The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome

Abstract

Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions.

Figure 1. The characteristics, cause, diagnostic use and neuropathology associated with brain sparing in human infants and children

Brain sparing occurs as an adaptive cardiovascular response to fetal hypoxia and may protect against worse brain damage, but does not spare the brain from injury.

Figure 2. Deficits in brain structure and function commonly observed in FGR offspring

Listed at the top are structural deficits within the total brain, grey matter and white matter of FGR human infants. The bottom describes deficits in motor function, cognition and learning, and behaviour that have been observed in children that were FGR.

Figure 3. A summary of human and animal experimental results showing the principal adverse mechanisms contributing to grey matter and white matter pathology in FGR

Chronic fetal hypoxia, hypoglycaemia, oxidative stress and inflammation are the likely causes of adverse neurodevelopment. Gross changes in brain volume are observed in both grey and white matter of the FGR brain, contributed by cell loss and sparsity of neuropil layers with altered axons, dendrites, synapses and myelination.