Impaired fetal brain growth and neurodevelopmental deficits at 2 years: deep phenotyping of maternal–fetal pathophysiology

Background Impaired fetal cranial growth trajectories, diverging before 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 we monitored the infants' health, growth, and development from birth to age 2 years to identify growth and development phenotypes. We grouped the observed cranial growth into five distinct phenotypes: median growth tracking (MGT; steady growth throughout pregnancy, close to the INTERGROWTH-21st 50th centile); early faltering growth (EFG; growth faltered throughout pregnancy); late faltering growth (LFG; higher but parallel growth to the MGT trajectory through the second trimester, with growth starting to falter by the early third trimester); accelerating growth (AG; growth close to the 50th centile through the second trimester followed by accelerated growth during the third trimester); and late median growth tracking (LMG; accelerated growth post 15 weeks' gestation, followed by a normalising growth rate in the third trimester). These phenotypes were associated with distinct growth, vision, and developmental outcomes at age 2 years. 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. In this study, we did placental histopathology, and genetic, epigenetic, and metabolomic wide association studies to better understand the pathophysiology of fetal phenotypes that manifest distinct characteristics in childhood. Findings We first explored the association between the previously identified fetal head circumference phenotypes, as described above, and placental physiology, metabolomic, and genetic outputs. The most severe growth and development deficiency was observed in the cranial EFG phenotype, which demonstrated fetal growth restriction before 25 weeks' gestation. It was associated with reduced umbilical cord blood flow and an increased maternal vascular malperfusion compared with the other four phenotypes. The EFG phenotype had a phospholipid signature with odds ratios (ORs) of 1·42 (95% CI 1·32–1·51) for phosphatidylcholine (PC) and of 1·41 (1·32–1·50) for ether lipids PC (O-) species associated with the EFG group in maternal samples at less than 16 weeks' gestation rather than plasmologens; there were also positive ORs for early maternal oxidised PC signatures (OR 1·41; 1·32–1·50), in a reciprocal pattern with the AG phenotype. There was a consistent epigenetic hypermethylation pattern in umbilical cord samples of peroxisomal genes PEX 10 and 14 and of genes encoding enzymes within the plasmalogen pathway (FASN, GNPAT, and PEDS 1); hypomethylation of the FAR1 gene (encoding the rate-limiting enzyme); and epigenetic hypermethylation of CPT1 and ACSL1 suggestive of impaired fetal fatty acid β-oxidation. Interpretation We 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. These mechanisms appear to exert cumulative downstream growth and developmental influences into childhood.