Sensory abnormalities in children with autism spectrum disorder

**Background:** Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social interaction and communication, with repetitive interests and activities. The World Health Organization estimates that 1 in 160 children has ASD. Folic acid (FA) supplementation is recommended at least 2 months before conception and in the first 2 months of pregnancy for neural tube defect prevention. In Brazil, mandatory FA fortification in wheat and corn flour was established in 2002. This review aimed to analyze the scientific production regarding maternal FA supplementation and its relationship with ASD.

**Methods:** This was a qualitative exploratory study of the metasynthesis type. Data searches were performed between February 2018 and February 2020 across BIREME, Virtual Health Library (VHL), and MEDLINE/PubMed databases. Inclusion criteria were original articles and systematic reviews, available in full text, free of charge, studies with human beings, published in English, Spanish, and Portuguese, addressing FA use related to ASD occurrence. Exclusion criteria included non-free publications, studies published outside 2013-2020, studies depicting ASD associated with other drugs or factors not corresponding to supplemental FA consumption, studies with animals, and those dealing with FA consumption at different periods of the periconceptional and gestational period. The search used DeCS and MeSH terms including 'autistic', 'autism', 'autism spectrum disorder', and 'folic acid'. The PRISMA-P checklist and PICO framework were used.

**Key Results:** A total of 384 articles were identified (220 from BIREME, 164 from PubMed), of which 17 were eligible. The main finding was that maternal FA supplementation in the preconception period and beginning of pregnancy has a protective effect against ASD. Schmidt (2013) reported a 40% decrease in the risk of developing ASD with preconception and early pregnancy FA use. Surén et al. (2013) found that maternal FA supplementation between the 4th week and before the 8th week after the beginning of pregnancy was associated with lower ASD risk. A Chinese study of 416 children with ASD and 201 with typical development found that children born to mothers without FA and micronutrient supplementation exhibited more severe social cognitive impairment. However, 8 of 15 studies were unable to safely determine the effects of FA. Raghavan et al. (2018) described a U-shaped relationship where increased risk for ASD occurred at both extremes of FA consumption (excess and insufficient), while moderate supplementation showed a protective effect. Wiens et al. (2017) reported that excessive FA consumption and high levels of nonmetabolized FA may have negative effects on neurological development. The review noted that FA fortification of food combined with supplementation may have created a population group with high serum levels of nonmetabolized FA when intake exceeds 200 mg/day.

**Clinical Implications:** The review supports recommending early FA supplementation in the preconception period and early pregnancy, as it prevents approximately 70% of neural tube defects and is associated with a protective effect against ASD. However, the optimal dose remains unclear, and excessive consumption may not be innocuous. The authors recommend future investigations to identify optimal doses and to determine whether FA consumption from the second trimester onward can be associated with increased ASD risk. Repeated biological measurements of folate, vitamin B12, and homocysteine during the first trimester, as well as genetic variant analysis, are needed for more conclusive evidence.