Folic acid supplementation and pregnancy: more than just neural tube defect prevention

James A. Greenberg, Stacey J. Bell, Yong Guan, Yan-Hong Yu

Abstract


Folate (vitamin B9) is an essential nutrient that is required for DNA replication and as a substrate for a range of enzymatic reactions involved in amino acid synthesis and vitamin metabolism. Demands for folate increase during pregnancy because it is also required for growth and development of the fetus. Folate deficiency has been associated with abnormalities in both mothers (anemia, peripheral neuropathy) and fetuses (congenital abnormalities).

This article reviews the metabolism of folic acid, the appropriate use of folic acid supplementation in pregnancy, and the potential benefits of folic acid, as well as the possible supplementation of L-methylfolate for the prevention of pregnancy-related complications other than neural tube defects.

The term folate is typically used as a generic name for the group of chemically related compounds based on the folic acid structure. Folate, or vitamin B9, is thought of as one of the 13 essential vitamins. It cannot be synthesized de novo by the body, and must be obtained either from diet or supplementation. Folic acid is a synthetic dietary supplement that is present in artificially enriched foods and pharmaceutical vitamins. Neither folate nor folic acid is metabolically active. Both must be reduced to participate in cellular metabolism. L-5-Methyltetrahydrofolate (L-methylfolate) is the predominant micronutrient form of folate that circulates in plasma and that is involved in biologic processes.

Periconceptional folic acid supplementation protects against fetal structural anomalies, including neural tube and congenital heart defects. Recent data suggest that it may also protect against preterm birth. Although additional studies are needed to better define the precise timing, dosing, and formulation, existing data suggest that dietary folic acid supplementation is a good idea for all reproductive-aged women.


Keywords


folic acid; L-methylfolate; dietary supplements

References


MRC Vitamin Study Research Group. “Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.” Lancet 338 (1991): 131–7.

Rieder, M.J. “Prevention of neural tube defects with periconceptional folic acid. Clin Perinatol 21 (1994): 483–503.

Pitkin, R.M. “Folate and neural tube defects.” Am J Clin Nutr 85 (2007): 285–8.

De Wals, P., Tairou, F., Van Allen, M.I., et al. “Reduction in neural-tube defects after folic acid fortification in Canada.” N Engl J Med 357 (2007): 135–42.

Pietrzik, K., Bailey, L., Shane, B. “Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics.” Clin Pharmacokinet 48 (2010): 535–48.

Bodnar, L.M., Himes, K.P., Venkataramanan, R., et al. “Maternal serum folate species in early pregnancy and risk of preterm birth.” Am J Clin Nutr 92 (2010): 864–71.

Suh, J.R., Herbig, A.K., Stover, P.J. “New perspectives on folate catabolism.” Annu Rev Nutr 21 (2001): 255–82.

Miller, A.L. “The methylation, neurotransmitter, and antioxidant connections between folate and depression.” Altern Med Rev 13 (2008): 216–26.

Ulrich, C.M., Kampman, E., Bigler, J., et al. “Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps.” Cancer Epidemiol Biomarkers Prev 9 (2000): 427–33.

Weisberg, I.S., Jacques, P.F., Selhub, J., et al. “The 1298 A->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine.” Atherosclerosis 156 (2001): 409–15.

US Food and Drug Administration. “Food Standards. Amendment of standards of identity for enriched grain products to require addition of folic acid.” Fed Regist 61 (1996): 8781–96.

Bureau of Food Regulatory. “International and Interagency Affairs, Health C. Regulatory impact analysis statement.” Canada Gazette Part II 132 (1998): 3029–33.

Jacques, P.F., Selhub, J., Bostom, A.G., et al. “The effect of folic acid fortification on plasma folate and total homocysteine concentrations.” N Engl J Med 340 (1999): 1449–54.

Dietrich, M., Brown, C.J., Block, G. “The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult nonsupplement users in the United States.” J Am Coll Nutr 24 (2005): 266–74.

Honein, M.A., Paulozzi, L.J., Mathews, T.J., et al. “Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects.” JAMA 285 (2001): 2981–6.

Williams, L.J., Mai, C.T., Edmonds, L.D., et al. “Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.” Teratology 66 (2002): 33–9.

Centers for Disease Control and Prevention (CDC). “Spina bifida and anencephaly before and after folic acid mandate – United States, 1995–1996 and 1999–2000.” MMWR Morb Mortal Wkly Rep 53 (2004): 362–5.

Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC. National Academy Press (1998).

Wilson, R.D., Johnson, J.A., Wyatt, P., et al. Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada and The Motherrisk Program. “Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies.” J Obstet Gynaecol Can 29 (2007): 1003–26.

Lamers, Y., Prinz-Langenohl, R., Brämswig, S., Pietrzik, K. “Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age.” Am J Clin Nutr 84 (2006): 156–61.

Pritchard, J.A., Adams, R.H. “Erythrocyte production and destruction during pregnancy.” Am J Obstet Gynecol 79 (1960): 750–7.

Cunningham, F., Leveno, K., Bloom, S., et al. Hematological disorders. In: Williams Obstetrics, 23rd ed. New York. McGraw-Hill (2009).

Koury, M.J., Ponka, P. “New insights into erythropoiesis: the role of folate, vitamin B12 and iron.” Annu Rev Nutr 24 (2004): 105–31.

Bentley, S., Hermes, A., Phillips, D., et al. “Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis.” Clin Therapeut 33 (2011): 204–10.

Behrman, R.E., Butler, A.S., eds. Preterm Birth: Causes, Consequences, and Prevention. Institute of Medicine. Washington, DC. The National Academies Press (2007).

Lockwood, C.J., Kuczynski, E. “Risk stratification and pathological mechanisms in preterm delivery.” Paediatr Perinat Epidemiol 15 (2001): 78–89.

Fisk, N.M., Atun, R. “Market failure and the poverty of new drugs in maternal health.” PLoS Med 5 (2008): e22.

Malinow, M.R., Rajkovic, A., Duell, P.B., et al. “The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocysteine in fetal metabolism.” Am J Obstet Gynecol 178 (1998): 228–33.

Tchernia, G., Blot, I., Rey, A., et al. “Maternal folate status, birthweight and gestational age.” Dev Pharmacol Ther 4 (Suppl) (1982): 58–65.

Keen, C.L., Clegg, M.S., Hanna, L.A., et al. “The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications.” J Nutr 133.5 Suppl 2 (2003): 1597–1605.

Neggers, Y., Goldenberg, R.L. “Some thoughts on body mass index, micronutrient intakes and pregnancy outcome.” J Nutr 133.5 Suppl 2 (2003): 1737–40.

Allen, L.H. “Multiple micronutrients in pregnancy and lactation: an overview.” Am J Clin Nutr 81 (2005): 1206–12.

Haider, B.A., Bhutta, Z.A. “Multiple-micronutrient supplementation for women during pregnancy.” Cochrane Database Syst Rev 4 (2006): CD004905.

Czeizel, A.E., Puhó, E.H., Langmar, Z., et al. “Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study.” Eur J Obstet Gynecol Reprod Biol 148 (2010): 135–40.

Muggli, E.E., Halliday, J.L. “Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006.” Med J Aust 186 (2007): 243–8.

Bukowski, R., Malone, F.D., Porter, F.T., et al. “Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.” PLoS Med 6 (2009): e1000061.

Courtemanche, C., Elson-Schwab, I., Mashiyama, S.T., et al. “Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro.” J Immunol 173 (2004): 3186–92.

Christian, P., Jiang, T., Khatry, S.K., et al. “Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal.” Am J Clin Nutr 83 (2006): 788–94.

Dhur, A., Galan, P., Hercberg, S. “Folate status and the immune system.” Prog Food Nutr Sci 15 (1991): 43–60.

Johnson, W.G., Scholl, T.O., Spychala, J.R., et al. “Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery.” Am J Clin Nutr 81 (2005): 664–8.

Engel, S.M., Olshan, A.F., Siega-Riz, A.M., et al. “Polymorphisms in folate metabolizing genes and risk for spontaneous preterm and small-for-gestational age birth.” Am J Obstet Gynecol 195 (2006): 1231.e1–11.

Botto, L.D., Mulinare, J., Erickson, J.D. “Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps.” Am J Med Genet A 121A (2003): 95–101.

Bailey, L.B., Berry, R.J. “Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage.” Am J Clin Nutr 81 (2005): 1213–7.

Huhta, J.C., Linask, K., Bailey, L. “Recent advances in the prevention of congenital heart disease.” Curr Opin Pediatr 18 (2006): 484–9.

Ionescu-Ittu, R., Marelli, A.J., Mackie, A.S., Pilote, L. “Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada.” BMJ 338 (2009): b1673.

Huhta, J.C., Hernandez-Robles, J.A. “Homocysteine, folate, and congenital heart defects.” Fetal Pediatr Pathol 24 (2005): 71–9.

Wen, S.W., Chen, X.K., Rodger, M., et al. “Folic acid supplementation in early second trimester and the risk of preeclampsia.” Am J Obstet Gynecol 198 (2008): 45.e1–7.

Ray, J.G., Laskin, C. “Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review.” Placenta 20 (1999): 519–29.

Wen, S.W., Zhou, J., Yang, Q., et al. “Maternal exposure to folic acid antagonists and placenta mediated adverse pregnancy outcomes.” CMAJ 179 (2008): 1263–8.

Yang, J., Xie, R.H., Krewski, D., et al. “Exposure to trimethoprim/sulfamethoxazole but not other FDA category C and D anti-infectives is associated with increased risks of preterm birth and low birth weight.” Int J Infect Dis 15 (2011): e336–41.

Williams, P.J., Bulmer, J.N., Innes, B.A., Broughton Pipkin, F. “Possible roles for folic acid in the regulation of trophoblast invasion and placental development in normal early human pregnancy.” Biol Reprod 84 (2011): 1148–53.

Morris, M.S., Jacques, P.F., Rosenberg, I.H., Selhub, J. “Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors.” Am J Clin Nutr 91 (2010): 1733–44.

Frankenburg, F.R. “Folate supplementation: is it safe and effective?” J Clin Psychiatry 70 (2009): 767–9.


GOST Style Citations


1. MRC Vitamin Study Research Group. “Prevention of neural tube defects: results of the Medical Research Council Vitamin Study.” Lancet 338 (1991): 131–7.

2. Rieder, M.J. “Prevention of neural tube defects with periconceptional folic acid. Clin Perinatol 21 (1994): 483–503.

3. Pitkin, R.M. “Folate and neural tube defects.” Am J Clin Nutr 85 (2007): 285–8.

4. De Wals, P., Tairou, F., Van Allen, M.I., et al. “Reduction in neural-tube defects after folic acid fortification in Canada.” N Engl J Med 357 (2007): 135–42.

5. Pietrzik, K., Bailey, L., Shane, B. “Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics.” Clin Pharmacokinet 48 (2010): 535–48.

6. Bodnar, L.M., Himes, K.P., Venkataramanan, R., et al. “Maternal serum folate species in early pregnancy and risk of preterm birth.” Am J Clin Nutr 92 (2010): 864–71.

7. Suh, J.R., Herbig, A.K., Stover, P.J. “New perspectives on folate catabolism.” Annu Rev Nutr 21 (2001): 255–82.

8. Miller, A.L. “The methylation, neurotransmitter, and antioxidant connections between folate and depression.” Altern Med Rev 13 (2008): 216–26.

9. Ulrich, C.M., Kampman, E., Bigler, J., et al. “Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps.” Cancer Epidemiol Biomarkers Prev 9 (2000): 427–33.

10. Weisberg, I.S., Jacques, P.F., Selhub, J., et al. “The 1298 A->C polymorphism in methylenetetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine.” Atherosclerosis 156 (2001): 409–15.

11. US Food and Drug Administration. “Food Standards. Amendment of standards of identity for enriched grain products to require addition of folic acid.” Fed Regist 61 (1996): 8781–96.

12. Bureau of Food Regulatory. “International and Interagency Affairs, Health C. Regulatory impact analysis statement.” Canada Gazette Part II 132 (1998): 3029–33.

13. Jacques, P.F., Selhub, J., Bostom, A.G., et al. “The effect of folic acid fortification on plasma folate and total homocysteine concentrations.” N Engl J Med 340 (1999): 1449–54.

14. Dietrich, M., Brown, C.J., Block, G. “The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult nonsupplement users in the United States.” J Am Coll Nutr 24 (2005): 266–74.

15. Honein, M.A., Paulozzi, L.J., Mathews, T.J., et al. “Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects.” JAMA 285 (2001): 2981–6.

16. Williams, L.J., Mai, C.T., Edmonds, L.D., et al. “Prevalence of spina bifida and anencephaly during the transition to mandatory folic acid fortification in the United States.” Teratology 66 (2002): 33–9.

17. Centers for Disease Control and Prevention (CDC). “Spina bifida and anencephaly before and after folic acid mandate – United States, 1995–1996 and 1999–2000.” MMWR Morb Mortal Wkly Rep 53 (2004): 362–5.

18. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC. National Academy Press (1998).

19. Wilson, R.D., Johnson, J.A., Wyatt, P., et al. Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada and The Motherrisk Program. “Pre-conceptional vitamin/folic acid supplementation 2007: the use of folic acid in combination with a multivitamin supplement for the prevention of neural tube defects and other congenital anomalies.” J Obstet Gynaecol Can 29 (2007): 1003–26.

20. Lamers, Y., Prinz-Langenohl, R., Brämswig, S., Pietrzik, K. “Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age.” Am J Clin Nutr 84 (2006): 156–61.

21. Pritchard, J.A., Adams, R.H. “Erythrocyte production and destruction during pregnancy.” Am J Obstet Gynecol 79 (1960): 750–7.

22. Cunningham, F., Leveno, K., Bloom, S., et al. Hematological disorders. In: Williams Obstetrics, 23rd ed. New York. McGraw-Hill (2009).

23. Koury, M.J., Ponka, P. “New insights into erythropoiesis: the role of folate, vitamin B12 and iron.” Annu Rev Nutr 24 (2004): 105–31.

24. Bentley, S., Hermes, A., Phillips, D., et al. “Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis.” Clin Therapeut 33 (2011): 204–10.

25. Behrman, R.E., Butler, A.S., eds. Preterm Birth: Causes, Consequences, and Prevention. Institute of Medicine. Washington, DC. The National Academies Press (2007).

26. Lockwood, C.J., Kuczynski, E. “Risk stratification and pathological mechanisms in preterm delivery.” Paediatr Perinat Epidemiol 15 (2001): 78–89.

27. Fisk, N.M., Atun, R. “Market failure and the poverty of new drugs in maternal health.” PLoS Med 5 (2008): e22.

28. Malinow, M.R., Rajkovic, A., Duell, P.B., et al. “The relationship between maternal and neonatal umbilical cord plasma homocyst(e)ine suggests a potential role for maternal homocysteine in fetal metabolism.” Am J Obstet Gynecol 178 (1998): 228–33.

29. Tchernia, G., Blot, I., Rey, A., et al. “Maternal folate status, birthweight and gestational age.” Dev Pharmacol Ther 4 (Suppl) (1982): 58–65.

30. Keen, C.L., Clegg, M.S., Hanna, L.A., et al. “The plausibility of micronutrient deficiencies being a significant contributing factor to the occurrence of pregnancy complications.” J Nutr 133.5 Suppl 2 (2003): 1597–1605.

31. Neggers, Y., Goldenberg, R.L. “Some thoughts on body mass index, micronutrient intakes and pregnancy outcome.” J Nutr 133.5 Suppl 2 (2003): 1737–40.

32. Allen, L.H. “Multiple micronutrients in pregnancy and lactation: an overview.” Am J Clin Nutr 81 (2005): 1206–12.

33. Haider, B.A., Bhutta, Z.A. “Multiple-micronutrient supplementation for women during pregnancy.” Cochrane Database Syst Rev 4 (2006): CD004905.

34. Czeizel, A.E., Puhó, E.H., Langmar, Z., et al. “Possible association of folic acid supplementation during pregnancy with reduction of preterm birth: a population-based study.” Eur J Obstet Gynecol Reprod Biol 148 (2010): 135–40.

35. Muggli, E.E., Halliday, J.L. “Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006.” Med J Aust 186 (2007): 243–8.

36. Bukowski, R., Malone, F.D., Porter, F.T., et al. “Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.” PLoS Med 6 (2009): e1000061.

37. Courtemanche, C., Elson-Schwab, I., Mashiyama, S.T., et al. “Folate deficiency inhibits the proliferation of primary human CD8+ T lymphocytes in vitro.” J Immunol 173 (2004): 3186–92.

38. Christian, P., Jiang, T., Khatry, S.K., et al. “Antenatal supplementation with micronutrients and biochemical indicators of status and subclinical infection in rural Nepal.” Am J Clin Nutr 83 (2006): 788–94.

39. Dhur, A., Galan, P., Hercberg, S. “Folate status and the immune system.” Prog Food Nutr Sci 15 (1991): 43–60.

40. Johnson, W.G., Scholl, T.O., Spychala, J.R., et al. “Common dihydrofolate reductase 19-base pair deletion allele: a novel risk factor for preterm delivery.” Am J Clin Nutr 81 (2005): 664–8.

41. Engel, S.M., Olshan, A.F., Siega-Riz, A.M., et al. “Polymorphisms in folate metabolizing genes and risk for spontaneous preterm and small-for-gestational age birth.” Am J Obstet Gynecol 195 (2006): 1231.e1–11.

42. Botto, L.D., Mulinare, J., Erickson, J.D. “Do multivitamin or folic acid supplements reduce the risk for congenital heart defects? Evidence and gaps.” Am J Med Genet A 121A (2003): 95–101.

43. Bailey, L.B., Berry, R.J. “Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage.” Am J Clin Nutr 81 (2005): 1213–7.

44. Huhta, J.C., Linask, K., Bailey, L. “Recent advances in the prevention of congenital heart disease.” Curr Opin Pediatr 18 (2006): 484–9.

45. Ionescu-Ittu, R., Marelli, A.J., Mackie, A.S., Pilote, L. “Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada.” BMJ 338 (2009): b1673.

46. Huhta, J.C., Hernandez-Robles, J.A. “Homocysteine, folate, and congenital heart defects.” Fetal Pediatr Pathol 24 (2005): 71–9.

47. Wen, S.W., Chen, X.K., Rodger, M., et al. “Folic acid supplementation in early second trimester and the risk of preeclampsia.” Am J Obstet Gynecol 198 (2008): 45.e1–7.

48. Ray, J.G., Laskin, C. “Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: a systematic review.” Placenta 20 (1999): 519–29.

49. Wen, S.W., Zhou, J., Yang, Q., et al. “Maternal exposure to folic acid antagonists and placenta mediated adverse pregnancy outcomes.” CMAJ 179 (2008): 1263–8.

50. Yang, J., Xie, R.H., Krewski, D., et al. “Exposure to trimethoprim/sulfamethoxazole but not other FDA category C and D anti-infectives is associated with increased risks of preterm birth and low birth weight.” Int J Infect Dis 15 (2011): e336–41.

51. Williams, P.J., Bulmer, J.N., Innes, B.A., Broughton Pipkin, F. “Possible roles for folic acid in the regulation of trophoblast invasion and placental development in normal early human pregnancy.” Biol Reprod 84 (2011): 1148–53.

52. Morris, M.S., Jacques, P.F., Rosenberg, I.H., Selhub, J. “Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors.” Am J Clin Nutr 91 (2010): 1733–44.

53. Frankenburg, F.R. “Folate supplementation: is it safe and effective?” J Clin Psychiatry 70 (2009): 767–9.





DOI: http://dx.doi.org/10.18370/2309-4117.2017.34.57-63

Refbacks

  • There are currently no refbacks.


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

ISSN 2411-1295 (Online), ISSN 2309-4117 (Print)