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Oral Contraceptives & Folate: A Research Review

Oral Contraceptives & Folate: A Research Review

Oral contraceptives are among the most commonly used and highly effective drugs in the developed world. Research has highlighted however that the widespread use of oral contraceptives may be significantly affecting bodily levels of many essential vitamins and minerals.1-5

Depletion of any essential vitamin and mineral is worrying; one that is of particular concern for women of child bearing age however is folate. Here we take a closer look at the impact of oral contraceptives on folate status and the possible wider health implications of this:

Folate – an important B vitamin
Folate is an important B vitamin; it is essential for nerves to function properly and for the formation of red blood cells and DNA. It is also a crucial nutrient to support methylation, a vital process which amongst many other functions, helps to prevent the build-up of homocysteine. Folate is also known to be particularly important during the first 4 weeks of pregnancy to help prevent neural tube defects (NTDs).

Folate & NTDs
The neural tube is a hollow embryonic structure from which the brain and spinal cord form; it closes within the first month of conception and incomplete closure can lead to neural NTDs such as spina bifida, anencephaly and encephalocele. Folate is believed to be essential for this process. Back in 1992, the Department of Health recommended that women intending to become pregnant should increase folate intake by an extra 400mcg daily from preconception until 12 weeks of gestation to reduce first occurrences of NTDs – which accounts for 95% of all cases. Folate is the generic term for naturally occurring dietary folate and folic acid (the form of the vitamin found in supplements and fortified foods). The effect of supplementation with folic acid in the prevention of NTDs is now well documented.6-8 Unlike the US and a number of other countries where food is fortified with folic acid, in the UK supplementation remains the recommended method of preventing neural tube and associated defects.

Oral contraceptives & folate status – A research timeline

1. Shortly after the introduction of oral contraceptives, studies appeared in the literature to suggest their consumption might negatively impact on user’s folate status.9-13

2. In 1968 Shojania et al reported in Lancet that compared to a control group, users of oral contraceptives had lower mean serum folate levels and that the percentage of subnormal folate levels was higher too.14 They also reported that the rate of decrease in mean serum folate levels increased with longer duration of use of oral contraceptives, but folate levels returned to baseline levels within 3 months of cessation of use.

3. Likely mechanisms that have been suggested for these observations include the possibility that oral contraceptives might cause folate polyglutamates to be malabsorbed and/or increase the rate of urinary excretion of folates, and/or accelerate the metabolism of folates through an induction of folic acid metabolising microsomal enzymes.15

4. Further studies have confirmed these reports, although others have yielded equivocal findings.16-18 Potential confounders contributing to these different results might include differences in dietary intake, duration of use and compliance with oral contraceptives, use of tobacco and alcohol, and the use of dietary supplements.16 However, it is unlikely that the use of oral contraceptives might alone cause anaemia or megaloblastic changes in females with a good dietary intake of folic acid and in those who can absorb it properly. In those rare reports of megaloblastic anaemia associated with oral contraceptive use, the women have usually had other conditions that contributed to the folate deficiency.16,19

5. A recent systematic review and meta-analysis concluded “Because of the reduction in blood folate concentrations associated with the use of oral contraceptives, it is critical for women of childbearing age to continue folate supplementation during oral contraceptive use”.20

6. In recognition of this, an oral contraceptive fortified with folate was made available in 2012 in some markets as an aid in reducing the risk of neural tube defects in a pregnancy conceived during use or shortly after the discontinuation of oral contraceptive products.21,22

7. There is also some evidence that oral contraceptives can increase the rate of progression of cervical dysplasia to cervical cancer, and that folic acid can slow or reverse this dysplasia.23,24

The case for folate supplementation in women taking oral contraceptives is particularly robust for two primary reasons:

1) To replenish levels depleted by oral contraceptives to ensure folate can fulfil crucial physiological roles

2) To support folate status and reduce the risk of NTDs in a pregnancy conceived during use or shortly after the discontinuation of oral contraceptives

Additional points to consider:

Folate & B12 - High intake of folate can mask a B12 deficiency24 so it is often suggested that these two nutrients are taken together in supplement form. Even just a small amount of B12 may help to counter the negative impact of higher folate intake. A recent systematic review concluded that oral contraceptives exert a negative influence on vitamin B12 status25 and supports the concept that supplementation of B12 might be considered in oral contraceptive users.26 Inadequate maternal vitamin B12 status is also an independent risk factor for NTDs.27

MTHFR polymorphism - In recent years, the subject of genetic MTHFR polymorphisms has been highlighted. This polymorphism is relatively common and makes it more difficult for the body to utilise folate in the forms most commonly found in supplements such as folic acid. Not surprisingly, the MTHFR C677T variant has been implicated in an increased risk of neural tube defects.28 5-Methyltetrahydrofolate (5-MTHF) is an active, body-ready form of folate which is readily utilised and may be an effective supplement option, particularly for those who carry the polymorphism.

References:
1. Theuer RC. Effect of Oral Contraceptive Agents on Vitamin and Mineral Needs: A Review. J Reprod Med. 1972; 8:13-9.
2. Berg G, Kohlmeier L, Brenner H. Effect of Oral Contraceptive Progestins on Serum Copper Concentration. Eur J Clin Nutr. 1998; 52:711-5.
3. Ghayour-Mobarhan M, Taylor A, New SA, Lamb DJ, Ferns GA. Determinants of Serum Copper, Zinc and Selenium in Healthy Subjects. Ann Clin Biochem. 2005; 42:364-75.
4. Tamura T, Picciano MF. Folate and Human Reproduction. Am J Clin Nutr 2006;83: 993-1016.
5. Prevention of Neural Tube Defects: Results of the Medical Research Council Vitamin Study. Mrc Vitamin Study Research Group. Lancet. 1991; 338:131-7.
6. MRC Vitamin study research group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet 338, 131–137.
7. Czeizel AE, Dudás I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. New England Journal of Medicine. 1992 Dec 24;327(26):1832-5.
8. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, Mulinare J, Zhao P, Wong LY, Gindler J, Hong SX. Prevention of neural-tube defects with folic acid in China. New England Journal of Medicine. 1999 Nov 11;341(20):1485-90.
9. Trowbridge M, Jr., Wadsworth R, Moffitt E. Malabsorption associated with gluten enteropathy, do oral contraceptives interfere with folate metabolism? J Maine Med Assoc 1968; 59: 240-242.
10. Paton A. Oral contraceptives and folate deficiency. Lancet 1969; 1: 418.
11. Ryser J, Farquet J, Petite J. Megaloblastic anemia due to folic acid deficiency in a young woman on oral contraceptives. Acta Haematol 1971; 45: 319-324.
12. Whitehead N, Reyner F, Lindenbaum J. Megaloblastic changes in the cervical epithelium. Association with oral contraceptive therapy and reversal with folic acid. JAMA 1973; 226: 1421-1424
13. Shojania AM. Oral contraceptives: effect of folate and vitamin B12 metabolism. Can Med Assoc J 1982; 126: 244-247
14. Shojania A M, Hornady G, Barnes P. Oral contraceptives and serum-folate level. Lancet 1968; 1: 1376-1377.
15. Shojania AM. Oral contraceptives: effect of folate and vitamin B12 metabolism. Can Med Assoc J 1982; 126: 244-247
16. Pritchard J, Scott D, Whalley P. Maternal folate deficiency and pregnancy wastage. IV. Effects of folic acid supplements, anticonvulsants, and oral contraceptives. Am J Obstet Gynecol 1971; 109: 341-346.
17. Castren O M, Rossi R R. Effect of oral contraceptives on serum folic acid content. J Obstet Gynaecol Br Commonw 1970; 77: 548-550.
18. Green T, Houghton L, Donovan U, Gibson R, O’connor D. Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females. J Am Diet Assoc 1998; 98: 49-55.
19. Paton A. Oral contraceptives and folate deficiency. Lancet 1969; 1: 418.
20. Shere, Mahvash, et al. "Association between use of oral contraceptives and folate status: a systematic review and meta-analysis." Journal of Obstetrics and Gynaecology Canada 2015. 37: 430-438.
21. Castano PM, Aydemir A, Sampson-Landers C, Lynen R. The folate status of reproductive-aged women in a randomised trial of a folate-fortified oral contraceptive: dietary and blood assessments. Public health nutrition. 2014 Jun;17(6):1375-83.
22. Fruzzetti, F. Beyaz P An oral contraceptive fortified with folate Women's Health 8.1 (Jan 2012): 13-9.
23. Butterworth CE, Hatch KD, Gore H, et al. Improvement in cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr 1982; 35:73-82.
24. Reynolds EH. What is the safe upper level of folic acid for the nervous system? Implications for folic acid fortification policies. Eur J Clin Nutr. 2016 May; 70(5):537-40
25. Check WA. Folate for oral contraceptive users may reduce cervical cancer risk. J Am Med Assoc 1980; 244:633-4.
26. Dante G et al. Vitamin and mineral needs during the oral contraceptive therapy: a systematic review. Int J Reprod Contracept Obstet Gynecol. 2014 Mar;3(1):1-10
27. Basnayake S, de Silva SV, Miller PC, Rogers S. A Trial of Daily Vitamin Supplementation as a Means of Reducing Oral Contraceptive Side Effects and Discontinuation in Sri Lanka. Contraception. 1983; 27:465-72
28. Adams MJ Jr, Khoury MJ, Scanlon KS, Stevenson RE, Knight GJ, Haddow JE et al. Elevated Midtrimester Serum Methylmalonic Acid Levels as a Risk Factor for Neural Tube Defects. Teratology. 1995; 51:311-7.
29. Yadav U, Kumar P, Yadav SK, Mishra OP, Rai V. Polymorphisms in folate metabolism genes as maternal risk factor for neural tube defects: an updated meta-analysis. Metab Brain Dis (2015) 30:7–24.

Additional resources:
Wakeman, M - Review article: The effects of oral contraceptives on nutrient status with special consideration to folate.