Everything You Need to Know about Folate

Folate is a water-soluble B vitamin (B9) found naturally in various foods. (See the paragraph at the end of this article for a range of essential foods)

While many recognize its crucial role in developing a baby’s nervous system, this vitamin benefits everyone, regardless of age.

Folate is fundamental for

Cell Metabolism. Vital for the body's energy production and overall functioning.
DNA Construction and Repair. Essential for synthesizing, repairing, and maintaining DNA, especially during growth phases such as embryonic development and in tissues with high cell turnover, like bone marrow and the gastrointestinal tract.
Red Blood Cell Production. Necessary for creating red blood cells in the bone marrow. A folate deficiency can lead to anaemia, resulting in fatigue and other health issues.
Epigenetic Maintenance. Ensures the stability and heritability of genetic modifications over successive cell divisions.
Amino Acid Metabolism. Converts amino acids and other compounds in the body to support overall health and growth.
Redox Defense. Balances oxidants and antioxidants, preventing oxidative stress-related damage that can lead to diseases.
Toxic Metabolite Control. Regulates the accumulation of harmful substances like homocysteine, reducing the risk of chronic conditions, including heart disease and Alzheimer's disease.

Folate is one of the 13 essential vitamins crucial for health and cannot be produced by the body. It must be obtained either from diet or supplementation.

The body has about 1,000-20,000 mcg of folate stores, and adults need about 400 mcg/d to replenish the daily losses. Folate is linked to other essential micronutrients, including B vitamins and choline.

A deficiency and insufficiency in folate can become evident in 8-16 weeks. It may lead to megaloblastic anaemia, congenital disabilities, cardiovascular disease, cancer, autism spectrum disorder, infertility, depression, anxiety disorders and cognitive impairment such as dementia or Alzheimer's.

You will find how I deliberately use the word folate in some paragraphs and folic acid in others. It is not a coincidence; although these two terms are often used interchangeably, they are different. You will soon find out why after reading my article below.

A history...

1931: A Pioneering Revelation

Dr Lucy Wills stumbled upon liver and yeast extracts, notably in budget-friendly Marmite (a spread made from brewer's yeast), as a potential cure for macrocytic anaemia in women. The key ingredient was yet unknown.

1941: Cracking the Code

The substance behind the curative properties, initially called "the Wills Factor," was isolated as folate.

1943-1945: Birth of Folic Acid

The newfound vitamin underwent crystallization, chemical identification, and synthesis as pteroylglutamic acid. It officially became known as folic acid.

1960s: Connecting the Dots

Professors Richard Smithells and Brian Hibbard, along with pathologist Elizabeth Hibbard, hypothesized a link between apparent folate insufficiency and pregnancy complications, including congenital malformations.

1983-1991: A Groundbreaking Trial

The British Medical Research Council (MRC) Vitamin Study Group, led by Smithells, initiated a landmark trial. Women taking 400 mcg of folic acid daily experienced a 70% reduction in the risk of developmental abnormalities like neural tube defects (NTDs).

A Pivotal Turning Point

Multiple studies reinforced the positive impact of folic acid on preventing NTDs.

Today

Public health recognizes the crucial link between folic acid intake and preventing NTDs. All women are now advised to consume 400 mcg (.4 mg) of daily folate from food or supplements throughout their childhood.

Folate in preconception health

Are you embarking on the journey of parenthood?

Begin replenishing folate at least a year before pregnancy for both parents, a crucial step, especially if the mother is using oral contraception. These pills have been linked to depleting essential nutrients like folate.

Although folate deficiency is uncommon in wealthy nations, over 40% of people in most countries face folate insufficiency.

Folate supplementation before conception can reduce the risk of infertility, miscarriage, premature birth, small for gestational age (SGA) at birth, neural tube defects and autism by 50-70%.

It can also shield against certain paediatric cancers, such as colon cancer, neuroblastomas, leukaemia and some brain tumours in future offspring.

Folate supplementation can also give an aspiring mother a greater chance of ovulation and a shorter time to pregnancy. It is ideal for those with irregular cycles or undergoing assisted reproductive treatments.

Healthy men with lower folate in their diets have higher rates of sperm DNA damage and chromosomal abnormalities. This duo can cause miscarriages or disrupt embryonic development.

While still debated, there is a correlation between folate and sperm count when supplemented with zinc. A 26-week study revealed a whopping 74% increase in total sperm count in both fertile and subfertile men with combined folic acid and zinc supplementation.

Folate in pregnancy

Before diving into pregnancy, ensuring optimal folate levels is key. Folate plays a crucial role in placenta development and guards against birth defects and potential miscarriage.

Folate deficiency and insufficiency during pregnancy are commonly associated with NTDs, affecting embryonic brain and spinal cord development. NTDs pose significant risks like early death or lifelong disability.

Folate supplementation can also prevent other anomalies such as congenital heart defects, musculoskeletal malformations and orofacial defects such as cleft palate. It's a budget-friendly strategy to reduce the risk of gestational diabetes, gingivitis, and pre-eclampsia during pregnancy.

Adequate maternal folate levels may shield children from future challenges like obesity and high blood pressure, mainly if born to mothers with cardiometabolic risk factors. The positive impacts extend to psychological aspects, influencing emotional intelligence, resilience, attention, autism, and social and behavioural outcomes.

BUT …

Despite its merits, there's a cautionary tale. Elevated folic acid levels in mothers during pregnancy can lead to insulin resistance, diabetes, and obesity in children later in life. Excessive levels may promote cancer cell growth, impact psychomotor development, and harm embryo brain development, potentially leading to neurodevelopment disorders like autism.

Researchers unveil concerns about a potential doubling of autism risk when mothers have very high folic acid levels after birth. Excessive vitamin B12 levels could triple the risk. If both are incredibly high, the risk skyrockets 17.6 times.

Some studies (although still debated) have also found that high maternal blood folic acid during pregnancy could adversely affect lung function, leading to wheezing, respiratory tract infection or asthma in early childhood.

While consuming folate-rich foods is safe, excessive folic acid from supplements and fortified foods may pose harm. The challenge lies in how folic acid is metabolized in some mothers, with potential long-term effects on newborns.

Experts advocate for establishing a safe upper limit of folic acid intake for pregnant women. Yet, it can be a complex puzzle, considering factors like folic acid dose, supplement type, bioavailability, timing of supplementation initiation, maternal metabolism, genetic tendencies, and more.

Folate in postnatal health

While the importance of folate and folic acid during pregnancy is well-known, its role in the postnatal period is less explored.

Literature reviews indicate that healthy women can become folate-depleted in the early postnatal period. Folates are transported across the mammary epithelium, allowing folate levels in breast milk to be maintained at the mother's expense. This highlights the need for nursing mothers to prioritize folate-rich foods and supplements to sustain their stores.

A folate-rich diet helps mothers maintain their folate levels, supports brain development, and enhances infant cognitive performance. Breastfed infants generally receive ample folate, but the exact needs clarification for formula-fed babies regarding folic acid bioavailability and effects and whether a tolerable upper intake level should be defined.

It is also encouraged to have adequate spacing between pregnancies for physical recovery, allowing time to replenish essential nutrients depleted during pregnancy, birth, and breastfeeding. This includes nutrients like folate, iron, iodine, zinc, and essential fatty acids. Regardless of the type of birth, be it vaginal or caesarean, a healing and strengthening period is necessary before embarking on the next pregnancy journey.

Recent studies bring forth a noteworthy connection between folic acid supplementation during pregnancy and protection against postnatal depression. This shield against depression lasts for 8 to 21 months after childbirth. Lower folate levels are associated with a higher risk of depression and more severe depressive symptoms.

This figure taken by Bobrowski-Khoury et al. 2021 shows the effects of folate deficiency on the foetus and its brain development.

Folate versus Folic Acid, is there a difference?

The short answer is YES.

Folate and folic acid may sound similar, but they play distinct roles in our health. The difference occurs during metabolism.

Folate is found naturally in vitamin B-rich foods and is essential for our well-being. When we consume it through our diet, our body efficiently absorbs and converts it into an active form for various bodily functions.

Conversely, folic acid is synthetic in fortified foods and supplements. Although the liver converts it into active folate, excess folic acid can pose challenges, entering the bloodstream without complete processing.

Liver saturation due to excess folic acid can hinder the metabolism, cellular transport, and regulatory functions of natural folate forms. This interference might have repercussions like poor detoxification, miscarriage, and potential inhibition of active folate transport to the brain—an integral factor in brain health.

On the other hand, natural food folate, received through a balanced diet, proves more bioavailable. The upper small intestine readily absorbs it to convert it into active folate, which benefits various bodily processes. Thanks to the efficient conversion, no upper limit is set for raw food folate.

Important.

People with specific genetic variations in the Methylenetetrahydrofolate reductase (MTHFR) gene will provide an impaired key enzyme with the same name (MTHFR), slowing the conversion of folic acid into active folate.

Although the incidence of a mutation varies widely depending on ethnic group and region, the most well-known mutations in the MTHFR gene are the C677T and A1298C variants, which can occur in as many as 1 in 4 people.

When MTHFR activity is impaired, folic acid cannot be activated as quickly, leading to higher levels of unmetabolised folic acid in the blood and an increased risk of having a baby with NTD.

Interesting fact: Recent animal studies suggest that MTHFR gene mutations may not only affect immediate offspring but can cast a shadow on subsequent generations. Developmental abnormalities were observed in genetically normal grandchildren, persisting up to the fourth and fifth generations.

Folate metabolism plays an epigenetic role during development, and the effects can persist for multiple generations. That is why the impact of folate fortification programs may not become immediately apparent after one generation, but more on that below.

In addition to NTDs, MTHFR mutations have been linked to Alzheimer's disease, cardiovascular disease, diabetic nephropathy, pregnancy complications, infertility in men, mood disorders, migraines, Parkinson's disease, psoriasis, and various cancers.

It is important to note that not all individuals with MTHFR mutations will necessarily experience health issues; predicting specific conditions is complex. Seeking advice from healthcare professionals or genetic counsellors tailored to individual circumstances is the wisest approach.

Is folic acid fortification beneficial?

Several food safety agencies in some countries have implemented a mandatory folic acid food fortification program for several years. While others have taken a more measured approach due to the likelihood that folic acid appears to assume different guises depending on the circumstances.

The intake level of folic acid can be safe and beneficial for some people while potentially causing harm to others.

In countries such as the United States and Canada, mandatory folic acid food fortification was proven to reduce the rate of neural tube defects. (In addition to prevalent supplement use, ultrasound screening, and public health programs)

However, this was followed by detecting unmetabolised folic acid in up to 95% of people tested.

Under most circumstances, adequate folate intake appears to assume a protective role against cancer. However, since the fortification program, research has linked higher folic acid levels to an increased risk of cancer, including bowel and prostate cancers. It has also increased the incidence of breast cancer in postmenopausal women.

Furthermore, overconsumption of folic acid may hide a lurking vitamin B12 deficiency. This coupling can lead to compromised brain function, accelerated cognitive decline in the elderly, megaloblastic anaemia, and heightened risks of NTD during pregnancy.

Research into the immunity-folic acid relationship suggests excessive intake can hinder immune function. unmetabolised folic acid has been found to

Research has similarly examined the relationship between immunity and high folic acid intake. These studies found that circulating unmetabolised folic acid caused adverse changes in the immune system by negatively impacting natural killer cells, which are crucial for combating viral infections and cancer.

The quest for a safe upper dose becomes paramount with folic acid inundating diets through fortification and supplements. Continuous monitoring of fortification programs is essential to address emerging concerns promptly.

Spotting folate deficiency: A Guide to Diagnosis

Identifying a folate deficiency involves a thorough process, including clinical assessment, a review of your medical history, a physical examination focusing on any symptoms you might be experiencing, and specialised laboratory tests.

However, blood tests are the most common method to confirm a folate deficiency. These tests provide crucial insights into your folate levels and overall health.

Serum Folate Levels: Measures the amount of folate circulating in your blood. A low serum folate level can serve as an indicator of deficiency.

Red Blood Cell Folate Levels: Assesses the folate content within your red blood cells, offering a more accurate reflection of tissue folate status compared to serum levels.

Complete Blood Count (CBC): A CBC evaluates the composition of your blood, including red and white blood cells and platelets. Signs of anaemia, a common outcome of folate deficiency, can be revealed.

Homocysteine and Methylmalonic Acid Levels: Elevated levels of homocysteine and methylmalonic acid in the blood indicate folate deficiency. These tests provide insights into the severity of the deficiency.

Understanding the results of these tests allows healthcare professionals to tailor interventions and address folate deficiency effectively. If you suspect a deficiency or show related symptoms, consult your healthcare provider for a comprehensive assessment.

Consumption and supplementation of folate

The introduction mentions that the body cannot make folate from scratch and must obtain it from foods or dietary supplements.

Top Folate-rich Foods

Leafy Greens and Cruciferous Vegetables. Folate, derived from the Latin "folium", meaning leaf, is abundant in green veggies like spinach, turnip greens, kale, rocket, broccoli, brussels sprouts, edamame, asparagus, artichokes, cauliflower, romaine lettuce, cabbage and Bok choy. Best enjoyed raw, fermented, or steamed to preserve folate content. Avoid boiling or blanching for optimal benefits.
Yeast. Nutritional yeast, marmite, vegemite, and brewer's yeast are rich sources. Sprinkle nutritional yeast on various dishes, spread marmite/vegemite on toast or sandwiches, and consider brewer's yeast in supplements or mixed with multiple foods.
Seeds, Nuts, and dried fruits. Sunflower, flax, chestnuts, almonds, and more are folate-packed. Enjoy them raw or lightly roasted, stored in a cool, dark place for freshness.
Legumes. Beans, peas, and lentils are folate sources. Opt for sprouting to boost folate availability, and steer clear of canned legumes to retain folate content.
Wheat-based foods. Steamed buns, whole wheat, and wheat germ boast higher folate. Fermentation is recommended for maintaining or enhancing folate levels in the metabolic activities of yeast. Prolonged storage and the milling process led to a severe folate loss.
Eggs. Egg yolks, especially organic ones, are rich in folate. Enhance folate retention by frying or boiling eggs.
Offal. The liver is one of the most concentrated and bioavailable sources of folate. Optimal preparation methods include sous-vide (60 °C/75 min), steaming, and grilling to retain folate.

Dietary Supplements

For Aspiring Parents

Aim for 400 micrograms (mcg) of folate/folic acid in daily supplements.

For Postnatal Women (While Breastfeeding)

Increase daily supplement intake to 600-800 mcg for a healthy pregnancy.

For Pregnant Women

Consume 500 mcg through supplements; for non-breastfeeding, 400 mcg is recommended.

Important.

If opting for folic acid supplements, ensure the total daily intake (including fortified foods) stays below 1000 mcg for overall well-being.

Unlocking Folate's Power for Lifelong Health

If folate is optimised, it can prevent and mitigate the chronic diseases listed below.

Cardiovascular Disease: Folate, along with other B vitamins, aids in the metabolism of amino acid homocysteine. High homocysteine levels are linked to heart disease and stroke. By optimising folate, you support the conversion of homocysteine to methionine, potentially lowering the risk of cardiovascular issues.
Neurological Disorders: Adequate folate intake prevents neural tube defects during pregnancy. Beyond that, folate deficiency has ties to cognitive decline, dementia, and neurodegenerative disorders like Alzheimer's disease.
Certain Cancers: Folate optimisation may act as a protective shield against specific cancers, especially colorectal cancer.
Depression and Mental Health Disorders: Folate plays a pivotal role in neurotransmitter synthesis, including serotonin, a mood-regulating chemical. Low folate levels are associated with an increased risk of depression and mental health disorders.

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DR NAUF ALBENDAR

My name is Dr Nauf AlBendar and I am the founder of The Womb Effect. As a medical scientist with a BSc in Molecular Genetics and Genomics, an MSc in Nutrition & Food Science and a PHD in clinical medicine, I have developed a deep appreciation and understanding for the developmental origins of health and disease.

postnatal, Preconception, PregnancyNauf Al BendarJanuary 10, 2024folate, folic acid, NTD, neural tube defects, food fortification, MTHFR, Methylenetetrahydrofolate reducatse, folic acid fortificationComment