Placental dysfunction is associated with altered microRNA expression in pregnant women with low folate status

Scope: Low maternal folate status during pregnancy increases the risk of delivering small for gestational age (SGA) infants, but the mechanistic link between maternal folate status, SGA and placental dysfunction is unknown. microRNAs (miRNA) are altered in pregnancy pathologies and by folate in other systems. We hypothesized low maternal folate status causes placental dysfunction, mediated by altered miRNA expression. Methods and results: A prospective observational study recruited pregnant adolescents, and assessed third trimester folate status and placental function. miRNA array, QPCR and bioinformatics identified placental miRNAs and target genes. Low maternal folate status is associated with higher incidence of SGA infants (28% vs. 13%, p<0.05) and placental dysfunction, including elevated trophoblast proliferation and apoptosis (p<0.001), reduced amino acid transport (p<0.01) and altered placental hormones (PAPP-A, progesterone, hPL). miR-222-3p, miR-141-3p and miR-34b-5p were upregulated by low folate status (p<0.05). Bioinformatics predicted a gene network regulating cell turnover. QPCR demonstrated key genes in this network (ZEB2, MYC and CDK6) were reduced (p<0.05) in placentas with low maternal folate status. Conclusions: This study supports that placental dysfunction contributes to impaired fetal growth in women with low folate status, and suggests altered placental expression of folate-sensitive miRNAs and target genes as a mechanistic link.