PURPOSE: In our practice, testing hypo-fertile patients for circulating homocysteine (Hcy) and the two principal MTHFR SNPs (677C >
T and 1298A >
C) has been routine for the past 7 years. Couples carrying a genetic background known to be associated with the disease were proposed treatment regimens consisting of 5-methyl tetrahydrofolate (5-MTHF) together with nutritional support of the one-carbon cycle (1-CC). Some patients preferred to continue with folic acid (FA) as prescribed by their referring gynecologist/obstetrician: this gave us the opportunity to compare outcomes between the two groups of patients. METHODS: After successful live birth deliveries, we compared health characteristics and circulating Hcy in the offspring from ages 2 to 6 years, i.e., after cessation of breastfeeding and before puberty. Follow-up included children of 21 couples who were treated with FA vs 36 couples treated with 5-MTHF. RESULTS: In the FA-treated group, we found two children with autism spectrum disorder (ASD) syndrome, one child with significantly elevated circulating Hcy (19 µM at the age of 2 years), and one child affected by oculo-auriculo-vertebral spectrum (OAVS), a syndrome known to be linked to DNA methylation. No pathology of any kind was detected in children of the 5-MTHF treatment group. CONCLUSION: Treatment with 5-MTHF is safe and effective for both males and females. It should be implemented in order to avoid disruption of methylation linked to folate metabolism during oocyte maturation and pregnancy, and subsequently in the offspring. This type of treatment should be considered to avoid metabolic diseases linked to elevated homocysteine.