New Research Finds Folic Acid and Zinc Supplementation in Men Not Effective for Treating Infertility

Infertility is a disorder of the reproductive system defined by the inability of a couple having regular intercourse without using contraception to achieve a pregnancy in one year, or after 6 months if the woman is older than 35.[1]

According to the National Institutes of Health (NIH), approximately 9% of men and 11% of women of reproductive age in the U.S. have experienced infertility.[2] In one-third of infertile couples the problem is with the man, in one-third the problem is with the woman and in one-third the problem either cannot be identified or is with both the man and the woman.[3]

The most common cause of infertility in women is a failure to ovulate, which occurs in 40% of infertile women.[4] Other causes of infertility in women include endometriosis, uterine fibroids, scarring in the uterus from prior surgery or infections, and autoimmune diseases such as lupus. The most common cause of infertility in men is decreased or absent sperm production.[5]

Dietary supplement use is very common for both men and women among couples who are trying to conceive a child.[6] Supplements for male fertility often contain folic acid and zinc, likely because both substances have been shown to play key roles in the formation and maintenance of normal healthy sperm.[7]

Dietary supplement companies rarely conduct the type of large, well-designed, randomized clinical trials needed to prove the health claims that they make about their products because the Food and Drug Administration does not require such trials. Fortunately, the NIH sometimes funds such trials, like the one published in the Jan. 7, 2020, issue of the Journal of the American Medical Association (JAMA) that showed supplementation with folic acid and zinc in men among couples undergoing infertility treatment does not increase the chances of achieving a successful pregnancy.[8]

Overview of folic acid and zinc

Folate is a B-vitamin that is naturally present in many foods. Cells throughout the body need folate to make DNA and to divide.[9] Folic acid is a form of folate that is used to fortify foods and included as an ingredient in many dietary supplements. The recommended daily intake for folate varies by life stage (see Table below).[10] Folate is found in many vegetables (especially asparagus, brussels sprouts and dark green leafy vegetables), fruits and fruit juices (especially oranges and orange juice), nuts, beans and peas.[11] Folic-acid–fortified foods include enriched flour, cornmeal, pasta, rice and cereals.

Average Recommended Daily Folate and Zinc Intakes

Abbreviations: mcg DFE, micrograms of dietary folate equivalents; mg, milligrams
Sources: National Institutes of Health, Office of Dietary Supplements, Zinc and Folate Fact Sheets for Consumers

Zinc is an essential mineral required for good health.[12] It is naturally present in some foods, added to other foods, and an ingredient found in many dietary supplements. Cells throughout the body need zinc to make proteins and DNA and carry out other critical functions.[13] Zinc also helps the body’s immune system combat bacterial and viral infections, promotes wound healing and is needed for normal childhood growth and development.[14] Like folate, the recommended daily intake for zinc varies by life stage (see Table above). Dietary sources of zinc include oysters, red meat, poultry, crab, fortified breakfast foods, beans, nuts, whole grains and dairy products.

Healthy people can easily get the recommended amounts of both zinc and folate by eating a balanced diet.

The JAMA clinical trial[15]

For the trial, researchers enrolled 2,370 couples (men age 18 or older and women age 18 to 45) planning infertility treatment at four medical centers in the U.S. from June 2013 to December 2017. The trial excluded couples if they planned to use sperm donors or maternal surrogates or if the male partners had certain conditions that resulted in the absence of sperm in the semen or other known causes of infertility that were unlikely to benefit from supplementation. The men were instructed to abstain from using dietary supplements containing folic acid or zinc not provided by the research team, as well as medications known to interact with folic acid and zinc.

The men were randomly assigned in equal numbers to receive either supplements containing five milligrams (mg) of folic acid and 30 mg of zinc or a placebo daily for six months. The researchers assessed semen quality in the men at the time of enrollment and at six months after randomization. Female partners of the men were followed for nine months after randomization and up to nine additional months to assess pregnancy outcomes.

The researchers found no significant difference in the proportion of participants who achieved a live birth with their partner: 34% in the supplement group and 35% in the placebo group. Notably, men in the supplement group had lower overall semen quality than those in the placebo group, primarily due to an increased rate of DNA fragmentation.

Finally, adverse events overall were more frequent in the men receiving the supplements than in those receiving a placebo (32% versus 27%, respectively), primarily because of significantly higher rates of abdominal discomfort or pain, nausea, vomiting and skin redness.

The researchers concluded that their findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility.

What You Can Do

If you are a man and you and your female partner are being treated for infertility, you should avoid taking folic acid and zinc supplements.
 

References

[1] National Institutes of Health. Eunice Kennedy Shriver National Institute of Child Health and Human Development. Infertility and fertility. https://www.nichd.nih.gov/health/topics/factsheets/infertility. Accessed August 28, 2020.

[2] Ibid.

[3] Ibid.

[4] National Institutes of Health. Eunice Kennedy Shriver National Institute of Child Health and Human Development. What are some possible causes of female infertility? January 31, 2017. https://www.nichd.nih.gov/health/topics/infertility/conditioninfo/causes/causes-female. Accessed October 1, 2020.

[5] National Institutes of Health. Eunice Kennedy Shriver National Institute of Child Health and Human Development. What are some possible causes of male infertility? January 31, 2017. https://www.nichd.nih.gov/health/topics/infertility/conditioninfo/causes/causes-male. Accessed October 1, 2020.

[6] Palmsten K, Flores KF, Chambers CD, et al. Most frequently reported prescription medications and supplements in couples planning pregnancy: The LIFE study. Reprod Sci. 2018;25(1):94-101.

[7] Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: A randomized clinical trial. JAMA. 2020;323(1):35-48.

[8] Ibid.

[9] National Institutes of Health, Office of Dietary Supplements. Folate fact sheet for consumers. July 11, 2019. https://ods.od.nih.gov/factsheets/Folate-Consumer/. Accessed August 28, 2020.

[10] Ibid.

[11] Ibid.

[12] National Institutes of Health, Office of Dietary Supplements. Zinc: Fact sheet for health professionals. July 15, 2020. https://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/. Accessed August 28, 2020.

[13] National Institutes of Health, Office of Dietary Supplements. Zinc fact sheet for consumers. December 10, 2019. https://ods.od.nih.gov/pdf/factsheets/Zinc-Consumer.pdf. Accessed August 28, 2020.

[14] Ibid.

[15] Schisterman EF, Sjaarda LA, Clemons T, et al. Effect of folic acid and zinc supplementation in men on semen quality and live birth among couples undergoing infertility treatment: A randomized clinical trial. JAMA. 2020;323(1):35-48.