Phase III studies are continuing and, because of the low prevalence of multiple sclerosis in Asia, no investigational sites in that region have been included. Rates of alcohol consumption amongst women of reproductive age are steadily increasing, with almost half of all young women in the UK are reported to drink during the week and a fifth reported to binge drink. Chronic high alcohol intake during pregnancy is associated with fetal alcohol spectrum disorder, which encompasses a range of developmental problems, including characteristic facial features, altered neurodevelopment, cognitive and behavioural disabilities and fetal growth restriction. It is recognised that FASD is entirely preventable through alcohol abstinence but worldwide 30%, and up to 60%, of pregnant women consume alcohol during pregnancy.
Diagnosis of FASD is difficult due to phenotypic variation and it is often a diagnosis of exclusion. One of the most consistent features of FASD is FGR. Poor placental development is a major underlying pathology; placentas from pregnancies with FGR are lower in weight, have increased apoptosis and reduced cell proliferation and are characterised by a more superficial invasion of trophoblast into uterine spiral arteries. FGR is also associated with altered placental function, in particular reduced activity of amino acid transporters. Alcohol and its teratogenic metabolite acetaldehyde freely cross the placenta, and accumulate in fetal blood at concentrations similar to those found in maternal blood. Length of fetal exposure to alcohol is entirely dependent on maternal metabolism, which varies between women. Despite alcohol being the most common and widely available social drug, and its association with FGR, relatively little is understood regarding its effects on the developing placenta in human pregnancies, particularly in the earliest stages of pregnancy. In the mouse, continuous exposure to high levels of ethanol during pregnancy decreases fetal growth, affecting pup development and mortality. Even at moderate levels of exposure there is significant facial dysmorphia in mice. A reduction in fetal weight and neonatal growth is also observed in rats.
Placental development is significantly altered with increased placental weight in rats following chronic high ethanol liquid diet. This R428 cost increase is accompanied by trophoblast morphological irregularities and altered blood vessel development in the nutrient-exchanging labyrinth zone. In sheep on a high ethanol diet, placental transport of system A-dependent a-amino isobutyric acid is reduced. Significant reductions in system A transport is also seen in human term placental tissue, where the effect of alcohol is dose-dependent and towards chronic levels. Acetaldehyde, a metabolite of alcohol, has well established genotoxic effects in human and in animal models. After exposure to acetaldehyde, it is found is freely present in the placenta, amniotic fluid and fetal liver in rat and sheep.