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“Even though COCs (combined oral contraceptives) are among the most prescribed drugs, with more than 100 million users worldwide, various side effects may occur during their assumption, most of which may correlate to nutritional deficiency of vitamins and minerals.”1
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This excerpt is taken from the introduction to a 2022 Review on ‘Counteracting side effects of combined oral contraceptives through the administration of specific micronutrients’, and published in the European Review for Medical and Pharmacological Sciences. It speaks volumes on the potential for COCs to deplete essential nutrients. And since COCs are ‘among the most prescribed drugs, with more than 100 million users worldwide’, it also highlights the need for women to have easy access to accurate information on nutrient intakes and depletions with COCs, to enable informed health decisions. This is a complex topic; the full breadth of which we can’t cover in this article. We can however make a good start by reviewing 5 essential nutrients that are commonly depleted by the pill. Read on to find out more.
Folate
Folate is a water-soluble vitamin that has critical roles to play in DNA synthesis and cell division. It’s no accident that it sits right at the top of this list. Shortly after the introduction of oral contraceptives, studies appeared to suggest their consumption might reduce blood folate levels.2-6 The hormonal content of oral contraceptives was however much higher in the 1960s and 70s when these initial studies were carried out, which has raised the question of how relevant these results still are today? A more recent systematic review and meta-analysis answered this question and concluded, “because of the reduction in blood folate concentrations associated with the use of oral contraceptives, it is crtical for women of childbearing age to continue folate supplementation during oral contraceptive use.”7
Folate is particularly important during the early stages of pregnancy and folate supplementation during this time is associated with a reduced risk of neural tube defects (NTDs), congenital heart defects and orofacial clefts.8
In recognition of the importance of folate for women during reproductive years and the potential folate-depleting effects of oral contraceptives, a product fortified with folate was made available in 2012 in some markets to help reduce the risk of NTDs in a pregnancy conceived during use or shortly after discontinuation of oral contraceptive products.9,10
There is also some evidence that oral contraceptives may increase the rate of progression of cervical dysplasia to cervical cancer, and that folate may slow or reverse this dysplasia.11,12
It is crucial that women of child-bearing age pay particular attention to their folate status and this is especially important if they are taking COCs. You will find folate in foods such as leafy green vegetables. You can also take folate in supplements. Many supplements contain the synthetic form of folic acid which needs to be converted to the more active form of 5- methyltetrahydrofolate (5-MTHF) in the body. There is however a fairly common genetic variant which may reduce the ability to make this conversion. Supplementing directly with the body-ready form of 5-methyltetrahydrofolate (5-MTHF) by-passes the need for this conversion and may be a more effective choice.
Vitamin B12
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Several studies have found low levels of vitamin B12 in women using oral contraceptives, compared to non-users.13-23 There is a close relationship between folate and vitamin B12 metabolism in the body, however it is still not well understood how oral contraceptives may cause low vitamin B12. As with low folate levels, low maternal B12 status is also considered to be an independent risk factor for neural tube defects (NTDs).24
In addition to its protective role in pregnancy, vitamin B12 is involved in over 100 daily functions; it helps the blood to carry oxygen and is essential for healthy nerves, DNA synthesis, fatty acid synthesis and energy production. Our vitamin B12 levels depend directly on dietary intake from food or dietary supplements. It is found in rich supply in animal products and can’t be reliably supplied by a plant-based diet.
A recent systematic review found that combined oral contraceptives deplete vitamin B1225 and supports the view that vitamin supplements may be helpful in women taking these oral contraceptives.26
Vitamin E
Vitamin E is well known for its diverse and crucial effects on health – as an important antioxidant, for skin health, immune function and to protect cardiovascular health too. It is a fat-soluble vitamin and is incorporated into fat-rich cell membranes where it helps to provide essential protection against oxidative damage.
Research has shown that oral contraceptives increase markers of oxidative stress and decrease blood levels of vitamin E. 27-29 Research has also found an increase in blood clotting activity in combined oral contraceptive users, which may be linked to reduced levels of alpha-tocopherol found in these subjects. Supplementation with vitamin E may help to reduce platelet over-activity.30-33
Many people are unaware that the term vitamin E actually refers to a group of compounds which include several different tocopherols and tocotrienols. It is important therefore to choose a supplement that reflects this natural mix.
Magnesium
In a 2022 review of micronutrients and oral contraceptives, the authors wrote, “mineral status appears frequently affected in women taking hormonal therapies, especially for what concerns magnesium, zinc and selenium levels.”1 In fact, research shows that poor magnesium levels are common among women taking COCs and many studies have shown lower serum magnesium levels in oral contraceptive users compared to both non users and women taking other forms of contraception.34-40
This is particularly concerning when you consider that the body has widespread needs for magnesium and the average Western diet is already unlikely to provide enough. And this is especially true when coupled with a fast-paced 21st century lifestyle – characterised by poor sleep, high intensity exercise and chronic stress – all factors which may further deplete magnesium.
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When magnesium depletion occurs, it alters the calcium: magnesium ratio; “the resulting altered calcium: magnesium ratio influences processes of blood coagulation, increasing the risk of venous thrombosis, as described in a meta-analysis of 26 observational studies.”1,41-42
It seems reasonable therefore for women taking combined oral contraceptives to consider supplementing with additional magnesium. Magnesium glycinate is a calming and relaxing supplement form which is generally well tolerated and may be particularly helpful.
Vitamin B6
Many micronutrients work together and it is crucial to consider these inter relationships, as well as the context or ‘bigger picture’, when choosing to supplement. Vitamin B6 has important roles as a co-factor in many enzymatic reactions including supporting the conversion of an amino acid called tryptophan into the ‘happy’ neurotransmitter serotonin, supporting energy production and working together with nutrients such as folate and vitamin B12 to support methylation processes and DNA synthesis.43 Vitamin B6 may also be involved in modulating magnesium levels and has similar effects to vitamin E in reducing breast pain.44-46 In a large cross-sectional study involving 3362 adults, researchers found inadequate intake of vitamin B6 was related to an increased risk of anxiety and depression in women.47
Pyridoxal-5-phosphate is an active form of vitamin B6 which has been found to be reduced in oral contraceptive users compared to non-users.48,49 This demonstrates the likelihood of reduced levels of B6 in women taking combined oral contraceptives. Studies have also shown that daily supplementation with vitamin B6 reduces common side effects of oral contraceptives.50-52
Vitamin B6 can be supplemented in the active form of pyridoxal-5-phosphate and may be an important consideration for women taking combined oral contraceptives.
So what supplements should I consider while taking the combined oral contraceptive pill?
Research clearly demonstrates that combined oral contraceptives have the potential to deplete many essential nutrients. Here we have highlighted just a few, and sadly there are many more. It seems reasonable to recommend therefore, on the back of even just the evidence presented here, that women taking combined oral contraceptives may benefit from supplementing their diets with a daily multivitamin and mineral supplement. Selecting a high quality daily multivitamin and mineral supplement that provides essential nutrients in active forms seems a worthwhile investment in both immediate and long term health.
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Association between use of oral contraceptives and folate status: a systematic review and meta-analysis. J Obstet Gynaecol Can. 2015 May; 37 (5): 430-438. 8. Bailey LB, Berry RJ. Folic acid supplementation and the occurrence of congenital heart defects, orofacial clefts, multiple births, and miscarriage. Am J Clin Nutr 2005; 81: 1213-1217. 9. 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. 10. Fruzzetti, F. Beyaz P An oral contraceptive fortified with folate Women’s Health (Jan 2012): 13-9. 11. 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. 12. Check WA. Folate for oral contraceptive users may reduce cervical cancer risk. J Am Med Assoc 1980; 244:633-4. 13. Fallah S, Sani Fv, Firoozrai M. Effect of contraceptive pill on the selenium and zinc status of healthy subjects. Contraception 2009; 80: 40-43. 14. Wilson SM, Bivins BN, et al. Oral Contraceptive Use: Impact on Folate, Vitamin B(6), and Vitamin B(1)(2) Status. Nutr Rev. 2011; 69:572-83. 15. Mooij PN, Thomas CM, et al. Multivitamin supplementation in oral contraceptive users. Contraception 1991; 44:277-88 16. Lussana F, Zighetti Ml, et al. Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb Res 2003; 112: 37-41. 17. Shojania AM. Oral contraceptives: effect of folate and vitamin B12 metabolism. Can Med Assoc J 1982; 126: 244-247. 18. Wertalik L, Metz E, et al. Decreased Serum B 12 Levels With Oral Contraceptive JAMA 1972; 221: 1371-1374. 19. Sutterlin M, Bussen S, et al. Serum Folate And Vitamin B12 Levels In Women Using Modern Oral Contraceptives (Oc) Containing 20 Microg Ethinyl Estradiol. Eur J Obstet Gynecol Reprod Biol 2003; 107: 57-61. 20. Riedel B, Bjorke Monsen A, et al. Effects Of Oral Contraceptives And Hormone Replacement Therapy On Markers Of Cobalamin Status. Clin Chem 2005; 51: 778-781. 21. Shojania Am, Wylie B. The Effect Of Oral Contraceptives On Vitamin B12 Metabolism. Am J Obstet Gynecol 1979; 135: 129-134. 22. Veninga K S. Effects Of Oral Contraceptives On Vitamins B6, B12, C, And Folacin. J Nurse Midwifery 1984; 29: 386-390. 23. Hielt K, Brynskov J, Hippe E, et al. Oral contraceptives and the cobalamin (vitamin B12) metabolism. Acta Obstet Gynecol Scand 1985; 64:59-63. 24. Adams MJ Jr, Khoury MJ, et al. Elevated Midtrimester Serum Methylmalonic Acid Levels as a Risk Factor for Neural Tube Defects. Teratology. 1995; 51:311-7. 25. 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. 26. 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. 27. Pincemail J, Vanbelle S, et al. Effect of different contraceptive methods on the oxidative stress status in women aged 40 48 years from the ELAN study in the province of Liege, Belgium. Hum Reprod 2007; 22: 2335- 2343. 28. Zal F, Mostafavi-Pour Z, Amini F, Heidari A. Effect of vitamin E and C supplements on lipid peroxidation and GSH-dependent antioxidant enzyme status in the blood of women consuming oral contraceptives. Contraception 2012; 86: 62-66. 29. Kowalska K, Milnerowicz H. Pro/antioxidant status in young healthy women using oral contraceptives. Environ Toxicol Pharmacol 2016; 43: 1-6. 30. Aftergood L, Alfin-Slater R B. Oral contraceptivealpha- tocopherol interrelationships. Lipids 1974; 9: 91-96. 31. Akinsanya M, Adeniyi T, et al. Effects of vitamin E and folic acid on some antioxidant enzymes activities of female Wistar rats administered combined oral contraceptives. African J Biochem Res 2010; 4: 238-242. 32. Brigg M. Letter: vitamin E status and oral contraceptives. Am J Clin Nutr 1975; 28:436. 33. Renaud S, Ciavatti M, et al. Influence of vitamin E administration on platelet functions in hormonal contraceptive users. Contraception 1987; 36: 347-358. 34. Hameed A, Rauf S, et al. Effect of oral and injectable contraceptives on serum calcium, magnesium and phosphorus in women. J Ayub Med Coll Abbottabad 2001; 13: 24-25. 35. Olatunbosun DA, Adeniyi FA, Adadevoh BK. Effect of oral contraceptives on Serum magnesium levels. Int J Fertil 1974; 19: 224-226. 36. Akinloye O, Adebayo TO, et al. Effects of contraceptives on serum trace elements, calcium and phosphorus levels. West Indian Med J 2011; 60: 308-315. 37. Blum M, Kitai E, et al. Oral contraceptive lowers serum magnesium. Harefuah 1991; 121: 363-364. 38. Stanton MF, Lowenstein FW. Serum magnesium in women during pregnancy, while taking contraceptives, and after menopause. J Am Coll Nutr 1987; 6: 313-319. 39. Seelig MS. Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment. Magnes Res 1990; 3:197-215. 40. Seelig MS. Interrelationship of magnesium and estrogen in cardiovascular and bone disorders, eclampsia, migraine, and premenstrual syndrome. J Am Coll Nutr 1993; 12:442-58. 41. Stegeman BH, de Bastos M, et al. Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis. BMJ 2013; 347: f5298. 42. Cowan JA. Introduction to the biological chemistry of magnesium. ed. J.A. Cowan. New York. VCH;1995. 43. Tanaka T, Scheet P, et al. Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet. 2009 Apr 10; 84(4): 477-482 44. Iezhitsa IN, Spasov AA, et al. Effect of magnesium chloride on psychomotor activity, emotional status, and acute behavioural responses to clonidine, d-amphetamine, arecoline, nicotine, apomorphine, and L-5-hydroxytryptophan. Nutr Neurosci 2011;14: 10-24. 45. Abraham GE, Schwartz UD, Lubran MM. Effect of vitamin B-6 on plasma and red blood cell magnesium levels in premenopausal women. Ann Clin Lab Sci 1981; 11:333-336. 46. Shobeiri F, Oshvandi K, Nazari M. Clinical effectiveness of vitamin E and vitamin B6 for improving pain severity in cyclic mastalgia. Iran J Nurs Midwifery Res 2015; 20: 723-727. Soltany S, Hemmati HR, et al. Effect of vitamin B6 on mastalgia: A double blind clinical trial. Koomesh 2016; 17: 950-956. 47. Kafeshani M, Feizi A, et al. Higher vitamin B6 intake is associated with lower depression and anxiety risk in women but not in men: A large cross-sectional study. Int J Vitam Nutr Res. 2020 Oct; 90(5-6): 484-492. 48. Lussana F, Zighetti ML, et al. Blood levels of homocysteine, folate, vitamin B6 and B12 in women using oral contraceptives compared to non-users. Thromb Res 2003; 112: 37-41. 49. Lumeng L, Cleary RE, Li TK. Effect of oral contraceptives on the plasma concentration of pyridoxal phosphate. Am J Clin Nutr 1974; 27: 326-333. 50. Villegas-Salas E, Ponce de León R, et al. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive. Contraception 1997; 55: 245-248. 51. Bermond P. Therapy of side effects of oral contraceptive agents with vitamin B6. Acta Vitaminol Enzymol 1982; 4: 45-54. 52. De Souza MC, Walker AF, et al. A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: a randomized, double-blind, crossover study. J Womens Health Gend Based Med 2000; 9: 131-139.
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