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Folic acid and zinc supplements did not improve semen quality or birth rates among couples seeking infertility care, a randomized trial found

Live birth rates were 34% when men in the couples received daily doses of folic acid and zinc, commonly regarded as semen quality enhancers, on top of standard infertility treatments, versus 35% in a placebo group (risk difference -0.9%, 95% CI -4.7% to 2.8%), reported Enrique Schisterman, PhD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, Maryland, and colleagues.

Men taking the supplement combination also saw no difference in sperm quality parameters such as sperm count, movement, or formation. In fact, this group showed lower sperm quality due to greater sperm DNA fragmentation, the researchers reported in . Men in the supplementation group had an average of 29.7% DNA fragmentation, versus 27.2% in the placebo group (mean difference 2.4%, 95% CI 0.5%-4.4%).

Co-author Lindsey Sjaarda, MD, told 麻豆传媒 that despite the incorporation of zinc and folic acid in products marketed to improve male fertility, the supplements had a clear "no benefit" result in this study, including some evidence of mild harm. "Our trial showed unequivocal evidence that this dietary supplement combination does nothing to improve semen quality or, most importantly, birth rates in couples seeking infertility care," Sjaarda said in an email.

Michael Drews, MD, founding partner of Reproductive Medicine Associates of New Jersey, who was not involved in the study, said "our subspecialty can be guilty of too quickly adopting untested and unproven treatments and practices before subjecting them to the scrutiny of the scientific method." Physicians can be especially guilty of this regarding "harmless" over-the-counter supplements, he added in an email to 麻豆传媒.

When a patient has good nutrition, Drews said that "the idea of enhancing male or female fertility through the use of nutritional or vitamin supplements makes little teleological evolutionary sense."

Zinc and folic acid are included in a number of male fertility supplements, many of which are unregulated for safety and efficacy, Schisterman and colleagues wrote. While some evidence has suggested the combination of zinc and folic acid may improve sperm quality, that research is limited by small sample sizes and varied results.

That prompted Schisterman and colleagues to conduct the 6-month . Participants included 2,370 couples enrolled at four reproductive and endocrinology study centers from June 2013 to December 2017, located in Salt Lake City, Chicago, Minneapolis, and Iowa City. Couples in which the man had azoospermia or other conditions unlikely to benefit from supplementation were excluded.

Supplement doses were 5 mg for folic acid and 30 mg for zinc. Men also attended bi-monthly study visits for semen and other biospecimen collection. Researchers administered female participants a monthly questionnaire and followed them up to 18 months after the start of the trial to assess pregnancy outcomes. Couples also received conventional fertility treatments such as ovulation induction and intrauterine insemination.

Three-quarters of the 2,370 men in the trial attended the 6-month study visit. Male participants were an average of age 33 years, primarily white, and of high socioeconomic status. All of the study participants were evaluated for live birth, but a third were missing semen quality measurements due to loss to follow up or lacked samples.

Overall, 820 participants achieved a live birth. In the group that received folic acid and zinc supplements, 404 had a live birth, as opposed to 416 in the placebo group.

Adverse events, mainly related to gastrointestinal symptoms, were slightly more common among participants receiving zinc and folic acid supplementation (32% vs 27% in the placebo group).

Schisterman and colleagues noted limitations to the study, including its restriction to a subfertile male population that was mostly white and of high socioeconomic status. In addition, it was possible that some couples conceiving during the trial did so before receiving any supplementation. And semen quality measures at 6 months were lacking for nearly one-third of participants, although the researchers said a sensitivity analysis indicated that the overall findings were probably not affected.

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