Thursday March 20 2008
Folic acid is found naturally as folate in leafy green vegetables
Folic acid may improve men’s chances of fathering a child, The Guardian reports. Women have long been encouraged to take folic acid when trying for a baby, but a new study has found “a link between high levels of the nutrient in men’s diets and the genetic quality of their sperm,” the newspaper says.
The study behind the story is a small cross-sectional survey of 89 healthy, non-smoking male volunteers. It found a link between folic acid intake and the frequency of abnormalities in sperm cells. By virtue of its design, limited conclusions can be drawn from the study and the results may have arisen by chance. Randomised controlled trials are needed to explore this relationship properly.
Where did the story come from?
Dr Suzanne Young and colleagues from the University of California, the Lawrence Livermore National Laboratory, and the Lawrence Berkeley National Laboratory carried out this research. The study was funded by the National Institutes of Health, the Environmental Protection Agency and the United States Department of Energy. It was published in Human Reproduction, a peer-reviewed medical journal.
What kind of scientific study was this?
Healthy sperm should have one copy of each sex chromosome (X or Y). Aneuploidy means the sperm contains an abnormal number of chromosomes. About 1% to 4% of a healthy male’s sperm have some type of abnormality of this kind. Why these abnormalities happen is poorly understood and the role of nutrition has not been explored.
In this small cross-sectional study, researchers contacted 97 volunteers who were healthy, non-smoking, current or retired employees of a university research laboratory. Participants were sent a questionnaire to collect information about their sociodemographic characteristics, medical and reproductive history, and lifestyle. The questionnaire also included a food frequency section that looked at the type and amount of foods eaten daily. Participants were also sent instructions for semen collection, a sterile container and a protective thermos to provide a sperm sample. To ensure completion and accuracy, participants were contacted by telephone and the food frequency question was completed within a week of providing the sperm sample.
The researchers analysed the sperm samples to determine whether they had any abnormalities. They looked for abnormalities associated with the genetic disorders Klinefelter’s, triple X, XYY, Turner and Down’s syndromes. Eighty-nine men were available for analysis after excluding those with low sperm counts or unusable food consumption data. The researchers used statistical methods to assess whether there was any relationship between the frequency of different types of abnormality (per 10,000 sperm) and low, moderate or high daily intake (from diet and through supplements) of different micronutrients (vitamin C, vitamin E, beta-carotene, folate and zinc). The researchers also took into account some factors that could also affect sperm health, e.g. disease history, body mass index, occupational history and use of tobacco, alcohol or caffeine, among other exposures.
What were the results of the study?
The researchers found that several micronutrients were associated with a lower frequency of different abnormalities. High folic acid intake was associated with 19% fewer abnormalities (all types) than moderate intake and 20% fewer than men with a low micronutrient intake. There were also reductions in specific types of abnormality. For example, there were 26% fewer sperm with no sex chromosome in the high-intake group compared with the low-intake group. There were also 30% fewer sperm with two X chromosomes (associated with triple X syndrome) and abnormalities on chromosome 21 (associated with Down’s syndrome) in the high-intake group compared with the moderate-intake group.
However, men in the low-intake folic acid group had fewer sperm with two X chromosomes (associated with triple X syndrome) and abnormalities on chromosome 21 (associated with Down’s syndrome) than in the moderate-intake group. High total zinc intake reduced the frequency of two X chromosomes by about 50% compared with the moderate-intake group and 39% compared with the low-intake group. Zinc was not associated with lowering the risk of other abnormalities. Vitamin C and vitamin E had no association with sperm abnormalities, but high beta-carotene intake reduced YY abnormalities.
The researchers calculated that there was a reduction of 3.6% in the frequency of total abnormalities for every 100 microgram increase in daily total folate. When considering the different types of abnormalities separately, the magnitude of reduction was similar for two X chromosomes, no chromosomes and abnormality on chromosome 21.
There was a reduction of 2.8% in sperm having two Y chromosomes for every 1,000 microgram increase in daily total beta-carotene.
What interpretations did the researchers draw from these results?
The researchers conclude that micronutrient intake affects male reproductive health. They say that they have found that total folic acid intake is associated with a statistically significant reduction in frequency of sperm abnormalities in healthy males. They say that there are “no consistent relationships between intakes of zinc or the antioxidant vitamin C, vitamin E or beta-carotene on the frequencies of aneuploid sperm”.
What does the NHS Knowledge Service make of this study?
This is a small cross-sectional study and has some limitations, mainly those associated with this type of study design:
- Cross-sectional studies cannot establish causal links between factors. This study cannot prove that low levels of micronutrient intake cause abnormalities in sperm. Randomised controlled trials that compare men who take micronutrients with those who do not would be the most robust way to answer this question.
- As the researchers point out, the intake of folic acid varied with the intake of other micronutrients, so they “could not definitively determine whether the results derived specifically from folate intake”. Again, randomised controlled trials would better establish this.
- The researchers point out that the men involved in the study were high supplement-users (e.g. consuming more than double the recommended daily intake for folic acid) so, from these results, the importance of micronutrients from diet only are unclear. The findings may have limited application to members of the general population as the participants were a healthy non-smoking group.
- The food frequency questionnaire has some problems, particularly how well it estimates the amount of food eaten. As the authors say, intake of the different nutrients measured through the questionnaire may not reflect the concentrations in the blood or cells and in sperm production processes.
- Performing a number of different analyses on a dataset, as the researchers here did, increases the likelihood that positive findings have arisen by chance only. The researchers don’t appear to have adjusted for this. However, they say that the consistent associations that different analyses found between folate intake and different types of sperm aneuploidy “argue that the finding is not simply due to chance”. The truth is that, in science, it is rarely 100% certain that a result is not due to chance. Without correcting for these separate analyses, there is an increased likelihood that chance is responsible for the positive results here.
The study gives some evidence of a link between folate intake and sperm abnormalities. However, larger studies, particularly those with a more robust study design (e.g. randomised controlled trials), would give more confidence that any relationship between folic acid and sperm quality was real.
Links to the headlines
Folic acid boosts prospect of fatherhood, study claims. The Guardian, March 20 2008
Vitamin B 'helps men father healthy children'. The Daily Telegraph, March 20 2008
Taking folic acid can enhance fertility in men, researchers say. The Independent, March 20 2008
'Popeye' dad diet. The Sun, March 20 2008
Folic acid 'makes men more fertile'. Metro, March 20 2008
Folate 'may keep sperm healthy'. BBC News, March 20 2008
Folic acid linked to healthy sperm. Channel 4 News, March 20 2008
Links to the science
Young SS, Eskenazi B, Marchetti FM, et al. The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men. Hum Reprod 2008; Mar 19 [Epub ahead of print]
Pena-Rosas JP, Viteri FE. Effects of routine oral iron supplementation with or without folic acid for women during pregnancy. Cochrane Database Syst Rev 2006, Issue 3
Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2001, Issue 3