Does supplementation with 400 mg or more of folic acid for two weeks increase success

of IVF for men and women having fertility issues?

DFM 450
Michael Hoyt
Thao Tran
April, 18 2018
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Introduction

The recommended dietary allowance (RDA) for Folate is 400 microgram (mg) of

dietary folate equivalents (DFE) per day (Gropper, Smith, & Carr, pg. 349). The

synthetic form of folate, folic acid, has a Tolerable Upper Intake Level for adults of 1000

mg from supplemental or fortified foods (Gropper, Smith, & Carr, pg. 351).

Preconception nutrition for males is also important since men account for one out of three

infertility cases (Americanpregancy.org). ​The inability to conceive can be a very stressful

situation, baring a huge strain on individual. Infertility is a terrifying health issue many

couples face. 1 in ten people face this problem in the United States ​(​Independent.com,

2018)​. Prior to conception, ​many women take the vitamin folic acid to reduce the risk of

birth defects such as spina bifida. Women are encouraged to take at least 400 microgram

of folic acid a day to prevent defects in their babies. Folate is vital for DNA synthesis and

RNA transfer which promote cell growth and critical to take preconception, during, and

throughout a women’s pregnancy​(Independent.com, 2018)​. For those with fertility

issues, conceiving has been a big obstacle making couple exploring the idea of IVF, ​in

vitro fertilization,​ treatment. There is growing evidence that couples, especially the

female, who increase their folic acid intake have a higher chance of conceiving in

conjunction to their ​IVF treatment.

Literature Review

Folate is a water-soluble B vitamin that is naturally present in certains foods,

fortified into others, and available as a dietary supplement. Folate is the generic term used

for both naturally occurring food. Folic acid is the oxidized monoglutamate form of the
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vitamin used in dietary supplements and fortified foods. ​Folic acid aids in a number of

important functions in the body. Specifically, folic acid aids in the production of new

cells within the body leading to the creation of DNA. Furthermore, a fetus uses the

mother’s supply of folic acid for early brain development. When there is insufficient folic

acid, a child is at a higher risk of developing birth defects​. A study published in the

Obstetrics and Gynecology ​in 2014 looked specifically at the role of diet in the human

fertility and how it can play apart in increasing fertility rates in women. Folate plays a

role in the synthesis of DNA, transfer RNA, cysteine and methionine which all

contributes to rapid cell growth before, during, and after conception. Participants in this

study were women enrolled in the Environment and Reproductive Health Study at

Massachusetts General Hospital Fertility Center ​(Gaskins et al., 2014)​.

316 women who were between the ages of 18-46 and eligible for assisted

reproductive technology treatment participated in this study. Before the study started, the

participant’s diet was assessed before the treatment using a food frequency questionnaire

asking how often, on average, they consumed specified amount of certain foods.

Supplement, prescription, dosage, and frequency were taken into account. Dietary folate

equivalents (DFE) were calculated and folate was adjusted for total energy intake using

the nutrient residual method ​(Gaskins et al., 2014)​. The participants were classified into

groups based on total folate and separately by supplemental and food folate. Descriptive

statistics were calculated for demographic characteristics, dietary nutrients, and

stimulation protocol types according to each group. The participants were not prescribed

a specific dosage. Researchers found that pre-treatment of supplemental folic acid above
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800 microgram a day was related to a higher chance of live birth​ (Gaskins et al., 2014)​.

The average folic acid intake of all the participants was 1778 microgram a day; folate

intake came from both supplements and food sources. Researchers found an association

between folate and fertilization rates in vitro models which can contribute to folate’s

main impact before the embryo is transferred. There is also a stronger association with

supplemental folate do to its wider intakes and greater absorption compared to food

sources.

This study did have its limitation regarding diet assessment from the food

questionnaire. Participants answers could have been subjective which can skew the

results. Since the study was strictly observational, there were outside factors such as

lifestyle that were poorly measured. Although this study had its limitations, it also has

many strength such as its ability to evaluate early endpoints in couples attempting to

conceive naturally and wide folate range in their population. Overall, researchers

concluded that supplemental folate was related to a higher probability of live births with

women undergoing ​assisted reproductive technology. ​This study has the potential to

assist in other ongoing research to further strengthen the correlation between folate and

fertility.

In another prospective study in the ​Reproductive BioMedicine Online​, researchers

explored the relationship between folic acid supplementation and IVF pregnancy

outcome in women. Participants were recruited from the Fertility Unit in Karolinska

University Hospital and the Centre for Reproduction at Uppsala University Hospital.

Infertile women were asked to participate in the study and there were two groups;
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randomly selected infertile women and healthy fertile women. The researchers used a

longitudinal cohort study to compare the use of folic acid supplements and folate status

between both the infertile and fertile group of women. A questionnaire assessed general

background, use of dietary supplements, self-reported anthropometrics, and blood work

were used prior to the start of the study ​(Folic acid supplementation and IVF pregnancy

outcome in women with unexplained infertility, 2014)​. 368 women were included in the

study, those who were in the infertile group used significantly more supplement than

fertile group. The intake of folic acid alone was low in both groups; only 16 of 180

infertile women and none of fertile women chose to take folic acid. The median total folic

acid intake was within the recommended amount for the infertile group. Overall this

study did not show a positive impact on pregnancy or live birth following assisted

reproductive treatment. There was a correlation between more folic acid intake and better

folate status when comparing infertile women to fertile women, but a correlation between

increase folic acid and was not found ​(Folic acid supplementation and IVF pregnancy

outcome in women with unexplained infertility, 2014)​.

As far as is known, there is limited studies on folic acid supplement use and

pregnancy outcome in women with unexplained infertility.

Scovell and Ramasamy reviewed ​epidemiological​ studies and concluded that

epigenetic regulation in offspring development could be affected from a deficiency in

paternal micronutrients. They examined studies performed on mice and men which both

indicated subjects deficient in folate had sperm with more abnormalities. The

investigation the role of supplemental folate, zinc, and antioxidants ​in the ​Young et al.
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study in 2008 showed ​men above the 75 percentile of folate ​had a lower frequency in

aneuploidy. This study gathered 97 men from a non-clinical setting who were healthy and

non-smokers (at least not within six months). It analyzed their sperm samples by using

fluorescent in situ hybridization to determined aneuploidy. These men had previous

worked for a university research laboratory or were currently working at one. 15 men of

each decade ranging from 20 to 70 years of age were selected. A food frequency

questionnaire was administered to estimate daily total intake from diet and supplements

within one week of providing a sperm sample. Samples were collected within two hours

of masturbation by ​anonymous delivery to a drop box and participants were instructed

not to ejaculate 2 to 7 days prior. Seven men were excluded from further analysis due to

azoospermia​ or ​low sperm count.

Possible errors in this study are derived from how the nutritional amounts were

collected by the diet recall and limited information in how they verified each individual’s

amount of folate. Relying on the participants to remember what they ate rather that giving

them a set diet or specific supplementation amount could have altered the results

negatively. Based on the questionnaire the median intake of folate was ​475 micrograms

(µg) with a low of 114 µg and a high of 1150 µg. ​More research is necessary to ​elucidate

whether or not supplementation of folic acid can reduce congenital abnormalities in men

with a well-balanced diet.

Centers for Disease Control and Prevention (CDC) website has preconception

care for both females and males. It focuses primarily on women, but mentions how

women and men should improve their physical and mental health along with making
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better lifestyle changes. The CDC only provides diet recommendations for women and

fails to mention any for men (CDC, 2018a, 2018b). The advice given to women is to start

at least one month in advance before getting pregnant, CDC strongly recommends

women to take 400 mcg of folic acid every day (CDC, 2018c). The article does mention

that this B vitamin can help prevent major birth defects and that everyone requires it

make new cells but is not stated on the link for things for males to focus on (CDC,

2018c). No methodology or sample size is provided only suggestions on what women

and men should improve before becoming pregnant.

According to the fertilityinstitute.com, women who are pursuing pregnancy

should take folic acid as part of their fertility plan recommended by their doctor(s). The

demand for folate prior to and during pregnancy is especially important to women with

fertility problems since it promotes fertility and is required in higher amounts due to

stress (fertilityinstitute.com). This site mentions a study done by Dr. Wai Yee Wong that

infertile men experienced a 74 percent increase in their normal sperm count over 26

weeks when taking folic acid and zinc supplements. This was a double-bind, randomized

study performed on 108 fertile men and 103 sub-fertile men who received five ​µg of folic

acid and 66 µg of zinc sulfate daily. The median sperm concentration in sub-fertile men

who received both folic acid and zinc significantly increased by 4.5 million

cells/milliliter (mL) after 26 weeks of intervention. The other invention groups had no

significant changes in semen variables

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Conclusion

The majority of research on folate is primarily pertaining to the vitamin and its

role in the female body. More research involving male preconception nutrient is

necessary to evaluate and determine the impact of folate could have on improving

conception in those who are infertile.

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References

Folic acid supplementation and IVF pregnancy outcome in women with unexplained
infertility.
(2014). Reproductive BioMedicine Online, 28(6), pp.766-772.

Gaskins, A. J., Chiu, Y.-H., Williams, P. L., Ford, J. B., Toth, T. L., Hauser, R., … for
the
EARTH Study Team. (2015). Association between serum folate and vitamin B-12
and
outcomes of assisted reproductive technologies. The American Journal of Clinical
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Gaskins, A. J., Afeiche, M., Wright, D. L., Toth, T. L., Williams, P. L., Gillman, M. W.,
…
Chavarro, J. E. (2014). Dietary Folate and Reproductive Success Among Women
Undergoing Assisted Reproduction. Obstetrics and Gynecology, 124(4), 801–809.
http://doi.org/10.1097/AOG.0000000000000477

Gropper, Sareen S., Smith, Jack L, & Carr, Timothy P. Advanced Nutrition and
Human
Metabolism (7th ed.). Boston, MA: Cengage Learning.

Independent.com. (2018). In vitro Fertilization, Part I: A Brief History. [online] Available

at:
https://www.independent.com/news/2010/jul/02/em-vitroem-fertilization-part-i-br
ief-history/ [Accessed 18 Apr. 2018].

N.A. (2014). The Link between Folic Acid and Female and Male Fertility. Retrieved
April 3, 2018 from http://fertilityinstitute.com/2014/07/11/the-link-
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acid-and- female-and- male-fertility/

N.A. (2018a). Before Pregnancy: Information for Men. Retrieved March 21, 2018 from
https://www.cdc.gov/preconception/men.html

N.A. (2018b). Before Pregnancy: Women. Retrieved March 21, 2018 from
https://www.cdc.gov/preconception/women.html Women

N.A. (2018c). Facts About Folic Acid. Retrieved March 21, 2018 from
https://www.cdc.gov/ncbddd/folicacid/about.html
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N.A. (2017). Preconception Health for Men: Tips On Preconception Health for Men.
Retrieved April 5, 2018 from
http://americanpregnancy.org/getting-pregnant/mens- preconception-health/

Thaler, C. J. (2014). Folate Metabolism and Human Reproduction. Geburtshilfe Und

Frauenheilkunde, 74(9), 845–851. http://doi.org/10.1055/s-0034-1383058

Scovell, Jason M. & Ramasamy, Ranjith. (2014). Should Men Take Prenatal
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Wong, W.Y., Merkus, H.M.W.M., Thomas, C.M.G., Menkveld, R., Zielhuis, G.A.,
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Steegers-Theunissen, R.P.M. (2002). Effects of folic acid and zinc sulfate on
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Young, S.S., Eskenazi, B., Marchetti, F.M., Block, G., & Wyrobek, A.J. (2008). The
association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy
non-smoking men. Human Reproduction, May, 23(5), 1014–1022. Retrieved
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