early maternal oxidised PC signatures, in a reciprocal pattern with the accelerating growth phenotype. There was a consistent epigenetic hypermethylation pattern of a) peroxisomal genes PEX 10 and 14; b) genes encoding enzymes within the plasmalogen pathway: FASN, GNPAT and PEDS 1; c) hypomethylation of the FAR1 gene (encoding the rate-limiting enzyme); and d) epigenetic hypermethylation of CPT1 and ACSL1 suggestive of impaired fetal fatty acid β-oxidation. Interpretation We have provided placental, epigenetic and molecular characterisation of the pathophysiology underlying early fetal cranial and brain volume impaired growth, with consistency between epigenetic and metabolomic results. It is likely that these mechanisms exert cumulative downstream growth and developmental influences into childhood.