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

Objective To provide updated guidance on pre-conception folic acid and multivitamin supplementation for primary and secondary (recurrence) prevention of neural tube defects and other folate-sensitive congenital anomalies. Target population Women aged 12–45 years who could become pregnant should be aware of the risk of serious birth defects without adequate pre-conception and first-trimester folic acid supplementation. Options Optimizing folic acid supplementation is complex and depends on factors including dosage; type of supplement; bioavailability of folate from food, timing of initiating supplementation; and metabolic and genetic factors. For all women who could become pregnant, a low daily dosage of folic acid is recommended before conception and throughout pregnancy and breastfeeding. High-dosage folic acid supplementation is recommended only for women who can become pregnant and have had a previous pregnancy affected by a neural tube defect or other folate-sensitive congenital anomaly. Directed personalized approaches could be considered and adopted for women who can become pregnant and have complex risks (genetic, medical, or surgical risk factors), using new knowledge of co-factor metabolism and synergy, as well as red blood cell or serum folate testing. Such approaches would require changes to current provincial health care maternal serum folate screening/testing. Outcomes New approaches to oral folic acid supplementation, including triage tools, need to be considered to optimize the benefits of decreasing risk of neural tube defects and folate-sensitive congenital anomalies. Benefits, harms, and costs Oral folic acid supplementation, or dietary folate intake combined with a multivitamin/micronutrient supplement, is associated with lower rates of neural tube defects, other folate-sensitive birth defects, and obstetrical complications. The costs are those attributable to daily vitamin supplementation and a healthy, folate-rich diet. Evidence A literature search was designed and carried in PubMed and the Cochrane Library databases from 1990 to 2021 using following MeSH terms and keywords (and variants): folic acid supplementation; folate food fortification; primary neural tube defect prevention; prevention of recurrence of neural tube defects; folate-sensitive birth defects; folate supplementation benefit; folate supplementation risk; folate pregnant woman physiology; pregnant woman RBC folate level; pregnant woman serum folate levels; folate and epilepsy; folate and obesity. This guideline was based upon expert guidelines or opinions, systematic reviews, randomized controlled clinical trials, and observational case-control studies and case series retrieved, published in English from 1990 to 2021. Validation Methods The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations). Intended audience Maternity health care providers (physicians, midwives, nurses) and other providers of pregnancy-related wellness and health counselling. SUMMARY STATEMENTS 1.Prevention of folate-sensitive anomalies should be evidence-based, and the benefits of preventing anomalies should balance any risks of folic acid supplementation (high). 2.Birth defects related to folate deficiency account for 2%–3% of prenatal or neonatal major anomalies and 4%–5% of total structural malformations or developmental conditions identified after birth. Folate-sensitive birth defects include neural tube defects, certain congenital heart and urinary tract defects, oral facial clefts, and limb-reduction anomalies (high). RECOMMENDATIONS 1.Any woman aged 12–45 years who can become pregnant should be advised by their health care provider to maintain a healthy, folate-rich diet and should undergo a brief periodic dietary review (strong, moderate). 2.Health care providers can consider promoting regular consumption of choline-rich foods (meat, egg yolk) during wellness visits (such as for birth control renewal, Pap testing, gynaecologic examination), whether or not the patient is contemplating pregnancy (strong, moderate). 3.Health care providers should advise all women aged 12–45 years considering or planning a pregnancy about the benefits of taking an oral daily multivitamin containing folic acid (0.4֪–1.0 mg) to optimize serum and red blood cell folate levels (strong, high). 4.Folic acid should be taken in a daily oral multivitamin that includes a 2.6-μg dose of vitamin B12 (strong, high). 5.Any woman aged 12–45 years who can become pregnant and has pre-conception obesity (body mass index >30.0 kg/m2) may require a more personal and focused assessment for folate supplementation to prevent fetal anomalies, such as a pre-conception fasting serum folate concentration assessment. If a woman with obesity has had a previous fetus or child with a folate-sensitive fetal anomaly other than a neural tube defect, she should take a folic acid supplement containing the recommended dosage for women at increased risk (4–5 mg) (conditional, low). 6.High-dosage folate supplementation (oral dosage of 4–5 mg/d) should be used only for women at high risk; women who can become pregnant and who have had a previous pregnancy affected by a neural tube defect, have had a neural tube defect themselves, or have a first-degree relative with a neural tube defect (strong, moderate). 7.High-dosage supplementation requires 2 separate periods of supplementation: from pre-conception to 12 weeks gestation (see below), and from 12 weeks gestation until completion of breastfeeding, when the folic acid supplementation dosage reverts to the low-dosage regimen (strong, high). There are 2 options for supplementation in the first period: 1.Standard option: a total pre-conception oral daily dosage of 4 mg folic acid (1 oral multivitamin supplement that contains 1.0 mg of folic acid and 2.6 μg of vitamin B12, an iron supplement of 16–20 mg/d, and 3 1.0-mg folic acid tablets); (strong, high) or 2.Personalized option: requires the patient to first take an oral daily multivitamin containing folic acid (0.4֪–1.0 mg) and vitamin B12 within the first 4–6 weeks of a 3-month pre-conception period, then complete a blood test to determine her fasting serum folate level. A daily dosage of folic acid supplementation (from this pre-conception period until 12 weeks gestation) of 0.4–1.0 mg would be chosen if results were in the optimal range, and a daily dosage of more than 1.0 mg, if the results were sub-optimal (strong, moderate–high). 8.Moderate-dosage folate supplementation: Women who can become pregnant and have either an increased risk of having a fetus with an NTD or other folate-sensitive congenital anomaly or other medical-surgical conditions associated with a risk of folate deficiency require 2 separate periods of supplementation (strong, high). •From pre-conception to 12 weeks gestation, the supplementation dosage is 1.0 mg of folic acid daily (1 oral multivitamin supplement that contains 1.0 mg folic acid and 2.6 μg vitamin B12, and an iron supplement of 16–20 mg/d). •After 12 weeks gestation, the folic acid supplementation dosage reverts to the low-dosage regimen. 9.Low-dosage folate supplementation: Women who can become pregnant and are at low risk of having a fetus with an NTD or other folate-sensitive congenital anomaly should consume a pre-conception and first-trimester diet of folate-rich foods along with a daily oral multivitamin supplement that contains 0.4 mg (400 μg) of folic acid and 2.6 μg of vitamin B12, and an iron supplement of 16–20 mg daily for at least 2–3 months before conception, throughout the pregnancy, and for 4–6 weeks postpartum or as long as breastfeeding continues (strong, high).