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. 1982 Feb 1;126(3):244–247.

Oral contraceptives: effect of folate and vitamin B12 metabolism.

A M Shojania
PMCID: PMC1862844  PMID: 7037144

Abstract

Women who use oral contraceptives have impaired folate metabolism as shown by slightly but significantly lower levels of folate in the serum and the erythrocytes and an increased urinary excretion of formiminoglutamic acid. The vitamin B12 level in their serum is also significantly lower than that of control groups. However, there is no evidence of tissue depletion of vitamin B12 associated with the use of oral contraceptives. The causes and clinical significance of the impairment of folate and vitamin B12 metabolism in these women is discussed in this review of the literature. Clinicians are advised to ensure that women who shop taking "the pill" because they wish to conceive have adequate folate stores before becoming pregnant.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmed F., Bamji M. S., Iyengar L. Effect of oral contraceptive agents on vitamin nutrition status. Am J Clin Nutr. 1975 Jun;28(6):606–615. doi: 10.1093/ajcn/28.6.606. [DOI] [PubMed] [Google Scholar]
  2. Areekul S., Panatampon P., Doungbarn J., Yamarat P., Vongyuthithum M. Serum vitamin B12, serum and red cell folates, vitamin B12 and folic acid binding proteins in women taking oral contraceptives. Southeast Asian J Trop Med Public Health. 1977 Dec;8(4):480–485. [PubMed] [Google Scholar]
  3. Barone C., Bartoloni C., Ghirlanda G., Gentiloni N. Megaloblastic anemia due to folic acid deficiency after oral contraceptives. Haematologica. 1979 Apr;64(2):190–195. [PubMed] [Google Scholar]
  4. Bianchine J. R., Bonnlander B., Macaraeg P. V., Jr, Hersey R., Bianchine J. W., McIntyre P. A. Serum vitamin B 12 binding capacity and oral contraceptive hormones. J Clin Endocrinol Metab. 1969 Nov;29(11):1425–1428. doi: 10.1210/jcem-29-11-1425. [DOI] [PubMed] [Google Scholar]
  5. Bianco G., Accatino G., Ciocca Vasino A., Neretto G. Anemia megaloblastica da carenza di acido folico conseguente a somministrazione di contraccettivi orali. Descrizione di due casi clinici. Minerva Med. 1978 May 5;69(22):1513–1516. [PubMed] [Google Scholar]
  6. Boots L., Cornwell P. E., Beck L. R. Effect of ethynodiol diacetate and mestranol on serum folic acid and vitamin B12 levels and on tryptophan metabolism in baboons. Am J Clin Nutr. 1975 Apr;28(4):354–362. doi: 10.1093/ajcn/28.4.354. [DOI] [PubMed] [Google Scholar]
  7. Bovina C., Tolomelli B., Rovinetti C., Marchetti M. Effect of estradiol on folate coenzymes in the rat. Int J Vitam Nutr Res. 1971;41(4):453–456. [PubMed] [Google Scholar]
  8. Briatico G., Guiso G., Jori A., Ravazzani C. Effects of contraceptive agents on drug metabolism in various animal species. Br J Pharmacol. 1976 Oct;58(2):173–181. doi: 10.1111/j.1476-5381.1976.tb10393.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Buhac I., Finn J. W. Folsäuremangelanämie als Folge des langfristigen Gebrauchs peroraler kontrazeptiver Mittel. Schweiz Med Wochenschr. 1971 Dec 24;101(51):1879–1881. [PubMed] [Google Scholar]
  10. Butterworth C. E., Jr, Krumdieck C. L., Stinson H. N., Cornwell P. E. A study of the effect of oral contraceptive agents on the absorption, metabolic conversion and urinary excretion of a naturally-occurring folate (citrovorum factor). Ala J Med Sci. 1975 Oct;12(4):330–335. [PubMed] [Google Scholar]
  11. Castrén O. M., Rossi R. R. Effect of oral contraceptives on serum folic acid content. J Obstet Gynaecol Br Commonw. 1970 Jun;77(6):548–550. doi: 10.1111/j.1471-0528.1970.tb03565.x. [DOI] [PubMed] [Google Scholar]
  12. Chalmers D. M., Levi A. J., Chanarin I., North W. R., Meade T. W. Mean cell volume in a working population: the effects of age, smoking, alcohol and oral contraception. Br J Haematol. 1979 Dec;43(4):631–636. doi: 10.1111/j.1365-2141.1979.tb03796.x. [DOI] [PubMed] [Google Scholar]
  13. DOCTOR V. M., TRUNNELL J. B. Effect of sex hormones on conversion of folic acid to citrovorum factor by rat. Proc Soc Exp Biol Med. 1955 Oct;90(1):251–253. doi: 10.3181/00379727-90-21998. [DOI] [PubMed] [Google Scholar]
  14. Da Costa M., Rothenberg S. P. Appearance of a folate binder in leukocytes and serum of women who are pregnant or taking oral contraceptives. J Lab Clin Med. 1974 Feb;83(2):207–214. [PubMed] [Google Scholar]
  15. Davis R. E., Smith B. K. Pyridoxal, vitamin B12 and folate metabolism in women taking oral contraceptive agents. S Afr Med J. 1974 Sep 21;48(46):1937–1940. [PubMed] [Google Scholar]
  16. Fisch I. R., Freedman S. H. Oral contraceptives and the red blood cell. Clin Pharmacol Ther. 1973 Mar-Apr;14(2):245–249. doi: 10.1002/cpt1973142245. [DOI] [PubMed] [Google Scholar]
  17. Fleming A. F. Urinary excretion of folate in pregnancy. J Obstet Gynaecol Br Commonw. 1972 Oct;79(10):916–920. doi: 10.1111/j.1471-0528.1972.tb12188.x. [DOI] [PubMed] [Google Scholar]
  18. Flury R., Angehrn W. Folsäuremangelanämie infolge Einnahme oraler Kontrazeptiva. Schweiz Med Wochenschr. 1972 Nov 4;102(44):1628–1629. [PubMed] [Google Scholar]
  19. Girdwood R. H. Drug-induced anaemias. Drugs. 1976;11(5):394–404. doi: 10.2165/00003495-197611050-00003. [DOI] [PubMed] [Google Scholar]
  20. Green J. D. Megaloblastic anemia in a vegetarian taking oral contraceptives. South Med J. 1975 Feb;68(2):249–250. doi: 10.1097/00007611-197502000-00029. [DOI] [PubMed] [Google Scholar]
  21. Heilmann E., Menke A., Rethmeier H. J., Seelbach W. [Vitamin B12 and folic acid in women taking oral contraceptives]. Inn Med. 1976 Nov;3(8):442–445. [PubMed] [Google Scholar]
  22. Hertz R. Interference With Estrogen-induced Tissue Growth in the Chick Genital Tract by a Folic Acid Antagonist. Science. 1948 Mar 19;107(2777):300–300. doi: 10.1126/science.107.2777.300. [DOI] [PubMed] [Google Scholar]
  23. Hertz R., Sebrell W. H. IMPAIRMENT OF RESPONSE TO STILBESTROL IN THE OVIDUCT OF CHICKS DEFICIENT IN L. CASEI FACTOR ("FOLIC ACID"). Science. 1944 Sep 29;100(2596):293–294. doi: 10.1126/science.100.2596.293. [DOI] [PubMed] [Google Scholar]
  24. Holmes R. P. Megaloblastic anemia precipitated by the use of oral contraceptive. A case report. N C Med J. 1970 Jan;31(1):17–18. [PubMed] [Google Scholar]
  25. Johnson G. K., Geenen J. E., Hensley G. T., Soergel K. H. Small intestinal disease, folate deficiency anemia, and oral contraceptive agents. Am J Dig Dis. 1973 Mar;18(3):185–190. doi: 10.1007/BF01071971. [DOI] [PubMed] [Google Scholar]
  26. Kaplan N. M. Clinical complications of oral contraceptives. Adv Intern Med. 1975;20:197–214. [PubMed] [Google Scholar]
  27. Karlin R., Dumont M., Long B. Etude des taux sanguins d'acide folique au cours des traitements oestro-progestatifs. J Gynecol Obstet Biol Reprod (Paris) 1977 Jun;6(4):489–495. [PubMed] [Google Scholar]
  28. Krumdieck C. L., Boots L. R., Cornwell P. E., Butterworth C. E., Jr Estrogen stimulation of conjugase activity in the uterus of ovariectomized rats. Am J Clin Nutr. 1975 May;28(5):530–534. doi: 10.1093/ajcn/28.5.530. [DOI] [PubMed] [Google Scholar]
  29. Laffi R., Tolomelli B., Bovina C., Marchetti M. Influence of short-term treatment with estradiol-17 on folate metabolism in the rat. Int J Vitam Nutr Res. 1972;42(2):196–204. [PubMed] [Google Scholar]
  30. Larsson-Cohn U. Oral contraceptives and vitamins: a review. Am J Obstet Gynecol. 1975 Jan 1;121(1):84–90. doi: 10.1016/0002-9378(75)90980-1. [DOI] [PubMed] [Google Scholar]
  31. Lewis F. B. Folate deficiency due to oral contraceptives. Minn Med. 1974 Dec;57(12):945–946. [PubMed] [Google Scholar]
  32. Lindenbaum J., Whitehead N., Reyner F. Oral contraceptive hormones, folate metabolism, and the cervical epithelium. Am J Clin Nutr. 1975 Apr;28(4):346–353. doi: 10.1093/ajcn/28.4.346. [DOI] [PubMed] [Google Scholar]
  33. Martinez O., Roe D. A. Effect of oral contraceptives on blood folate levels in pregnancy. Am J Obstet Gynecol. 1977 Jun 1;128(3):255–261. doi: 10.1016/0002-9378(77)90618-4. [DOI] [PubMed] [Google Scholar]
  34. Maxwell J. D., Hunter J., Stewart D. A., Ardeman S., Williams R. Folate deficiency after anticonvulsant drugs: an effect of hepatic enzyme induction? Br Med J. 1972 Jan 29;1(5795):297–299. doi: 10.1136/bmj.1.5795.297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. McLean F. W., Heine M. W., Held B., Streiff R. R. Relationship between the oral contraceptive and folic acid metabolism. Serum folate concentrations. Am J Obstet Gynecol. 1969 Jul 1;104(5):745–747. doi: 10.1016/0002-9378(69)90619-x. [DOI] [PubMed] [Google Scholar]
  36. Meguid M. M., Loebl W. Y. Megaloblastic anaemia associated with the oral contraceptive pill. Postgrad Med J. 1974 Jul;50(585):470–472. doi: 10.1136/pgmj.50.585.470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Necheles T. F., Snyder L. M. Malabsorption of folate polyglutamates associated with oral contraceptive therapy. N Engl J Med. 1970 Apr 9;282(15):858–859. doi: 10.1056/NEJM197004092821509. [DOI] [PubMed] [Google Scholar]
  38. Paine C. J., Grafton W. D., Dickson V. L., Eichner E. R. Oral contraceptives, serum folate, and hematologic status. JAMA. 1975 Feb 17;231(7):731–733. [PubMed] [Google Scholar]
  39. Palva I. P. Megaloblastisk anemi orskad av orala kontraseptiva. Nord Med. 1971;86(49):1491–1491. [PubMed] [Google Scholar]
  40. Paton A. Oral contraceptives and folate deficiency. Lancet. 1969 Feb 22;1(7591):418–418. doi: 10.1016/s0140-6736(69)91386-5. [DOI] [PubMed] [Google Scholar]
  41. Pietarinen G. J., Leichter J., Pratt R. F. Dietary folate intake and concentration of folate in serum and erythrocytes in women using oral contraceptives. Am J Clin Nutr. 1977 Mar;30(3):375–380. doi: 10.1093/ajcn/30.3.375. [DOI] [PubMed] [Google Scholar]
  42. Prasad A. S., Lei K. Y., Moghissi K. S., Stryker J. C., Oberleas D. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid. Am J Obstet Gynecol. 1976 Aug 15;125(8):1063–1069. doi: 10.1016/0002-9378(76)90809-7. [DOI] [PubMed] [Google Scholar]
  43. Pritchard J. A., Scott D. E., Whalley P. J. Maternal folate deficiency and pregnancy wastage. IV. Effects of folic acid supplements, anticonvulsants, and oral contraceptives. Am J Obstet Gynecol. 1971 Feb 1;109(3):341–346. doi: 10.1016/0002-9378(71)90326-7. [DOI] [PubMed] [Google Scholar]
  44. Roetz R., Nevinny-Stickel J. Serumfolat, Serumeisen und totale Eisenbindungs-kapazität des Serums unter hormonaler Kontrazeption. Ergebnisse einer prospektiven Untersuchung. Geburtshilfe Frauenheilkd. 1973 Aug;33(8):629–635. [PubMed] [Google Scholar]
  45. Ross C. E., Stone M. K., Reagan J. W., Wentz W. B., Kellermeyer R. W. Lack of influence of oral contraceptives on serum folate, hematologic values, and uterine cervical cytology. Semin Hematol. 1976 Jul;13(3):233–238. [PubMed] [Google Scholar]
  46. Ryser J. E., Farquet J. J., Petite J. Megaloblastic anemia due to folic acid deficiency in a young woman on oral contraceptives. Acta Haematol. 1971;45(5):319–324. doi: 10.1159/000208642. [DOI] [PubMed] [Google Scholar]
  47. Salter W. M. Megaloblastic anemia and oral contraceptives. Minn Med. 1972 Jun;55(6):554–555. [PubMed] [Google Scholar]
  48. Shojania A. M. Effect of oral contraceptives on vitamin-B12 metabolism. Lancet. 1971 Oct 23;2(7730):932–932. doi: 10.1016/s0140-6736(71)92552-9. [DOI] [PubMed] [Google Scholar]
  49. Shojania A. M., Hornady G. J. Oral contraceptives and folate absorption. J Lab Clin Med. 1973 Dec;82(6):869–875. [PubMed] [Google Scholar]
  50. Shojania A. M., Hornady G. J., Scaletta D. The effect of oral contraceptives on folate metabolism. III. Plasma clearance and urinary folate excretion. J Lab Clin Med. 1975 Feb;85(2):185–190. [PubMed] [Google Scholar]
  51. Shojania A. M., Hornady G., Barnes P. H. Oral contraceptives and serum-folate level. Lancet. 1968 Jun 22;1(7556):1376–1377. doi: 10.1016/s0140-6736(68)92081-3. [DOI] [PubMed] [Google Scholar]
  52. Shojania A. M., Wylie B. The effect of oral contraceptives on vitamin B12 metabolism. Am J Obstet Gynecol. 1979 Sep 1;135(1):129–134. [PubMed] [Google Scholar]
  53. Smith J. L., Goldsmith G. A., Lawrence J. D. Effects of oral contraceptive steroids on vitamin and lipid levels in serum. Am J Clin Nutr. 1975 Apr;28(4):371–376. doi: 10.1093/ajcn/28.4.371. [DOI] [PubMed] [Google Scholar]
  54. Stephens M. E., Craft J., Peters T. J., Hoffbrand A. V. Oral contraceptives and folate metabolism. Clin Sci. 1972 Apr;42(4):405–414. doi: 10.1042/cs0420405. [DOI] [PubMed] [Google Scholar]
  55. Streiff R. R. Folate deficiency and oral contraceptives. JAMA. 1970 Oct 5;214(1):105–108. [PubMed] [Google Scholar]
  56. Toghill P. J., Smith P. G. Folate deficiency and the pill. Br Med J. 1971 Mar 13;1(5749):608–609. doi: 10.1136/bmj.1.5749.608-c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tolomelli B., Bovina C., Rovinetti C., Marchetti M. Studies on the folate coenzyme metabolism in the castrated rat and treated with 17 -estradiol. Proc Soc Exp Biol Med. 1972 Nov;141(2):436–439. doi: 10.3181/00379727-141-36792. [DOI] [PubMed] [Google Scholar]
  58. Tolomelli B., Rovinetti C., Bovina C., Marchetti M. Studies on folate metabolism in castrated rats and those treated with testosterone. Experientia. 1972 Feb 15;28(2):197–198. doi: 10.1007/BF01935757. [DOI] [PubMed] [Google Scholar]
  59. Trowbridge M., Jr, Wadsworth R. C., Moffitt E. Malabsorption associated with gluten enteropathy, do oral contraceptives interfere with folate metabolism? J Maine Med Assoc. 1968 Dec;59(12):240–242. [PubMed] [Google Scholar]
  60. Veyssier P., Philippe J. M., Dusehu E. Dysérythropoïse aiguë par carence folique révélant une maladie coeliaque. A propos d'une observation chez une femme sous contraception orale prolongée. Ann Med Interne (Paris) 1977 Oct;128(10):789–792. [PubMed] [Google Scholar]
  61. Wertalik L. F., Metz E. N., LoBuglio A. F., Balcerzak S. P. Decreased serum B 12 levels with oral contraceptive use. JAMA. 1972 Sep 18;221(12):1371–1374. [PubMed] [Google Scholar]
  62. Whitehead N., Reyner F., Lindenbaum J. Megaloblastic changes in the cervical epithelium. Association with oral contraceptive therapy and reversal with folic acid. JAMA. 1973 Dec 17;226(12):1421–1424. [PubMed] [Google Scholar]
  63. Wood J. K., Goldstone A. H., Allan N. C. Folic acid and the pill. Scand J Haematol. 1972;9(5):539–544. doi: 10.1111/j.1600-0609.1972.tb00981.x. [DOI] [PubMed] [Google Scholar]
  64. Wynn V. Vitamins and oral contraceptive use. Lancet. 1975 Mar 8;1(7906):561–564. doi: 10.1016/s0140-6736(75)91570-6. [DOI] [PubMed] [Google Scholar]

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