Reaching New Heights in Folate Supplementation

From L-R Zhariz Cheng - Product Manager; Nelinda Catherine Pangilinan, MD; Ma. Lourdes Abeleda, MD; Ma. Maureen Fortuna, MD; Prof. Silvia Pisoni; and Richard Jordias, MD

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In a satellite symposium during the recently concluded annual convention of the Philippine Obstetrical and Gynecological Society (POGS), Prof. Silvia Pisoni, consultant and professor of Innovative Ingredients and scientific advisor of Gnosis Biotech, in Milan, Italy, stressed the essential role which folate plays in human growth and development, and the importance of maintaining an adequate dietary intake of folate during various stages of human life. Dr. Lourdes Abeleda, chairman of the Department of Obstetrics and Gynecology at the Our Lady of Fatima University Medical Center, discussed ‘Oxidative Stress and Fertility’. Dr. Richard Jordias, president of the Philippine Society of Maternal Fetal Medicine, highlighted the role of folate deficiency in ‘Neural Tube Defects’; and Dr. Nelinda Catherine Pangilinan, president of the Philippine Ultrasound Society in Obstetrics and Gynecology, tackled the effect of folate supplementation in the ‘Prevention of Preeclampsia and Postpartum Depression’. Dr. Ma. Maureen F. Fortuna, Fellow of POGS and Training Officer of the Department of Obstetrics and Gynecology at the St. Paul’s Hospital, in Iloilo City, moderated the discussion.


Folate is an essential nutrient to the human body, playing a role in cell division and DNA synthesis—vital processes involved in human growth and development. It is contained in foods, but are unfortunately unstable and susceptible to oxidation; hence, the folate in foods lose activity during processing, manufacturing and storage.

Its bioavailability only ranges from 25% to 50%, depending on the kind of food. At room temperature storage, food sources of folate may lose up to 70% of their folate activity within three days, and the cooking process in water can increase the loss up to 95%.

Therefore, folate deficiency is prevalent, and represents one of the most common nutritional deficiencies due to the following reasons:

• Dietary intake is inadequate, and even in healthy people, the daily dietary intake is not sufficient to cover the body’s needs;
• The increased need is not matched by an increased intake due to enzyme defects involved in the absorption and metabolism of folate; and,
• Drugs commonly taken by people that interfere with the ability of the body to use folate.

There are some misconceptions about folate and folic acid (FA). The FA that is found most commonly in vitamin supplements and fortified food is not folate. It must be converted from folic acid to methyltetrahydrofolate (5-MTHF) before it can be used by the body. Quatrofol is the active form of folate, and readily available for transport and use in human body and tissues.

The biotransformation of FA to 5-MTHF is critically regulated by two polymorphic enzymes: dihydrofolate reductase (DHFR) and methyltetrahydrofolate reductase (MTHFR). DHFR is a polymorphic enzyme with possible low expression and there is a low activity of DHFR in the human liver. (Bailey 2009).

MTHFR is a rate-limiting enzyme that catalyzes the irreversible conversion to 5-MTHF in the methyl cycle. Around 10% of the world’s population is affected by homozygous (TT) MTHFR polymorphism. This is particularly common in some ethnics groups, in northern China (20%), southern Italy (26%), and Mexico (32%). (Wilcken 2004, Jamil 2014, Yakub 2012)

MTHFR is the enzyme involved not only in the folate cycle, but also crucial to the 1-carbon cycle (1-CC), responsible for methylation, a process that is essential for the regeneration and biochemical regulation of cells, imprinting genes and epigenetics.

Several studies have reported an increase in serum of UnMetabolized Folic Acid (UMFA) levels since the implementation of FA fortification, may lead to potential ‘overdosing’ and adverse effects. This causes a high level of ingestion of FA—up to 200-300 µg/daily intake—which leads to the direct appearance of UMFA in the plasma. (Morris, 2010)

The body cannot use UMFA, an excessive level of which may cause potential toxic effects, as follows:

• Acceleration of cognitive decline in the elderly with low levels of vitamin B12;
• Reduction of natural killer cytotoxicity; and,
• Reduction of the immune system’s capacity to kill malignant or premalignant cell.

While the scientific community is evaluating the possible concern of UMFA on public health, several publications recommend to replace FA present in dietary supplements, with the (6S)-5-MTHF. Quatrofol, a 4th generation folate, does not cause UMFA accumulation. Hence, it does not expose the body to unsafe levels of UMFA. (Pfeiffel et al., 2015; Obeid et al., 2015)

One-carbon metabolism is a network of cellular interrelated biochemical reactions involving the transfer of onecarbon groups from one biological compound to another (methylation). Its effectiveness depends on the availability of folate and on the relative methyl groups produced in the methylation cycle. In pregnancy, this is quite important. It supports the DNA synthesis, repair, and integrity, and provides methyl groups to ensure chromosome stability and proper gene expression.

Folate deficiency is casually related to various birth defects because of the direct effect on the impairment of this lifesustaining cycle. Impairment of one-carbon metabolism also increases homocysteine levels, a risk factor for recurrent embryo losses in early pregnancy.

The impairment of this conversion due to folate deficiencies, genetic factors (such as MTHFR polymorphism) and general factors (drugs, alcohol, smoking, ageing and specific pathologies can lead to ultimate increase in total plasma homocysteine, which is a marker for folate and vitamin B12 deficiency.

Folate supplementation also has clinical applications in the prevention of cardiovascular disease (CVD). In a randomized clinical trial conducted by Yong Huo et al., (JAMA, 2015), 20,702 Chinese hypertensive adults without a history of stroke or myocardial infarction (MI), were randomized to enalapril + FA, versus enalapril alone. A significantly reduced risk of first stroke, was noted in the enalapril + FA group, but only in the subjects without the TT polymorphism of the enzyme MTHFR.

In another controlled study evaluating the efficacy of nutraceuticals in lowering plasma homocysteine levels, the ideal homocysteine level (i.e. less than 10 µmol/L) was reached in 55.8% of cases in the group given Quatrofol, and it was significantly higher than in the control group. The treatment was considered safe, well tolerated and effective in reducing homocysteine levels.

Low concentrations of folate in the blood and high homocysteine level are also related to mood impairment and brain decline. UMFA is not able to cross the blood brain barrier (BBB) and may be bound to receptors (folate binding protein) blocking the 5–MTHF bound and its absorption. Folate supplementation has been shown in clinical trials to significantly alleviate depression up to an 81% response rate. (Guaraldi et al., 1993)

The improved bioavailability of folate in Quatrofol has been attributed to its unique glucosamine salt compared to (6S)-5-methyltetrahydrofolic calcium salt. In experimental animals, the peak plasma level was shown to be about 20% higher after single dosing of Quatrofol compared to the hematic peak of an equivalent dose of (6S)-5- methyltetrahydrofolate. (Miraglia N et al., 2016)

The choice of glucosamine as the salt for the metabolically active folate, the 5-MTHF, is the result of a research aimed to combine the effectiveness, safety and significant advantages of solubility compared to the previous calcium folate generations. Quatrofol is 100 times more soluble in water than the calcium salt. High water solubility means the product may be better absorbed by mucosal cells which may facilitate access to the blood and circulation with the potential for improved bioavailability.

Folate supplementation indeed plays a vital role in various stages of human growth and development. Therefore, humans need to maintain an adequate dietary intake of folate, preferably with an ideal salt for optimal bioavailability, throughout life.

Oxidative Stress and Fertility

Oxidation is a normal and necessary process that takes place in body. Free radicals are oxygen-containing molecules with an uneven number of electrons, which allows them to easily react with other molecules, and can cause large chain chemical reactions in the body because they react so easily with other molecules. However, this process can both be beneficial or harmful.

Excess oxidation is prevented by antioxidants, which are molecules that can donate an electron to a free radical without making themselves unstable. This causes the free radical to stabilize and become less reactive. Oxidative stress happens when there is an imbalance between free radicals and antioxidants in the body.

Reactive oxygen species (ROS), also called oxygen radicals or pro-oxidants, are molecules or ions formed by the incomplete one-electron reduction of oxygen. They include singlet oxygen, superoxides, peroxides, hydroxyl radical and hypochlorous acid. They can help fight off pathogens, but in excessive quantities, free radicals can start doing damage to fatty tissue, DNA, and proteins that can lead to a vast number of diseases.

Stress of daily living, diet, medications, alcohol, smoking, exposure to pollution and toxins, sedentary activity, and just about everything we do and don’t do can result in oxidation and inflammation producing potentially damaging free radicals.

Oxidative stress affects both female and male infertility.

Both ROS and superoxide dismutase (SOD) jointly catalyze the destruction of the O2- free radical, as second messengers to regulate endometrial function. (Sugino N et al., 2007) SOD increased in human endometrial stromal cells with decidualization and was a likely important component of implantation. (Suguino N et al., 2000)

Antioxidant capacity of follicular fluid during oocyte retrieval has been associated with characteristics of in-vitro fertilization (IVF) success. There is also an overall negative correlation between follicular fluid ROS and embryo quality. (Das S et al., 20016)

An acceptable threshold level of oxidative stress may represent healthy, metabolically active cells. (Wiener-Megnazi Z et al., 2004) However, excessive oxidative stress has been linked with increased risk of spontaneous abortion (Barrington JW et al., 1996); development of premature rupture of the fetal membranes (Plessinger MA et al., 2000); and preeclampsia (Bilodeau JF et al., 2003).

As for male infertility, evidence now suggests that ROS-mediated damage to sperm is a significant contributing pathology in 30–80% of cases. (Iwasaki and Gagnon, 1992; Zini et al., 1993; Ochsendorf, 1994; Shekarriz et al., 1995; Agarwal et al., 2006)

Treatment and prevention options for both female and male infertility include the following:

• Minimizing ‘lifestyle’ triggers of oxidative stress including smoking, unhealthy diet, overweight or obesity;
• Minimizing environmental exposure to heat, pollutions and toxins; and,
• Intake of vitamin and antioxidant supplements, with or without the addition of anti-inflammatory medications to decrease leukocyte ROS production.

Antioxidant vitamins include vitamins C and E; and Folic acid and its physiological reduced forms: 7,8-dihydrofolate (DHF); 5,6,7,8-tetrahydrofolate (THF) and 5-methyltetrahydrofolate (5-MTHF).

A randomized, double blind, controlled trial providing preconception multivitamins to female partners of couples trying to conceive, showed higher rates of conception among the women receiving multivitamins, possibly due to an increase in menstrual cycle regularity. (Czeizel AE et al., 1996)

Neural Tube Defects (Role of folate deficiency)

Adequate levels of folate is vital in the process of ‘neurolation’— which involves the rising, fusion, and closure of the neural folds during the earliest stages of development (around 3 weeks from fertilization, 5 weeks age of gestation). Common neural tube defects (NTDs) include anencephaly, meningo/encephalocoeles, and spina bifida.

The rapidly multiplying early neural tissues are the most sensitive of all embryonic tissues to critical levels of folates during this time of development. Folate inhibits the production of homocysteine, which is embryotoxic, by inhibiting the methylation and production of s-adenosyl methionine (SAM). SAM is needed for the proper construction and functioning of the DNA, proteins and lipids which make-up the ‘cytoskeleton’ of the neural tissues. The cytoskeleton is directly responsible for proper ‘neurulation’ (rising, fusion and closure of the neural tube).

A local study has shown that in pregnant women, dietary iron and folate were the least adequate. (Cheong, et al., 2003) Folic acid supplementation has been shown to reduce the risk of NTDs even in the low risk population by 50%. (Vergel et al., 1990; Czeizel and Dudas, 1992)

Based on a Cochrane Collaboration study, periconceptional folate supplementation has a strong, protective effect against NTDs. (Lumley J, et al., 2001)

The current expert recommendations is that all women capable of pregnancy should take a daily vitamin supplement that contains 0.4 to 0.8 mg (400 to 800 µg) of folic acid, and that health care providers offer or provide this counseling to their patients. (Grade A). (U.S. Preventive Services Task Force recommendation statement, (2009)

Folate Supplementation in the Prevention of Preeclampsia and Postpartum Depression

Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality.(Roberts JM et al., 2002); and women with a history of PE continue to be at increased risk for future cardiovascular events. (Irgens HU et al., 2001)

PE may also increase the risk of cardiovascular disease in the offspring through “fetal origins of adult diseases”. (Barker DJ et al., 1999)

Based on the findings of 13 cohort studies and one randomized controlled trial which assessed the relationship betweenfolate supplementation in pregnancy and risk of PE and gestational hypertension (GH), there was a significantly reduced risk of PE and GH in those given folate. (Liu C et al., 2018)

The Folic Acid Clinical Trial ( FACT) was a randomized, double blind, international, multicenter clinical analysis in 70 obstetrical centers in 5 countries (Argentina, Australia, Canada, Jamiaca and United Kingdom). High dose FA supplementation was shown to prevent PE in women with at least one of the following risk factors: pre-existing hypertension, pre-pregnancy diabetes, twin pregnancy, preeclampsia in a previous pregnancy, or BMI >35. (Shi W, 2018) Post-partum depression (PPD) is classified as a major episode of depression that occurs within the first 4 weeks postpartum or within the first 6 months postpartum. (ACOG Practice Bulletin, 2008) Etiology of PPD in unknown but linked to biological, genetic, hormonal, psychosocial and environmental factors. (Sockol LE, 2013)

Symptoms include reduced interest, sleep deprivation, sadness, anxiety, poor concentration, altered eating pattern, hopelessness, and irritability. (Van Vo T et al., 2017)

In a cohort study involving 1592 participants, the prevalence of PPD was significantly higher among participants who reported taking folate supplementation for a duration of 6 months or less than those who reported taking it for a duration of more than 6 months during pregnancy. (Yan J et al., 2017)

In summary, there are several phases in folate supplementation: the reproductive age, pre-conception, and first trimester of pregnancy; during the entire pregnancy up to post-partum and lactation period.

All women capable of pregnancy should take a daily vitamin supplement that contains 0.4 to 0.8 mg (400 to 800 µg) of folic acid.

Women with history of neural tube defects should routinely take 400 mcg of folic acid daily and increase dose to 4 mg per day one month prior to conception and throughout the first three months of pregnancy.

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