Effect of Folic Acid Supplementation on Fertility
Abstract
Folate is required during periods of rapid cell growth, and has therefore been thought to potentially improve reproduction during the preconception period. Folic acid supplementation is believed to decrease the incidence of ovulatory infertility and improve oocyte quality in women, as well as facilitate spermatogenesis in men. This review includes ten original research studies published within the last ten years that sought to establish an association between folic acid supplementation and fertility. Eight of the ten studies determined that either folic acid improved fertility and/or that low folate status reflected reduced fertility. Four out of the six male studies found improved sperm parameters with supplementation, and all four female studies found improved fertility with higher folic acid intake. Folic acid supplementation has been found to improve fertility in men and women, although it is unclear whether or not low folate status causes infertility. It is also possible that folate may interact with other nutrients, such as vitamin B12 or zinc. It appears that folic acid supplementation likely improves fertility in men and women, although more research is necessary.
Introduction
Infertility is defined as the inability to conceive after 12 months of regular unprotected intercourse (Pizzorno & Murray, 2013). It is a multifactorial disease process with many potential contributing factors (Begum, Moniruddin, & Nahar, 2009). According to the CDC, about 12% of women aged 15-44 experience difficulty getting pregnant or carrying a pregnancy to term (CDC Infertility, 2019). Diet and lifestyle modifications can improve fertility in both men and women.
Folic acid, also known as vitamin B9, is necessary for DNA and RNA synthesis, optimal protein synthesis, regulation of gene expression, and prevention of neural tube defects (Pizzorno & Murray, 2013). Folic acid is the synthetic form of vitamin B9 that is commonly added to supplements and processed foods, whereas folate is the naturally occurring form of vitamin B9 (Arnarson, 2017). In women, supplementation is thought to decrease the incidence of ovulatory infertility and improve oocyte quality and maturation. In men, both folic acid and vitamin B12 facilitate spermatogenesis, and low levels of folic acid have been associated with increased sperm DNA damage. Dietary sources of folic acid include: green leafy vegetables, asparagus, broccoli, orange juice, wheat germ, sunflower seeds, legumes, and fortified such as breakfast cereals or pasta (Insel, Ross, McMahon, & Bernstein, 2017).
Folate is required during periods of rapid cell growth, and has therefore been thought to potentially improve reproduction during the preconception period. Studies have found that women with greater amounts of supplementary folate had higher rates of pregnancy and live birth rates (Collins & Rossi, 2015). It is believed to decrease the incidence of ovulatory infertility, improve oocyte quality, facilitate spermatogenesis, and improve sperm parameters. The purpose of this literature review is to compare the most current research studies to determine whether or not folic acid supplementation improves fertility in men and women.
Methods
For this literature review, the researcher used the search parameters (folate OR “folic acid”) AND (fertility OR infertility), found in the abstract in ProQuest Central, PubMed, and Google Scholar. The search was limited to free full text and peer reviewed original research studies published within the last ten years that sought to establish an association between folic acid supplementation and fertility. This review includes the ten original research studies found within these parameters. The purpose of this literature review is to compare the most current research studies to determine whether or not folic acid supplementation improves fertility in men and women.
Results
In a study of 100 sub-fertile men, Canepa et al. (2018) found a significant improvement in semen quality after treatment. Treatment included a combination of nutraceuticals composed of myo-inositol, alpha-lipoic acid, folic acid, betaine and vitamins B2, B6, and B12. The researchers analyzed the participants’ semen before and after 90 days of treatment. They found an increase in sperm concentration, number of spermatozoa, progressive motility, total motile sperm count, and normal sperm morphology. The researchers concluded that this combination of nutraceuticals improved sperm parameters in sub-fertile men.
Similarly, Najafipour, Moghbelinejad, Aleyasin, and Jalilvand (2017) studied 280 Iranian men with impaired spermatogenesis. The researchers assessed the effect of two methylenetetrahydrofolate reductase (MTHFR) polymorphisms on male infertility and the effect of the vitamin B family on sperm parameters. The MTHFR gene is involved in folate metabolism and polymorphisms in the gene can contribute to male infertility. They found that daily consumption of vitamins B9 and B12 significantly improved sperm parameters and the fertility of men with with different genotypes of MTHFR polymorphisms.
Nadjarzadeh, Mehrsai, Mostafavi, Gohari, and Shidfar (2013) compared 32 sub-fertile men and 32 fertile male controls to determine the effects of various dietary antioxidants on semen parameters. The researchers determined nutrient consumption with food frequency questionnaires and assessed semen quality for volume, concentration, motility and morphology. They found that low intake of folate, zinc, and vitamin E were related to poor sperm concentration and motility.
Conversely, Aarabi et al. (2015) studied the effect of high-dose folic acid supplementation on 30 men with idiopathic infertility and found no significant improvements in sperm parameters. They did, however, find a trend towards improved sperm DNA integrity. They found a significant loss of methylation across the sperm epigenome, more prominent in individuals with MTHFR homozygosity. They also found that the affected genic regions could represent disease-related genes, genes involved in cancer and neurobehavioral disorders. They suggest a more personalized approach to folic acid supplementation based on the genetic background of the individuals.
In a study of 269 men, Yuan et al. (2017) found that folate levels were significantly lower among infertile men, and low folate levels were significantly correlated with low sperm concentration in fertile men. Folate deficiency also significantly reduced the expression of three key molecules essential to spermatogenesis. The researchers concluded that sufficient folate levels may be required for normal spermatogenesis and male reproductive health.
Murphy et al. (2011) studied 153 infertile men and 184 fertile male controls to determine whether or not idiopathic male infertility was associated with variants in folate, vitamin B12, and total homocysteine-related genes. The researchers found that infertile men had lower serum folate concentrations, but determined that low folate level was not shown to cause male infertility. Folate concentration was not found to be correlated with any semen parameters.
In a study of 60 fertile and 60 infertile Indian women, Dhanashree, Anuradha, and Ketan (2016) found that infertile women had lower levels of iron, zinc, folic acid, as well as lower intake of protein and calories. Intake of green leafy vegetables, eggs, chicken, nuts, and dried fruit was higher among fertile women. Green leafy vegetables, which are high in folic acid, were significantly correlated to fertility in these women. Frequency of green leafy vegetable intake was highest in fertile women, and the most fertile women consumed them three times per week.
Gaskins et al. (2012) assessed the folate intake for 259 women in relation to their reproductive hormone levels and risk of anovulation (no oocyte released during menstrual cycle). The researchers also analyzed the type of folate consumed and the difference between dietary and synthetic folate supplementation. Higher dietary folate intake had a marginally significant association with greater luteal progesterone levels. Higher intake of synthetic folate was significantly associated with higher luteal progesterone levels and decreased odds of anovulation by 64%. The researchers concluded that the findings could be due to the greater absorption rates of synthetic folate.
Two studies analyzed folate supplementation in women undergoing assisted reproductive technology (ART) treatment. Gaskins et al. (2014) studied the effects of folate supplementation on 232 women participating in ART treatment. Higher intake of supplemental folate was associated with higher live birth rates after ART treatment. Similarly, Gaskins et al. (2015) assessed folate and vitamin B12 supplementation on 100 women participating in ART treatment. The researchers found that higher folate and vitamin B12 levels before ART treatment were associated with higher live birth rates.
Discussion
Of the ten studies analyzed above, six studies assessed the effect of folic acid on semen parameters in men. Four found a positive correlation between folic acid supplementation and male fertility. One study found that folic acid supplementation did not significantly improve semen parameters (Aarabi et al., 2015). The final study by Murphy et al. (2011) concluded that although infertile men were found to have lower serum folate concentrations, low folate levels were not shown to cause male infertility and folate was not correlated with semen parameters. In contrast, Yuan et al. (2017) and Nadjarzadeh (2013) found low serum folate levels in infertile men and determined that folate may be a significant predictor of sperm parameters and male reproductive health.
All four of the studies on women found a positive correlation between folic acid and female fertility. Gaskins et al. (2012) found that synthetic folic acid supplementation improved reproductive hormone levels and decreased the incidence of anovulation. Both Gaskins et al. (2014) and (2015) found that folate supplementation was associated with higher live birth rates and improved reproductive health after ART treatment. Dhanashree et al. (2016) found a link between low serum folate levels and infertility, concluding that infertile women had lower levels of folic acid, and that fertile women consumed the highest amount of dark leafy greens (which are high in folic acid).
There are other factors to take into consideration when analyzing these results. First, it is possible that folic acid may affect fertility in combination with other vitamins, such as vitamin B12 or zinc. In a systematic review and meta-analysis, Irani et al. (2017) found that folate plus zinc had a statistically greater effect on sperm concentration, morphology, and serum folate level in sub-fertile men. However, folate supplementation alone did not appear to be effective on morphology and motility of sperm. Canepa et al. (2018) studied a combination of nutraceuticals, whereas Najafipour et al. (2017) studied the combined effects of vitamins B9 and B12. Both found positive effects on sperm parameters, but it is unknown whether folate or folate in combination with these other constituents caused the effect. Also, the type of folate consumed may affect bioavailability and absorption. Synthetic folate may be more effective than dietary (Gaskins et al., 2012).
Folic acid also plays an important role in preconception maternal nutrition. Women planning to become pregnant should take supplemental folic acid to prevent neural tube defects, as they may not consume enough from diet alone. Dietary sources of folic acid include: green leafy vegetables, asparagus, broccoli, orange juice, wheat germ, sunflower seeds, legumes, and fortified such as breakfast cereals or pasta (Insel et al., 2017). Folate is also very sensitive to heat. Cooking and processing can destroy up to 90 percent of folate, so it is best served raw or lightly cooked. Finally, maternal nutrition should include nutrient-dense whole foods both before and during pregnancy. Avocados are an excellent example because they are high in folate, potassium, fiber, monounsaturated fats, and lipid-soluble antioxidants (Comerford, Ayoob, Murray, & Atkinson, 2016).
Conclusion and Recommendations
It appears that folic acid supplementation likely improves fertility in men and women, although more research is necessary. Eight out of the ten research studies reviewed found a positive correlation between folic acid supplementation and fertility in men and women. Although infertile individuals have been found to have lower serum folate concentrations, it is not clear whether or not folate status directly causes infertility. However, folic acid supplementation within the recommended levels is not detrimental to fertility, and should be encouraged.
Fertility education is incredibly important. Women who do not seek preconception medical advice have low prevalence of folic acid consumption (Nilsen et al., 2016). Adherence to lifestyle changes (weight loss, tobacco use) and supplementation (folic acid) is often low among women trying to become pregnant (Joelsson et al., 2016). Preconception counseling for women of fertile age can help to improve natural fertility and prevent pregnancy complications.
Future studies would benefit from testing folic acid supplementation alone and in combination with other nutrients (such as vitamin B12) to determine whether or not folic acid alone improves fertility. Also, the correlation between serum folate levels and infertility remains unclear. Future studies may shed light on whether or not low concentration levels of folate necessarily mean that infertility is caused by the deficiency. Infertility affects a great number of men and women worldwide, and diet and lifestyle modifications are increasingly important to achieving natural fertility.
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