Maternal intake of folic acid and folate during mid-pregnancy may affect male reproductive health

The study showed that lower maternal intake of total folate during mid-pregnancy was linked with lower testes volume and sperm count, with a lower proportion of non-progressive and immotile spermatozoa in adult men.

"The findings were vague, as we saw signals of both potential lower fecundity in some markers and higher fecundity in other markers of male fecundity, warranting further investigation," the researchers wrote. "Still, pregnant women should follow the current recommendations on folate intake, owing to the well-established benefits for the child's health following sufficient folate intake in the periconceptional period."

In many countries, poor male fecundity is of concern. A prenatal origin has been suggested for poor male fecundity. Low sperm count is linked with a longer time to pregnancy, low fecundity, and an increase in the need for medically assisted reproduction to achieve pregnancy.

Folate is a methyl donor involved in DNA methylation and is essential for normal fetus development by gene expression regulation during different periods of fetus development. Thus, prenatal exposure to low maternal folate intake might have a programming function on the developing reproductive organs. However, in this field, only one cohort study of 347 Danish men has been conducted, which found no association between maternal intake of folic acid supplements and semen quality. Therefore, the potential association between prenatal folate exposure and male fecundity markers warrants further investigation.

To fill the knowledge gap, Anne Gaml-Sørensen from Aarhus University in Aarhus C, Denmark, and colleagues aimed to examine the association between maternal folate intake from diet and folic acid from supplements during pregnancy and fecundity markers in young men.

For this purpose, the researchers conducted a follow-up study using a Danish mother–son cohort of 787 young men born between 1998 to 2000. Percentage differences in reproductive hormone levels, testes volume, and semen characteristics were analyzed according to the calculation of total folate as dietary folate equivalents from supplements and diet in mid-pregnancy. The total folate was analyzed in quintiles, continuous per standard deviation decrease (SD: 318 μg/day) and as restricted cubic splines.

The team found that low maternal intake of total folate was linked with lower total sperm count (−5%), a lower proportion of non-progressive and immotile spermatozoa (−5%), and lower testes volume (−4%) per SD decrease in total folate intake. Spline plots supported these findings.

The research team highlighted that the finding of a lower proportion of immotile and non-progressive spermatozoa, and hence a more significant proportion of motile spermatozoa, in men of mothers with a lower folate intake on mid-pregnancy was surprising and maybe a chance finding.

"Lower maternal folate intake in mid-pregnancy is linked with lower testes volume and sperm count but with a lower proportion of immotile and non-progressive spermatozoa in adult men," the authors conclude. "Whether this affects the ability to obtain pregnancy warrants further investigation.

Reference:

Gaml-Sørensen A, Brix N, Høyer BB, Tøttenborg SS, Hougaard KS, Bonde JPE, Clemmensen PJ, Ernst A, Arendt LH, Olsen SF, Granström C, Henriksen TB, Toft G, Ramlau-Hansen CH. Maternal intake of folate and folic acid during pregnancy and markers of male fecundity: A population-based cohort study. Andrology. 2023 Mar;11(3):537-550. doi: 10.1111/andr.13364. Epub 2022 Dec 26. PMID: 36524586.