Maternal Plasma Folate, Vitamin B12 Levels and Multivitamin Supplement during Pregnancy and Risk of Autism Spectrum Disorders in the Boston Birth Cohort

Background:   The role of preconception/prenatal nutrition in the development of Autism Spectrum Disorder (ASD) is under-studied. Folate deficiency is a well-recognized risk factor for neural tubal defects.  For this reason, universal cereal grain fortification of folic acid, synthetic form of folate, has been implemented in the U.S. since 1998 and pregnant women are advised to take multivitamin supplements.  While some studies have suggested that mothers’ periconceptional multivitamin use, dietary folic acid intake and/or folic acid supplementation are associated with a decreased risk of ASD in their children, others have suggested the opposite effect.  Most previous studies were based on maternal self-report of vitamin intake. Only a few have simultaneously examined the relationships using self-report and biomarker data and inconsistencies have been reported.   Uncertainty remains whether excess folate and other B-vitamin exposure during critical gestational periods can adversely affect neurodevelopment. 

Objectives:   To understand the relationship between maternal multivitamin supplementation during pregnancy and maternal plasma biomarkers of folate and vitamin B12 measured 24-72 hours after delivery and risk of later ASD in children.   

Methods:   Data are from the Boston Birth Cohort, an ongoing longitudinal prospective birth cohort study that recruited low-income urban, primarily minority mother-offspring pairs (n=1,391) at the Boston Medical Center and followed them from birth through childhood between 1998-2013. Using electronic medical records, children ever diagnosed with autism, Asperger syndrome and/or pervasive developmental disorder not otherwise specified were categorized as having ASD (n=107); those without ASD, ADHD, intellectual and developmental disabilities constituted ‘typical’ group (n=1284). Cox proportional hazard regression was used to account for differential follow-up time and pertinent covariates were adjusted. 

Results:   Maternal multivitamin supplement of 3-5 times/week was associated with significantly lower risk of ASD in offspring across all trimesters (adjusted hazard ratio (HR): 0.33, 0.38 and 0.43 for 1^st, 2^nd and 3^rd trimesters respectively) (Table 1).  However, when maternal plasma folate and vitamin B12 levels were analyzed as exposure variables, high levels of maternal vitamin B12 (>600 pmol/L) were associated with significantly increased risk of ASD (HR: 3.01; 95% CI: 1.64 – 5.52; p value: 0.001).  High maternal folate levels  (>59 nmol/L) were also associated with increased risk of ASD (HR: 2.27; 95% CI: 1.26 – 4.09; p value: 0.007). The risk was greatest for those children whose mothers had both high plasma folate (>59 nmol/L) and vitamin B12 (>600 pmol/L) (HR: 17.59; p value: <0.001) (Table 2). 

Conclusions:   In this urban low-income minority birth cohort, we observed an elevated risk of ASD associated with high maternal plasma folate levels (>59 nmol/L), which far exceeds the excess cutoff suggested by the WHO (>45.3 nmol/L). Excess maternal vitamin B12 (>600 pmol/L) was also shown to be associated with greater ASD risk in offspring.  The risk of ASD was highest if mothers had both excess in folate and B12 levels.  Our findings warrant additional investigation and highlight the need to identify optimum prenatal folate and vitamin B12 levels that maximize health benefits, at the same time minimize the risk of excess and its associated adverse consequences such as ASD.