Hotaling and colleagues highlight a few interesting issues in their editorial “Is it time to start folate supplementation in men? The effect of paternal folate status on embryonic growth’’. The authors mention the Lambrot study showing that a folate deficient diet can cause negative pregnancy outcomes via changes in the sperm epigenome of mice. In addition,  the study performed in human by Aarabi et al.  showed that the use of 5 mg folic acid supplements during six months resulted in a mild but significant loss of methylation in the seminal DNA. Unfortunately, this study did not investigate  associations between methylation changes and reproductive, fetal or pregnancy outcomes. Because intakes of synthetic folic acid of on average more than 0.27 mg per day cannot be metabolized and appear as an oxidant in serum, more research has to be performed to find the lowest and safest dose of folic acid supplements for couples contemplating pregnancy1.

We are very much intrigued by the hypothesis that the lack of seminal fluid exposure might explain the absence of significant associations between the paternal folate status and early embryonic growth in IVF/ICSI pregnancies. The Boxmeer study published by our group in 2009 showed that seminal plasma folate was significantly higher compared to blood serum folate (25.3 vs 15.7 nmol/L). This study substantiates the hypothesis that paternal seminal plasma folate can have an impact on implantation and early embryonic growth after exposure of the cervix and endometrium.

We hope that more research will  be done to get a clearer understanding of the role of the father-to-be in order to further develop and improve  periconception care and health of future generations.

 1Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Am J Clin Nutr. 1997 Jun;65(6):1790-5.)