Maternal Periconceptional Folic Acid Intake and Risk of Autism Spectrum Disorders in the CHARGE Study

Background: Folic acid supplementation can prevent 50-70 percent of neural tube defects (NTDs) and has been associated with reduced risk of neurological disorders and decreased symptoms in children with autism (AU). Genetic and metabolic differences associated with the folate pathway have also been described for parents and children with autism.

Objectives: To determine whether women who took supplements containing folic acid before and during pregnancy were less likely to deliver children who developed AU, autism spectrum disorders (ASD), or developmental delays (DD) as compared with women not taking supplements during that time period.

Methods: Within the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, cases of AU and ASD were confirmed at the UC Davis M.I.N.D. Institute clinic using the Autism Diagnostic Observation Schedules and the Autism Diagnostic Interview by staff with established reliability. The Mullen’s Scales of Early Learning and the Vineland Adaptive Behavior Scales were used to confirm DD in children. Population-based controls were selected by stratified random sampling using birth files and typical development was confirmed based on the above assessments. Intake of prenatal vitamins, multivitamins, folic acid-specific vitamins, other supplements, and cereal was collected through telephone interviews and examined for the three months before and throughout pregnancy and breastfeeding. Daily average total supplemental folic acid was quantified for each mother based on reported dose, brands, and frequency of use for each source. Logistic regression models were fit adjusting for maternal education. We estimated odds ratios (aOR) comparing affected with unaffected children for maternal folic acid intake, along with 95% confidence intervals (CI). Group differences in mean folic acid intake were assessed using Wilcoxon two-sample tests.

Results: Families of 280 TD, 300 AU, 125 ASD, and 108 DD confirmed children participated in the CHARGE study from late 2003 through September 2008. Mean maternal folic acid intake was greater for mothers of TD children than for mothers of AU and ASD children throughout the entire index period, with the greatest difference observed for the month before and the first month of pregnancy (533.7 and 626.8 mcg for mothers of AU/ASD and TD children, respectively, p=0.02). This difference was primarily due to a higher proportion of mothers of TD children consuming prenatal vitamins before and during the first month of pregnancy (aOR=0.43; CI:0.28,0.67). A dose-related trend was observed; women reporting the highest average daily intake of total folic acid during the month before and the first month of pregnancy had the lowest risk of having children diagnosed with AU/ASD (p for trend = 0.01). Mothers of DD children also had lower mean daily folic acid intake (566.2 mcg) relative to mothers of TD children, although the difference was not significant (p=0.23).

Conclusions: Folic acid supplements taken in the periconceptional period may reduce the risk of AU and ASD. The level of supplementation needed is likely influenced by the genetic background of the mother and/or child, particularly for genes within the folate and methylation pathways. Replication of these findings and further investigations of mechanisms involved are warranted.