The effects of therapeutic drugs on brain development in infants with fetal growth restriction

Fetal growth restriction (FGR) refers to a fetus that does not reach expected full growth, secondary to placental dysfunction and reduced oxygen and nutrient availability. FGR is associated with mortality or morbidity, including suboptimal brain development. Infants with FGR have reduced brain volume and diffuse, multicellular neuropathology that mediates neurological dysfunctions. In utero, reduced fetal oxygenation initiates a haemodynamic response to preferentially direct cardiac output towards the brain via cerebral vasodilatation, termed 'brain sparing'. This brain sparing response is sustained in fetuses with FGR, contributing to altered development of cerebral blood vessels and increased permeability of the blood-brain-barrier (BBB). Antenatal and postnatal drug therapies are being pursued for FGR, including treatments to improve fetal growth and/or brain development. Given that drug access into the fetal brain may be heightened in FGR as a result of BBB dysfunction, the implications for short- and long-term brain growth and health should be considered. Here, we review evidence from experimental studies administering drug therapies antenatally or postnatally for FGR, and assess effects on the developing brain. We will describe the status for the antenatal use of magnesium sulphate for neuroprotection associated with preterm birth, sildenafil citrate to improve fetal growth and melatonin as a neuroprotectant in FGR, together with the postnatal administration of the neuroprotective agents ibuprofen, nanoparticles or cell therapies. Understanding drug treatment effects on the developing brain is critical, and this is particularly the case for FGR, where new therapies are needed but the implications for brain structure and function must be characterised.