Valproic acid, a drug commonly used to treat seizures and other psychiatric 
disorders, causes neural tube defects (NTDs) in exposed fetuses at a rate 20 
times higher than in the general population. Failure of the neural tube to close 
during development results in exencephaly or anencephaly, as well as spina 
bifida. In mice, nonspecific activation of the maternal immune system can reduce 
fetal abnormalities caused by diverse etiologies, including diabetes-induced 
NTDs. We hypothesized that nonspecific activation of the maternal immune system 
with interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating 
factor (GM-CSF) could reduce valproic acid (VA)-induced defects as well. Female 
CD-1 mice were given immune stimulant prebreeding: either IFN-gamma or GM-CSF. 
Approximately half of the control and immune-stimulated pregnant females were 
then exposed to 500 mg/kg VA on the morning of gestational day 8. The incidence 
of developmental defects was determined on gestational day 17 from at least 
eight litters in each of the following treatment groups: control, VA only, 
IFN-gamma only, IFN-gamma+VA, GM-CSF only, and GM-CSF+VA. The incidence of NTDs 
was 18% in fetuses exposed to VA alone, compared to 3.7% and 2.9% in fetuses 
exposed to IFN-gamma+VA, or GM-CSF+VA respectively. Ocular defects were also 
significantly reduced from 28.0% in VA exposed groups to 9.8% in IFN-gamma+VA 
and 12.5% in GM-CSF+VA groups. The mechanisms by which maternal immune 
stimulation prevents birth defects remain unclear, but may involve maternal or 
fetal production of cytokines or growth factors which protect the fetus from the 
dysregulatory effects of teratogens.