In utero physiology: role of folic acid in nutrient delivery and fetal development.

Despite the isolation of placental folate receptors 25 y ago and progress in defining the mechanism of folate delivery, considerable gaps remain in the literature for each level of the maternal-placental-fetal unit. Although a critical role of placental folate receptors in maternal-to-fetal folate transport was shown by use of the isolated perfused-placental cotyledon model a decade ago, in vivo confirmation is still needed. Knockout of folate receptors in mice, and knock-down of folate receptors by delivery of antisense oligonucleotides at gestation day 8 or antibodies to folate receptor, results in profound developmental abnormalities in the fetus, ranging from neural tube defects to neurocristopathies such as cleft-lip and cleft-palate, cardiac septal defects, and eye defects. These abnormalities can be prevented by ensuring the entry of folate into cells via alternative pathways. Controlled dietary folate restriction studies also identified adverse effects on reproductive performance, implantation, and fetal growth and other subtler (microscopic) defects in murine fetal development. Longitudinal follow-up showed that gestational folate deficiency results in behavioral changes-an anxiety phenotype-during adulthood in these mice, which supports the Barker hypothesis. The extent to which these findings are relevant to humans is unclear, however. Nevertheless, the high incidence of neural tube defects among North Indian women, who chronically subsist on one-third to one-half of the optimum folate needed to prevent birth defects, underscores the magnitude of the public health problem and emphasizes the urgent challenge to define the most efficient way to ensure adequate dietary folate for hundreds of millions of such women at risk in developing countries.