High-Dose Supplementation of Folic Acid in Infertile Men Improves IVF-ICSI Outcomes: A Randomized Controlled Trial (FOLFIV Trial)
A multicenter, randomized, double-blind placebo controlled trial (FOLFIV) was carried out to test the potential of high dose folic acid supplementation on sperm characteristics and IVF/ICSI outcomes in couples with male infertility.
Male participants were aged 18-60 years old, with at least one abnormal sperm parameter, according to the 2010 World Health Organization reference values, following 3-5 days of abstinence. This included sperm concentration <15 million spermatozoa/mL, motility <50%, vitality <60% and morphology <4%. Female partners were aged 18-38 years old without any known female infertility factors.
A questionnaire regarding lifestyle, job, smoking history and potential sexual intercourse issues was completed, during initial assessment (day 0) of male participants, with a semen and blood sample also collected.
To minimise potential bias chronic viral diseases (hepatitis B, hepatitis C, human immunodeficiency) in either partner, history of epilepsy, other chronic diseases (heart disease, diabetes, hypertension, cancer), past cancer treatment, ejaculatory duct obstruction, testicular/frozen sperm, prior folic acid supplementation or males with intolerance to folic acid were all excluded from the study.
In total 162 males meeting the inclusion exclusion criteria were then randomly allocated to take 3 tablets (5mg each) a day of folic acid or matching placebo for a period of 3 months, with semen and blood sample collected once complete. Adverse symptoms and adherence to dose frequency was assessed with end of study questionnaires. Allocated tablets were then continued until final semen collection for IVF/ICSI.
Controlled ovarian stimulation varied according to individual patients characteristics (age, BMI, AMH) with gonadotropin-releasing hormone (GnRH) antagonist, short or long GnRH-agonist protocols utilised. Ovulation was triggered once 3 follicles reached 17µm in diameter with oocyte retrieval carried out 36 hours later. IVF or ICSI was then performed using fresh sperm followed by the transfer of 1 or 2 embryos, 1, 2-3 or 5 days after oocyte retrieval . Luteal phase support began on day of oocyte retrieval and continued up until the 12th week of gestation in clinically pregnant women.
Primary study outcomes was both biochemical pregnancy rates and clinical pregnancy rates. Serum hCG level > 100 IU/mL following transfer was defined as a biochemical pregnancy, with clinical pregnancy confirmed on the 7th week of gestation by ultrasonography, defined by the presence of at least one fetus with positive heart activity.
Baseline characteristics of the men in both groups (treatment or placebo) showed no significant difference in age, BMI, ethnicity, prior medical history, FSH, genital infection and testicular trauma however testicular ultrasonography did show higher rates of varicocele (grade 1-3) in the folic acid group compared to placebo (49% vs 33%).
Similarly baseline characteristics of the women in both groups showed no significant differences in age, BMI, ethnicity and ovarian reserve (FSH, AMH, AFC). Of note, seven women in the folic acid group and five in the placebo group had a history of medical disease, while nine women had PCOS (folic acid = 5, placebo = 4) and one woman had endometriosis (folic acid).
Overall the distribution of primary infertility, pure male infertility and duration of infertility were all similar between the 2 groups implying minimal bias.
Unsurprisingly following 3 months of supplementation, serum levels of folic acid were significantly higher in the folic acid group, compared to placebo, however interestingly semen analysis failed to find any improvement in the WHO sperm parameters (concentration, total motility, progressive motility and morphology).
On the other hand DNA fragmentation testing found a statistically significant improvement (p<0.0001) in the folic acid group after 3 months, whilst no significant difference was seen in the placebo group.
Next, baseline analysis of IVF and ICSI attempts across both groups did not find any significant differences (potential bias) with similar fertilization rates, day of fresh transfer and mean number of embryos transferred.
However, intention-to-treat population (n = 162) analysis showed a significantly higher total number of pregnancies (including spontaneous and IVF/ICSI) among the folic acid group compared to placebo (26 vs 15 pregnancies or 31.33% vs 18.99%), in which each group had five spontaneous pregnancies during the trial.
Analysing strictly IVF/ICSI population (n=132) outcomes, a similar pattern was seen with higher biochemical pregnancy rate per oocyte retrieval (38.8% vs 16.9%), biochemical pregnancy rate per embryo transfer (44.1% vs 22.4%) and clinical pregnancy rate per embryo transfer (35.6% vs 20.4%) in the folic acid group.
SUMMARY: Can men take folic acid
In this study, males diagnosed as infertile, who took 15mg of folic acid a day for 3 months, had a significant increase in the biochemical pregnancy rate (44.1% vs 22.4%) and clinical pregnancy rate (35.6% vs 20.4%), compared to the placebo-controlled group, following a single fresh IVF/ICSI cycle.
- Small study size
- Live birth rate was not reported
Schisterman E F, et al. (2020). Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial. https://doi.org/10.1001/jama.2019.18714
Aarabi M, et al. (2015). High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism. https://doi.org/10.1093/hmg/ddv338
Tremellen K, et al. (2007). A randomised control trial examining the effect of an antioxidant (Menevit) on pregnancy outcome during IVF‐ICSI treatment. https://doi.org/10.1111/j.1479-828X.2007.00723.x
Wong W Y, et al. (2002). Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial. https://doi.org/10.1016/S0015-0282(01)03229-0
Bentivoglio G, et al. (1993). Folinic acid in the treatment of human male infertility. https://doi.org/10.1016/S0015-0282(16)56225-6
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