Maternal folic acid and multivitamin supplementation: International clinical evidence with considerations for the prevention of folate-sensitive birth defects

Abstract

More evidence is available for maternal intake, absorption, distribution, tissue specific concentrations, and pregnancy outcomes with folic acid (fortification/supplementation) during preconception – first trimester. This Quality Improvement prevention review used expert guidelines/opinions, systematic reviews, randomized control trials/controlled clinical trials, and observational case control/case series studies, published in English, from 1990 to August 2021. Optimization for an oral maternal folic acid supplementation is difficult because it relies on folic acid dose, type of folate supplement, bio-availability of the folate from foods, timing of supplementation initiation, maternal metabolism/genetic factors, and many other factors. There is continued use of high dose pre-food fortification ‘RCT evidenced-based’ folic acid supplementation for NTD recurrence pregnancy prevention. Innovation requires preconception and pregnancy use of ‘carbon one nutrient’ supplements (folic acid, vitamin B12, B6, choline), using the appropriate evidence, need to be considered. The consideration and adoption of directed personalized approaches for maternal complex risk could use serum folate testing for supplementation dosing choice. Routine daily folic acid dosing for low-risk women should consider a multivitamin with 0.4 mg of folic acid starting 3 months prior to conception until completion of breastfeeding. Routine folic acid dosing or preconception measurement of maternal serum folate (after 4–6 weeks of folate supplementation) could be considered for maternal complex risk group with genetic/medical/surgical co-morbidities. These new approaches for folic acid oral supplementation are required to optimize benefit (decreasing folate sensitive congenital anomalies; childhood morbidity) and minimizing potential maternal and childhood risk.

Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid–Sensitive Congenital Anomalies

“…Serum folate levels of 28e30 nmol/L (red blood cell folate level >907 nmol/L) have been extensively evaluated in pregnant populations, and there is clear evidence that this maternal red blood cell folate level protects against folic aciderelated NTDs in the fetus. 10 A 2021 comprehensive review article entitled "Maternal folic acid and multivitamin supplementation: International clinical evidence with considerations for the prevention of folate-sensitive birth defects," 11 provides the clinical evidence supporting the recommendations in this guideline. There are a number of clinical considerations to ensure that pregnant women achieve optimal serum folate levels, and the risk level of the patient must be taken into account.…”

“…Women who can become pregnant may have genetic, environmental, and immune factors that can affect serum levels of folate, thereby increasing the risk of NTDs and other folate-sensitive congenital anomalies and possibly requiring increased supplementation for prevention. Box 1 [10][11][12][13][14][15][16][17][18] summarizes the identified risk factors for NTDs or for low folate status in pregnancy and Table 1 illustrates the effects of medications on folate metabolism.…”

“…25 For every prospective pregnant woman, the health care provider should document an appropriate 3-generation pedigree for congenital anomalies (fetal or neonatal) and pregnancy outcome (live birth, stillbirth, pregnancy termination, and spontaneous loss) for both the mother's and father's families. Although pre-conception counselling is recommended for all pregnancies, it may have added value for those with a history of congenital anomalies in the mother's or father's families, adverse pregnancy outcomes, and maternal health conditions [26][27][28] (Box 2 11 ), and compliance should be emphasized. It is important to emphasize that, for recurrent NTD prevention, folic acid supplementation decreases risk from 3%e4% (the risk level in populations not receiving supplementation) to 1%.…”

Mandatory food fortification with folic acid

“…The title is also discordant with the body of the paper, which discusses the prevention of two lowprevalence conditions-spina bifida and anencephaly-without referring to other folate-sensitive congenital anomalies (eg, cardiac anomalies, orofacial clefts, limb defects, hydrocephalus, and urinary tract anomalies). 2 The second issue is that, by calling for universal fortification, the paper fails to contextualise prevention of birth defects in the resource realities of low-income and middle-income countries (ie, only women in the preconception and interconception period are targeted, rather than the entire population). The authors overlook realities of poor access to food and diet diversity, cultural practices, and costs of fortification.…”

Association and Interaction Effect of BHMT Gene Polymorphisms and Maternal Dietary Habits with Ventricular Septal Defect in Offspring

“…A recent review showed strong evidence that oral prenatal fortification and supplementation dosing of folic acid (FA) can prevent the incidence of VSD and atrial septal defect (ASD) [ 11 ]. Women with a diverse diet during pregnancy (dietary diversity score, DDS ≥5) had lower risks of having fetuses with total CHD and VSD [ 12 ].…”