Choosing Folate Forms For Your Fertility

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So you know that folate is important for your pregnancy and baby health, but when it comes to looking at foods and supplements for your journey into and throughout pregnancy, it might cause you some confusion.

Folate, is a water-soluble B group vitamin (B9) that is widely known for it’s importance in pregnancy health. But there is more to it than grabbing a folic acid containing prenatal off the chemist shelf to cover your needs.    

As new research emergences, the way we prescribe folate is also evolving. If you’re wondering what the difference is between the folate in your foods, the folic acid in supplements and the new buzz word, methyl folate, stick around, I’m going to break this down for you and explain the importance of getting the right folate for your fertility. So you can avoid a deficiency, dangerous build up and the complications associated with this for you and baby. 

Why Do You Need Folate For Preconception & Pregnancy Health?  

Folate promotes the healthy growth of your baby from conception and throughout childhood. It is critical for healthy DNA methylation to occur, an important biochemical process which is a component of embryonic development and healthy gene expression.  

Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development…. All methylation processes are carried out via a methyltransferase enzyme the one needed to convert folate into it’s activated form.¹ 

Folate supplementation during your preconception stage and early pregnancy can reduce the risk of birth defects affecting your baby’s brain and/or spinal cord, such as the neural tube defect Spina Bifida. It has also shown through research to prevent cardiovascular system and nervous system defects, along with cleft lip and cleft palate formation.^2,3 

Folate is also required for the formation of your red blood cells.  

Yes, it is hugely important to optimise your levels preconception and throughout pregnancy for a healthy baby.  

What Does A Deficiency Of Folate Contribute To?  

Inadequate vitamin B12 and other methylating nutrients such as folate, B6 and choline during pregnancy, increase the risk of pre-eclampsia,⁴ early term miscarriage,⁵ neural tube defects and poor brain development⁶due to poor methylation and consequent high homocysteine levels. 

You’ll start to understand what this means as I break this down for you.  

Types of Folate: 

Folate comes in several forms. First up let’s look at food as medicine. 

Folate is naturally found in vegetables, particularly the green leafy kind- spinach, kale, broccoli, cauliflower, brussels sprouts, watercress, turnips, greens, okra ns lettuce varieties).  

Although focus should be placed on green leafy vegetables; asparagus, beetroot, papaya, bananas and avocados are other fruits and vegetables which also contain folate.  

Liver, eggs, lentils, chickpeas, beans (especially fermented legumes), shiitake mushrooms, nuts and seeds such as quinoa are also good dietary sources of folate. 

Next up is the synthetic form, folic acid. This is found in many over the counter prenatal supplements, as well as fortified foods such as breads and cereals.  

As explained across on Bioceuticals blog,  

“In September 2009, mandatory fortification of flour with folic acid was introduced in Australia. This followed voluntary fortification, and promotion of folic acid supplementation which had been recognised as achieving reductions in the number of NTD.⁷ 

An investigation one year after the initiation of mandatory fortification showed that the prevalence of low serum and red blood cell (RBC) folate status had reduced in women of child bearing age^8, however a later paper questioned whether this was achieving levels sufficient enough to prevent NTD9, suggesting that supplementation should still be encouraged.”  

Hence the push and widespread awareness for folic acid supplementation throughout preconception and pregnancy and the subsequent roll out of prenatal brands containing abundant levels, easily found over the counter.  

So let’s look at how your body uses these forms of folate. 

Introducing The Folic Acid Cycle 

When you consume your natural food sources of folate, you gain a head start when it comes to metabolising it into the active form, to use in your body for all the benefits folate brings.  

While some folate rich foods are already in the activated methyl folate form, others are in the tetrahydrofolate form and require one more step before they are fully activated. 

This is a couple of steps ahead of synthetic folic acid, in the cycle which converts both these forms into the useful therapeutic bioactivate form of folate. 

This active form of folate we’re striving for is called methylfolate, 5-methyltetrahydrofolate (or for short, 5-MTHF) and can then be used as a methyl donor for the DNA and RNA synthesis, DNA maintenance, methylation and healthy cell division.   

5-MTHF is the main biologically active form of folate naturally found in breastmilk and umbilical cord serum and is able to cross the blood brain barrier, where it can perform important brain health functions. This activated form of folate also helps to reduce homocysteine levels in the body, which high levels have been associated with pregnancy complications such as miscarriage, pre-eclampsia, foetal growth restriction, abruption placenta and stillbirth.^10,11,12  

Getting folic acid into a biologically active methyl form, depends on the action of dihydrofolate reductase (DHFR) enzyme in the liver. This is however, a slow process in humans.   

Folic acid is first reduced by DHFR enzyme to DiHydroFolate (DHF), and then to tetrahydrofolate (THF), before it is converted to the biologically active 5-methyltetrahydrofolate. Food forms of folate (tetrahydrofolate) and the partially activated Folinic acid form of folate in supplements both bypass this DHFR before being converted into 5-MTHF. 

Note: fermenting foods has been shown to improve their levels of activated methyl folate. 

I’ll now refer to this activated form of folate as methyl folate.   

Quoted from the National Institutes of Health:  

“This is the primary form of folate found in blood, and is necessary for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.”  

This final stage of activation of tetrahydrofolate into methyl folate occurs through an enzyme called methylenetetrahydrofolate reductase (MTHFR) which is vitamin B2 dependent.  

The MTHFR enzyme is involved in folate metabolism, methylation and processing amino acids.  

The function of this MTHFR gene is impacted when there is a single nucleotide polymorphism (shortened to SNP or also referred to as a variant) in the MTHFR gene. To be specific, an MTHFR SNP leads to a change in the MTHFR enzyme produced by that gene, resulting in a reduced enzyme activity,13 thus lowering the conversion of 5,10-methylene THF to 5-MTHF (the final step) and impacting the recycling of Homocysteine back to methionine. Remember high homocysteine levels increase the risk for miscarriage and preeclampsia.  

Therefore, if this variant is present, the conversion into the active form of folate is impacted. Depending on if one has one (heterozygous) or two (homozygous) copies of the variants, determines how much function of this enzyme is impacted.  

It has been estimated that up to 60% of the US population have at least one copy of the MTHFR gene variants, therefore impacting their ability to metabolise synthetic folic acid. You can be checked for MTHFR gene variants through a blood test or saliva swab through your GP, Integrative GP, Naturopath or Nutritionist.  

What Role Does Food Play? 

 So you might be thinking at this stage that folate within your foods is on par with synthetic folic acid found in supplements. But food forms will always trump synthetic as they are abundant in the cofactors needed to encourage the MTHFR enzyme. Simply, the body knows how to process them.  

A potent example is vitamin B2- found in abundance in organ meats, meats as well as dairy, eggs and green vegetables. Vitamin B2, is an essential co-factor for the MTHFR enzyme and adequate vitamin B2 is able to help negate the reduce enzyme activity as a consequence of the MTHFR variants.  

Therefore, vitamin B2 (also known as Riboflavin, or the activated form, Riboflavin 5-phosphate) and B2 rich foods should always be given as a cofactor to support the normal function of the MTHFR enzyme, particularly in those with a variant.   

It is also important to mention that fermenting foods help to provide a tiny source of activated 5-MTHF.   

How Much Folate Is Needed? 

 The Australian recommendations for folate intake during pregnancy and breastfeeding is 600mcg for women aged between 14-50.   

To put this into perspective:  

• ½ cup spinach boiled = 131mcg 
• 1 cup broccoli cooked = just over 100mcg 
• 4 spears asparagus = 89 mcg 
• 1 cup romaine lettuce = 64mcg 
• ½ cup avocado = 59mcg  
• 1 egg = 22mcg 
• 85gm Beef mince = 7 mcg   
• 28gm beef liver, braised = around 29mcg folate per 2 capsules of beef liver  

So even if you ate all of that in one day, you’re still under 500mcg folate.  

When Is A Prenatal (With Folate) Needed? 

Preconception and pregnancy is not a time to risk folate deficiency, so gaining the additional folate through a supplement or food-based superfood powder is great insurance to top up your daily folate levels.   

Providing additional folate in the activated supplemental form along with consuming foods sources of bioavailable folate, will ensure you are absorbing effectively if you have partial or full copies of the MTHFR gene variants.  

Summarised in a 2020 research paper: 

“Supplementation with 5-MTHF in pregnancy could be advantageous over that with folic acid, because 5-MTHF is immediately active, does not require metabolic activation, and is directly bioavailable to the mother and foetus and is not influenced by the possible MTHFR gene mutations.”¹⁴ 

& summarised on the Bioceuticals blog:  

A paper published in 2014, stated that "Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase (DHFR) and overcomes metabolic defects caused by methylenetetrahydrofolate reductase (MTHFR) polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. "¹⁵ 

What Activated Folate Will Look Like On The Label.

You might find it listed as: 

• Quatrefolic Levomefolate glucosamine 
• Levomefolate calcium or Calcium L-5-methylterahydrofolate 

And you’ll usually see ‘equivalent to:  

• L-5-Methyltetrahydrofolate 
• 5-MTHF 
• Or Levomefolic acid 

Note: Folinic acid (Calcium Folinate) is a partially activated form of folate.  

If you know you don’t have any MTHFR gene variants, 400- 600mcg is adequate for your daily folate intake (foods and supplemental form) in your preconception stage and increasing to 600mcg in pregnancy. 

Otherwise aim for a total daily dosage of 500-800mcg activated folate and food folates preconception and throughout pregnancy, if you have either or both MTHFR gene variants. 

While there is no benefit to go beyond this dosage, you do not want to exceed 1000mcg due to unknown side effects of levels exceeding this amount (although this upper limit is actually referring to high dose synthetic folic acid complications). It is important to note that choline plays an important role in supporting methylation and is particularly important for those with a MTHFR gene variant.  

Your pregnancy supplementation and diet should also contain adequate choline, which is something I discuss in Path To Glowing Mumma.

When Is Folic Acid ok? 

MTHFR gene variant aside, there is still strong evidence indicating the benefits of supplying folate through the synthetic (non-active) folic acid form, for reducing neural tube defects. This hasn’t yet been evaluated for neural tube defect prevention specifically, for the activated form, L-5-MTHF.¹⁶   

But just because the research hasn’t been done, it doesn’t mean the activated form isn’t a better option. From a biochemical perspective, it makes sense. 

The Issue With Folic Acid In Foods & Supplements. 

Unlike food and methylated forms of folate, synthetic folic acid found in fortified foods and supplements (like your prenatal and B complex products), do come with risks.  

While there is strong research showing benefits of folic acid for neural tube defects, we can’t ignore the gene mutations that impair our ability to utilise folic acid and lead to dangerous unmethylated folic acid (UMFA) levels in your body. In effect, high dose folic acid supplementation can lead to a functional deficiency in folate. Crazy, right?!  

To avoid this, you don’t want to exceed a level of 200mcg of synthetic folic acid per day, as research shows from 200-280mcg folic acid per day (or more), can disturb the critical metabolism of folate in your body.¹⁷

If the level in your prenatal is 200mcg or less of folic acid (or better, partially activated folinic acid), together with a greater level of activated 5-MTHF, this is ok if you’re not getting any additional folic acid through fortified foods.  

I would suggest against taking a prenatal which only contains synthetic folic acid and especially over the level of 200mcg per dose. At these higher doses, a dangerous back log of synthetic folic acid can occur with your body, called unmethylated folic acid (UMFA). Your body cannot process it effectively through the folic acid cycle and into methyl folate.  

While natural folate supports fertility and pregnancy health, US Registered dietician Lily Nichols summaries the dangers of folic acid intake above 200mcg a day:  

“Moderate and high intake of folic acid can disturb folate metabolism (and methylation) in the body (even in people without MTHFR variations), potentially contributing to inflammation, infertility, and adverse pregnancy outcomes.” Lily has an awesome post outlining all the research across at lilynichols.com. 

As described in the paper “Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles”: 

“Detectable levels of UMFA occur temporarily in plasma after the consumption of >200 µg FA, with concentrations increasing parallel to that of total FA after supplementation. UMFA has been detected in cord and infant blood, a source of concern due to potential adverse effects on health…”¹⁷ 

High dose folic acid taken in the preconception period has also been associated with negative neurodevelopment outcomes in the offspring. This was highlighted in one 2017 study where 4-5 year old children of mothers who consumed >1000 mcg of folic acid per day in their preconception period scored lower on cognitive function tests.¹⁸  

One study including high dose folic acid supplementation in men has also revealed alterations of the human sperm epigenome and these effects were exacerbated by those with a MTHFR gene variant.19  

If you’re in your preconception stage, see my guide Path To Conscious Conception for dietary, lifestyle and supplementation support for your fella in the leadup.

High dose folic acid consumption can also mask a type of anaemia called megaloblastic anemia, where abnormally large red blood cells develop and therefore struggle to carry adequate oxygen. This is caused by either B12 or folate deficiency, or both, because they are both involved in red blood cell synthesis.  

The metabolism of folic acid is reliant on adequate B12 levels and if excessive intake of either occurs, this can lead to a false normal red blood cells on blood work, with a hidden deficiency of the other. This is most commonly excessive folic acid intake during pregnancy, leading to a missed B12 deficiency. If poor memory, muscle cramps or nerve tingling is occurring, this may be the case for you.  

As I explain in Path To Glowing Mumma, extensive bloods at different stages in your pregnancy can help detect these deficiency states.

There is also concern building that tongue tie development (also known as ankyloglossia) is linked to our increased intake of folic acid. The hypothesis that folic acid intake could cause thicker development of tissues such as the frenulum under the tongue (known as a tongue tie) and/or the tissue connecting the lip to the gum line (known as a lip tie) was explored in a 2020 observational case controlled study.²⁰   

This included 85 infants with tongue ties compared to a control group of 140 babies who didn’t have tongue or lip ties and looked at both preconception and pregnancy intake of folic acid. The biggest take away from this study was the regular intake of folic acid (average 400mcg per day) preconception lead to a 2 fold increase of tongue tie development. Preconception intake in this case is more reflective, due to the early development of frenulum at 6 weeks gestation.  

Note: GP’s and obstetricians may not have this further nutritional training and will likely recommend you go to the chemist and pick up a bottle of that prenatal Elevit. I hope you’re now starting to feel equipped with the reasons to say no to this option. Yes?

Instead, having a combination of mostly the active methyl folate, with lower levels (200mcg or less) folic acid in your pregnancy multivitamin (along with an abundance of natural folate rich foods) is something I have advised for some pregnant Mums in the past (more so because of other benefits within the formula such as low excipient levels over competitive brands). But, we now have more choice with a higher quality, low excipient Australian based prenatal products, which include solely activated folates. 

 Remember, if you have the common genetic variation in the MTHFR enzyme (up to 60% of the population), this will impact your ability to utilise the synthetic folic acid, found in most of the over-the-counter prenatal products. To avoid this issue, I now recommend all the supplemented folate to be supplied to be in the methyl folate form from preconception through to pregnancy (or next best, a combination of methyl folate and folinic acid). 

It is important to note however that some people do react to methyl folate and migraines, joint pain, behavioural issues, mood swings, psychotic outbursts, runny nose, insomnia are among these. Particularly if you’re already highly stimulated with anxiety or insomnia, methyl folate may make this worse.  

In this case you may need to change prenatal brands with slightly less methyl folate level per dose or even use a prenatal with some partially activated folate (in the form of folinic acid), or source a food based prenatal like Foraged Mothers Blend. Glycine and Niacin supplementation can help to overcome these symptoms, under the guidance of your functional health practitioner. Just note glycine is rich in slow cooked meals of meats on the bone.  

So back to the foods…  

Foods That Are Fortified With Folic Acid 

Aiming to avoid fortified foods with synthetic folic acid will help to avoid going over the 200mcg folic acid threshold per day. The easiest way to do this is prioritise home cooking from real foods so you know what is in your meals when it comes to folic acid content. Many but not all flour and flour products are fortified with folic acid here in Australia, so it is easy to reach this 200mcg per day without even taking into account levels in your prenatal. 

Folic acid fortified foods could include: 

• Fortified nutritional yeast 
• Fortified wheat flour and products made from them eg. breads, rolls, buns, muffins 
• Breakfast cereals 
• Energy drinks 
• Processed drinks  
• Meal replacement shakes and protein powders 

Taken from Food Standards Australia and New Zealand website (updated June 2016): 

Organic bread is not required to contain folic acid. Bread made from other cereal flours or meals such as rice, corn or rye (provided they do not contain any wheat flour) do not have to contain folic acid, though manufacturers may add it if they wish.  

Manufacturers must list folic acid in the ingredient list on the labels of foods fortified with folic acid. It is sometimes listed as folate. Unpackaged bread, including bread made at the point of sale doesn’t have to have ingredient information, though this information should be made available on request. 

Manufacturers must list added vitamins or minerals in the ingredient list on the food label.²¹ 

But the only way to know for sure is to check the ingredients list as manufacturers must list added vitamins or minerals on the ingredients list of the food label.   

Eg. A loaf of Bakers Delight white bread contains added folic acid, whereas your local market fresh organic sourdough loaf will likely contain grain, seeds, water, olive oil and culture. That’s it.   

Folate & Your Fertility 

By focusing on a real foods diet, where you make majority of your foods (or at least know the ingredients of the foods and meals you’re consuming, you will be in control of your folate intake and supporting your body with a form that your body knows what to do with. Foods as medicine will also provide other important nutrients such as vitamins B12 and B2 that help with folic acid metabolism and utilisation in your body.  

The best sources of folate are vegetables, particularly the green leafy kind- spinach, kale, broccoli, cauliflower, brussels sprouts, watercress, turnips, greens, okra ns lettuce varieties). Also, asparagus, beetroot, papaya, bananas, avocados, liver, eggs, lentils, chickpeas, beans, shiitake mushrooms, nuts and seeds such as quinoa. 

For at least 3 months before trying and during pregnancy, supplementing with an additional 400-800mcg (500-800mcg with any MTHFR gene variants) activated methyl folate, can provide a topping up effect so you reach the required 600mcg folate during pregnancy.  

Supplementing in this form will ensure your body can use this folate throughout pregnancy, for the many functions for you and your baby’s health and their rapid growth and development.  

Remember, the activated form of methyl folate), can directly enter the folic acid cycle,²²and is the best option for individuals with an impaired ability to convert folic acid associated with the MTHFR gene variant.  

By sourcing your folate from food and activated forms also ensures you avoid the risk of UMFA in your body and the risks involved with this we’re only just learning about, for you and baby.  

But know that a nourishing multi is not all about folate- other critical nutrients such as choline, further B vitamins B2, B6 and B12, magnesium, glycine and betaine are needed for healthy methylation and folate metabolism. Choline is critical for baby’s central nervous system development and adequate levels reduce the risk of neural tube defects. Among NTD’s, inadequate levels of choline during pregnancy also increases the risk of preeclampsia (PE),²³ early term miscarriage,²⁴ and poor brain developmen^t25 due to impaired methylation and elevated Homocysteine levels.  

Work With Me

If you’re pregnant, and wanting further support and access to quality supplemental support, you’ll want to check out what I have for you inside Path To Glowing Mumma.

 References

1. Menezo Y, Elder K, Clement A, Clement P. Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles. Biomolecules. 2022 Jan 24;12(2):197. doi: 10.3390/biom12020197. PMID: 35204698; PMCID: PMC8961567.
2. Qu P, Li S, Liu D, Lei F, Zeng L, Wang D, et al. A propensity-matched study of the association between optimal folic acid supplementation and birth defects in Shaanxi province, Northwestern China. Sci Rep. 2019 Mar 27;9(1):5271 DOI : 10.1038/s41598-019-41584-5.
3. Jahanbin A, Shadkam E, Miri HH, Shirazi AS, Abtahi M. Maternal folic acid supplementation and the risk of oral clefts in offspring. J Craniofac Surg. 2018 Sep;29(6):e534-e541 DOI : 10.1097/SCS.00000000000
4. Wadhwani NS, Patil VV, Mehendale SS, Wagh GN, Gupte SA, Joshi SR. Increased homocysteine levels exist in women with preeclampsia from early pregnancy. J Matern Fetal Neonatal Med. 2016 Aug 17;29(16):2719-25
5. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fert Stert. 2000 Dec 1;74(6):1196-9
6. Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome.  2019 Mar 13;11(3). pii: E608 d
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8. Brown RD, Langshaw MR, Uhr EJ, et al. The impact of mandatory fortification of flour with folic acid on the blood folate levels of an Australian population. Med J Aust 2011;194(2):65-67.
9. Rabovskaja V, Parkinson B, Goodall S. The cost-effectiveness of mandatory folic acid fortification in Australia. J Nutr 2013;143(1):59-66.
10. Quere, Isabelle, et al. “A woman with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages.” Fertility and sterility1 (1998): 152-154.
11. Cavallé-Busquets, Pere, et al. “Moderately elevated first trimester fasting plasma total homocysteine is associated with increased probability of miscarriage. The Reus-Tarragona Birth Cohort Study.” Biochimie(2020).
12. Unfried, Gertrud, et al. “The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage.” Obstetrics & Gynecology4 (2002): 614-619.
13. Zeisel SH. Nutrition in pregnancy: the argument for including a source of choline. Int J Women Health. 2013;5:193-9.
14. Ferrazzi, Enrico, Giulia Tiso, and Daniela Di Martino. “Folic acid versus 5-methyl tetrahydrofolate supplementation in pregnancy.” European Journal of Obstetrics & Gynecology and Reproductive Biology(2020).
15. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014;44(5):480-488.
16.  Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacoynamics. Clin Pharmacokinet. 2010 Aug 1;49(8):535-48.
17.  Sweeney M.R., McPartlin J., Weir D.G., Daly S., Pentieva K., Daly L., Scott J.M. Evidence of unmetabolised folic acid in cord blood of newborn and serum of 4-day-old infants. J. Nutr. 2005;94:727–730. doi: 10.1079/BJN20051572.
18. Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, Fernández-Somoano A, Tardón A, Ibarluzea J, Balluerka N, Murcia M, González-Safont L, Romaguera D, Julvez J, Vioque J; INMA Project. Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr. 2017 Sep;106(3):878-887. doi: 10.3945/ajcn.117.152769. Epub 2017 Jul 19. PMID: 28724645.
19. Aarabi, Mahmoud, et al. “High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.” Human molecular genetics22 (2015): 6301-6313.
20. Amitai Y, Shental H, Atkins-Manelis L, Koren G, Zamir CS. Pre-conceptional folic acid supplementation: A possible cause for the increasing rates of ankyloglossia. Med Hypotheses. 2020 Jan;134:109508. doi: 10.1016/j.mehy.2019.109508. Epub 2019 Nov 18. PMID: 31835174.
21. https://www.foodstandards.gov.au/consumer/nutrition/folicmandatory/pages/default.aspx
22. Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacoynamics. Clin Pharmacokinet. 2010 Aug 1;49(8):535-48.
23. ] Wadhwani NS, Patil VV, Mehendale SS, Wagh GN, Gupte SA, Joshi SR. Increased homocysteine levels exist in women with preeclampsia from early pregnancy. J Matern Fetal Neonatal Med. 2016 Aug 17;29(16):2719-25
24. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fert Stert. 2000 Dec 1;74(6):1196-9
25. Mahmoud AM, Ali MM. Methyl donor micronutrients that modify DNA methylation and cancer outcome. Nutrients. 2019 Mar 13;11(3). pii: E608 doi: 10.3390/nu11030608.