Focused Revision: Policy statement on folic acid and neural tube defects

Abstract

Addendum to: “Policy statement on folic acid and neural tube defects”. Helga V. Toriello, PhD; ACMG Professional Practice and Guidelines Committee Genetics in Medicine13:593–596 (2011); https://doi.org/10.1097/GIM.0b013e31821d4188, published online 05 May 2011. This document was reaffirmed by the American College of Medical Genetics and Genomics (ACMG) Board of Directors as of 12 April 2021 noting that the original document does not meet the criteria for an evidence-based practice guideline by the ACMG (2014), and is now reclassified as a Clinical Practice Resource. This addendum is a Focused Revision of the original document. Since the publication of the original article in 2011, a nonsystematic review of the literature for updated information on the role of folic acid supplementation in decreasing the prevalence of neural tube defects (NTDs) was done through PubMed and websites of various national health-care organizations, e.g., Centers for Disease Control and Prevention (CDC), National Center on Birth Defects and Developmental Disabilities (NCBDDD), and the US Preventive Services Task Force (USPSTF). Since 2011, multiple medical and public health organizations have reiterated the recommendation of universal folic acid prophylaxis of 400 µg (0.4 mg) daily in all women of child-bearing age to prevent the incidence of NTDs in fetuses.1.Bibbins-Domingo K. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement.JAMA. 2017; 317: 183-18910.1001/jama.2017.4413Crossref PubMed Scopus (162) Google Scholar, 2.American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin no. 201: pregestational diabetes mellitus.Obstet. Gynecol. 2018; 132: e228-e24810.1097/AOG.0000000000002960Crossref PubMed Scopus (128) Google Scholar, 3.Viswanathan M. Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2017; 317: 190-20310.1001/jama.2016.19193Crossref PubMed Scopus (94) Google Scholar, 4.Procter S.B. Campbell C.G. Position of the Academy of Nutrition and Dietetics: nutrition and lifestyle for a healthy pregnancy outcome.J. Acad. Nutr. Diet. 2014; 114: 1099-110310.1016/j.jand.2014.05.005Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar This folic acid dose should supplement the consumption of a folate-rich diet including enriched cereal grains. Studies have shown risk differences in populations of various racial and ethnic backgrounds, as well as in various geographical locations.5.Hendricks K.A. Simpson J.S. Larsen R.D. Neural tube defects along the Texas-Mexico border, 1993-1995.Am. J. Epidemiol. 1999; 149: 1119-11271:STN:280:DyaK1M3ps1WqtQ%3D%3D10.1093/oxfordjournals.aje.a009766Crossref PubMed Scopus (114) Google Scholar Shanxi Province in China has been documented to have the highest rate of NTDs in the world. While the Chinese government’s implementation of NTD prevention programs by food fortification with micronutrients including folic acid decreased the NTD incidence significantly (P < 0.05), study of this geographical area highlighted the significant role of geographical and environmental risk factors in the higher NTD incidence, which might not be addressed with diet and vitamin supplementation alone.6.Liao Y. Temporal and spatial analysis of neural tube defects and detection of geographical factors in Shanxi Province, China.PLoS One. 2016; 11: e015033210.1371/journal.pone.0150332Crossref PubMed Scopus (23) Google Scholar In 2010, the NCBDDD and the CDC launched an initiative with a global network of partners, including the World Health Organization, named Birth Defects COUNT (Countries and Organizations United for Neural Tube Defects Prevention).7.Centers for Disease Control and Prevention. Folic acid: birth defects COUNT. https://www.cdc.gov/ncbddd/birthdefectscount/ (2021).Google Scholar It aims to reduce the death and lifelong disability due to NTDs by increasing the intake of folic acid to at least 400 µg (0.4 mg) per day in all reproductive-age women. In the United States, some studies have found the highest risk for NTDs in Hispanic women, while others have not found such an association.5.Hendricks K.A. Simpson J.S. Larsen R.D. Neural tube defects along the Texas-Mexico border, 1993-1995.Am. J. Epidemiol. 1999; 149: 1119-11271:STN:280:DyaK1M3ps1WqtQ%3D%3D10.1093/oxfordjournals.aje.a009766Crossref PubMed Scopus (114) Google Scholar,8.Egbe A.C. Birth defects in the newborn population: race and ethnicity.Pediatr. Neonatol. 2015; 56: 183-18810.1016/j.pedneo.2014.10.002Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar In 2016, the US Food and Drug Administration approved voluntary folic acid fortification of corn masa flour to address this disparity and increase total daily folic acid intake in this subpopulation.9.Tinker S.C. Hamner H.C. Qi Y.P. Crider K.S.U.S. U.S. women of childbearing age who are at possible increased risk of a neural tube defect-affected pregnancy due to suboptimal red blood cell folate concentrations, National Health and Nutrition Examination Survey 2007 to 2012.Birth Defects Res. A. Clin. Mol. Teratol. 2015; 103: 517-5261:CAS:528:DC%2BC2MXmsF2mtb4%3D10.1002/bdra.23378Crossref PubMed Scopus (61) Google Scholar This is estimated to prevent 40 additional cases of NTDs in Hispanic infants every year.10.Flores A.L. Adding folic acid to corn masa flour: partnering to improve pregnancy outcomes and reduce health disparities.Prev. Med. 2018; 106: 26-3010.1016/j.ypmed.2017.11.003Crossref PubMed Scopus (10) Google Scholar As approximately 50% of pregnancies in the United States are unplanned, universal prophylaxis with daily folic acid of 400 µg (0.4 mg) is recommended for general reproductive-age women, in addition to a folate-rich diet. In women contemplating pregnancy, the intake should commence at least one month before conception and continue till 12 weeks gestation for maximal protection.1.Bibbins-Domingo K. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement.JAMA. 2017; 317: 183-18910.1001/jama.2017.4413Crossref PubMed Scopus (162) Google Scholar, 2.American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin no. 201: pregestational diabetes mellitus.Obstet. Gynecol. 2018; 132: e228-e24810.1097/AOG.0000000000002960Crossref PubMed Scopus (128) Google Scholar, 3.Viswanathan M. Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2017; 317: 190-20310.1001/jama.2016.19193Crossref PubMed Scopus (94) Google Scholar Although vitamin supplementation beyond 12 weeks is not required for neural tube protection, continuation of 400 µg (0.4 mg) folic acid as a standard component of many prenatal vitamins is recommended throughout the rest of the pregnancy to meet the fetal growth and developmental needs.11.Caffrey A. Gene-specific DNA methylation in newborns in response to folic acid supplementation during the second and third trimesters of pregnancy: epigenetic analysis from a randomized controlled trial.Am. J. Clin. Nutr. 2018; 107: 566-57510.1093/ajcn/nqx069Crossref PubMed Scopus (53) Google Scholar,12.McNulty B. Impact of continuing folic acid after the first trimester of pregnancy: findings of a randomized trial of folic acid supplementation in the second and third trimesters.Am. J. Clin. Nutr. 2013; 98: 92-981:CAS:528:DC%2BC3sXhtVChtbzP10.3945/ajcn.112.057489Crossref PubMed Scopus (64) Google Scholar For high-risk women, the recommendation of a higher folic acid dose supplementation of 4,000 µg (4 mg) daily has been reiterated by various US organizations.1.Bibbins-Domingo K. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement.JAMA. 2017; 317: 183-18910.1001/jama.2017.4413Crossref PubMed Scopus (162) Google Scholar, 2.American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics. ACOG practice bulletin no. 201: pregestational diabetes mellitus.Obstet. Gynecol. 2018; 132: e228-e24810.1097/AOG.0000000000002960Crossref PubMed Scopus (128) Google Scholar, 3.Viswanathan M. Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2017; 317: 190-20310.1001/jama.2016.19193Crossref PubMed Scopus (94) Google Scholar This high dose should be commenced at least three months prior to conception and continued until 12 weeks gestation till completion of major organ development, after which the dose can be reduced to 400 µg (0.4 mg) daily.13.Wilson R.D. Pre-conception folic acid and multivitamin supplementation for the primary and secondary prevention of neural tube defects and other folic acid-sensitive congenital anomalies.J. Obstet. Gynaecol. Can. 2015; 37: 534-55210.1016/S1701-2163(15)30230-9Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar This decreases the likelihood of any potential health consequences of long-term ingestion of high doses of folic acid, e.g., masking vitamin B12 deficiency–related neurological symptoms.14.Patel K.R. Sobczyńska-Malefora A. The adverse effects of an excessive folic acid intake.Eur. J. Clin. Nutr. 2017; 71: 159-1631:CAS:528:DC%2BC28Xhs1yis7zO10.1038/ejcn.2016.194Crossref PubMed Scopus (58) Google Scholar Continued experience has shown that even with adequate folate supplementation, not all cases of isolated NTDs can be prevented due to their multifactorial etiology.15.Chen C.-P. Chromosomal abnormalities associated with neural tube defects (I): full aneuploidy.Taiwan J. Obstet. Gynecol. 2007; 46: 325-33510.1016/S1028-4559(08)60002-9Crossref PubMed Scopus (47) Google Scholar,16.Wilde J.J. Petersen J.R. Niswander L. Genetic, epigenetic, and environmental contributions to neural tube closure.Annu. Rev. Genet. 2014; 48: 583-6111:CAS:528:DC%2BC2cXitFCkurbJ10.1146/annurev-genet-120213-092208Crossref PubMed Scopus (118) Google Scholar In 2017, a systematic review by the USPSTF reaffirmed the adequacy of current folic acid supplementation guidelines with recommended daily supplementation of 400–800 µg (0.4 to 0.8 mg) in all women at average risk. The task force acknowledged that it is difficult for most women to consume the recommended daily folic acid from food alone in spite of access to fortified food. However, in their review of case–control studies conducted after implementation of food fortification laws, the benefit of additional folic acid supplementation was noted to be smaller than that afforded by food fortification.3.Viswanathan M. Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2017; 317: 190-20310.1001/jama.2016.19193Crossref PubMed Scopus (94) Google Scholar,17.Williams J. Updated estimates of neural tube defects prevented by mandatory folic acid fortification - United States, 1995-2011.MMWR Morb. Mortal. Wkly. Rep. 2015; 64: 1-5255906784584791PubMed Google Scholar The USPSTF stated that the reflected reduced magnitude of protective effect of folic acid supplementation after food fortification could be attributed to study design.3.Viswanathan M. Folic acid supplementation for the prevention of neural tube defects: an updated evidence report and systematic review for the US Preventive Services Task Force.JAMA. 2017; 317: 190-20310.1001/jama.2016.19193Crossref PubMed Scopus (94) Google Scholar They concluded with high certainty that the net benefit of folic acid supplementation is substantial with inadequate evidence for any potential harm to the mother or baby.1.Bibbins-Domingo K. Folic acid supplementation for the prevention of neural tube defects: US Preventive Services Task Force recommendation statement.JAMA. 2017; 317: 183-18910.1001/jama.2017.4413Crossref PubMed Scopus (162) Google Scholar The USPSTF has therefore reaffirmed its 2009 recommendation of daily folic acid supplementation at a dose of 400–800 µg (0.4–0.8 mg) daily in all reproductive-age women. A Cochrane meta-analysis showed that higher doses of folate supplementation (>400 µg or >0.4 mg) with or without additional vitamins and minerals do not have any effect on the prevalence or recurrence of NTDs. According to the meta-analysis, the same or higher dose also has no potential protective role in other birth defects including, but not limited to, cleft lip/palate, congenital heart defects, miscarriages, limb reduction defects, urinary tract defects, or congenital hydrocephalus.18.De-Regil, L. M., Peña-Rosas, J. P., Fernández-Gaxiola, A. C. & Rayco-Solon, P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane Database Syst. Rev. CD007950 (2015).Google Scholar Although findings are based on low-quality data, the Society of Obstetricians and Gynaecologists of Canada recommends 1 mg folic acid per day for women who have a personal history of the abovementioned conditions. This dose is also recommended if they have a partner, prior offspring, or first or second degree relatives with the same.13.Wilson R.D. Pre-conception folic acid and multivitamin supplementation for the primary and secondary prevention of neural tube defects and other folic acid-sensitive congenital anomalies.J. Obstet. Gynaecol. Can. 2015; 37: 534-55210.1016/S1701-2163(15)30230-9Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Although some studies have reported a protective role of folic acid in fetal growth restriction and preterm birth, the findings have not been conclusive enough to warrant any change in the dose of prophylactic folic acid supplementation.19.Zhang Q. Effect of folic acid supplementation on preterm delivery and small for gestational age births: a systematic review and meta-analysis.Reprod. Toxicol. 2017; 67: 35-411:CAS:528:DC%2BC28XhvFWns77J10.1016/j.reprotox.2016.11.012Crossref PubMed Scopus (22) Google Scholar,20.Hodgetts V.A. Morris R.K. Francis A. Gardosi J. Ismail K.M. Effectiveness of folic acid supplementation in pregnancy on reducing the risk of small-for-gestational age neonates: a population study, systematic review and meta-analysis.BJOG. 2015; 122: 478-4901:CAS:528:DC%2BC2MXjtVSisr0%3D10.1111/1471-0528.13202Crossref PubMed Scopus (87) Google Scholar While folic acid’s preventive role is well established, avoidance of drugs that increase the risk of fetal NTDs, like the methotrexate or antiseizure medications (e.g., valproic acid or carbamazepine), should be considered during pregnancy, if clinically safe. Some other micronutrients that have been investigated to have a preventive role in fetal NTDs include thiamine, betaine, riboflavin, vitamin B6, vitamin C, vitamin E, niacin, iron, retinol, vitamin A, and choline.21.Chandler A.L. Neural tube defects and maternal intake of micronutrients related to one-carbon metabolism or antioxidant activity.Birth Defects Res. A. Clin. Mol. Teratol. 2012; 94: 864-8741:CAS:528:DC%2BC38Xht1KitbnP10.1002/bdra.23068Crossref PubMed Scopus (48) Google Scholar,22.Noventa, M., Vitagliano A. Quaranta M. Borgato S. Abdulrahim B. Gizzo S. Preventive and therapeutic role of dietary inositol supplementation in periconceptional period and during pregnancy: a summary of evidences and future applications.Reprod. Sci. 2016; 23: 278-28810.1177/1933719115594018Crossref PubMed Scopus (34) Google Scholar Recently, periconceptional myo-inositol supplementation has been shown to have a role in ameliorating the risk of fetal NTDs, especially in folate-resistant cases.23.D’Souza S.W. Copp A.J. Greene N.D.E. Glazier J.D. Maternal inositol status and neural tube defects: a role for the human yolk sac in embryonic inositol delivery?.Adv. Nutr. 2021; 12: 212-22210.1093/advances/nmaa100Crossref PubMed Scopus (10) Google Scholar More research with the above micronutrients is needed before a scientific recommendation can be made. AMERICAN COLLEGE OF MEDICAL GENETICS AND GENOMICS RECOMMENDATIONSDaily folic acid intake of 400 µg (0.4 mg) is recommended in all women of child-bearing age. In women planning a pregnancy, the intake is recommended to start at least 4 weeks prior to planned conception. This supplementation is advised in addition to consumption of folic acid fortified food from the preconception period at least through the first trimester.High-risk women are recommended to take a higher dose, 4,000 µg (4 mg) of daily folic acid supplementation at least 12 weeks prior to conception, with continuation of reduced folic acid supplementation dose of 400 µg (0.4 mg) after completion of 12 weeks gestation. Some criteria in defining high-risk status include (but are not limited to) personal, family, or prior pregnancy history of neural tube defects; type 1 diabetes mellitus; or exposure to high-risk medications during early pregnancy.In spite of patient compliance with supplementation, some fetal neural tube defects are of multifactorial or monogenic etiology, and cannot be completely prevented. 19 August 2021 A Correction to this paper has been published: https://doi.org/10.1038/s41436-021-01299-3 The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Policy statement on folic acid and neural tube defectsGenetics in MedicineVol. 13Issue 6PreviewIt now recognized that the use of folate fortification and/or supplementation before initiation of pregnancy can impact the risk of the fetus developing a neural tube defect. This document serves to update the policy statement issued by the American College of Medical Genetics and published in 2005. Full-Text PDF Open Archive