Folate Supplementation in Pregnancy
Why is Folate Important
In 1991 in the prestigious medical journal Lancet, there was a report that showed that the frequency of neural tube defects could be reduced by supplemental folic acid.
In 1992, the U.S. Public Health Service recommended that all women who might become pregnant get 400 micrograms (mcg) of folic acid daily to reduce the risk of having a baby with neural tube defects. However, since the neural tube closes very early in pregnancy at about 28 days after conception or by 6 weeks of pregnancy, some women may miss the vulnerable period during which folate is critical if they wait until their first OB visit which is usually not until 8-12 weeks of pregnancy. More importantly, this critical window may occur before a woman even recognizes that she is pregnant. Ideally, women should be on folate before the time of conception to optimize the reduction in neural tube defects.
In 1998, the United States began a public health intervention that required food manufactures to fortify cereal grain products labeled as enriched with 140 mcg of folic acid per 100 g of flour. Since wheat products are one of the most commonly consumed foods by American women, this allowed for a larger percentage of women to have folate supplementation pre-pregnancy. After this intervention was started, the number of pregnancies affected by and babies born with neural tube defects began to decline.
According to the CDC, neural tube defects have decreased since the beginning of folic acid fortification, such that "about 1,300 babies are born each year without a neural tube defect who might otherwise have had a neural tube defect."
However, while neural tube defects have declined neurodevelopmental disorders have risen. Data collected by the CDC suggests that in recent decades several neurodevelopmental disorders have seen considerable rises in prevalence. Chief amongst these include autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The CDC reports that one and every 44 children in the United States will be diagnosed with a disorder on this ASD spectrum. This represents a 200-fold increase from the 1970s when the prevalence was assessed at 1 in 10,000 children. While it is possible that some of this increase is due to the expanded diagnosis of ASD to include previously otherwise categorized disorders in children, there has certainly been an increase in ASD rates over the recent decades.
This rapid rise in autism rates strongly implicates environmental rather than genetic mechanisms as mutation rates in populations are not known to rise that quickly. An array of environmental factors including toxins and pollutants have been proposed as causative or contributory in this increase.
One environmental exposure that has increased substantially over recent decades is the intake of folate in the synthetic, oxidized form as folic acid. Reduced forms of folate are obligatory for metabolic processes that include nucleotide synthesis, cellular proliferation and supply of methyl groups needed for methylation reactions including those essential for epigenetic control.
Due to the specific metabolic roles, the recommended daily intake for folate in women during pregnancy to support the growing fetus is 1.5-fold greater than for nonpregnant women. Since this recognition, mandatory fortification programs have been implemented to increase the intake of folic acid. This has led to fortified breakfast cereals and other snacks being promoted for their health benefits as "medical foods." Consequently, total folate intake in the form of folic acid has risen substantially in the past 25 years resulting in supraphysiologic concentrations of folate in the blood primarily as an increase in unmetabolized folic acid.
Is All Folate Supplementation the Same?
The terms folate and folic acid are often used interchangeably, but they are not the same. Folic acid is a synthetic version of folate and is present in most vitamins and fortified foods such as bread and other products made from flour. Folate is found naturally in foods such as leafy greens.
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme in the body that converts dietary folate and supplemental folic acid to folinic acid and then to methyl folate which is the active form of folate. This is the form of folate that is used in the body by cells to perform the important functions of folate. For people with mutations in the MTHFR gene, there may be a deficiency in methyl folate because of difficulties in converting folic acid to the active form.
Inadequate levels of methyl folate can adversely impact the cardiovascular system, the nervous system and most importantly for our discussion reproductive function.
The lack of methyl folate during early pregnancy can have impacts on fetal development including neural tube defects and cardiac defects. The risk of these birth defects is increased in women with MTHFR mutations. Population studies show that in ethnic groups that have a high rate of MTHFR mutations, there is a higher occurrence of neural tube defects. There also are some studies that show an increased risk of miscarriages in women with MTHFR mutations.
There are 2 major MTHFR mutations that include C677T and A2398C. Because we all have 2 genes, we could have 2 normal genes, a normal gene and one of the abnormal genes, 2 abnormal genes, or one each of the abnormal genes. The mutation C677T is more abnormal than the A2398C mutation. Therefore, two C677T genes would be the most severe abnormality. The other gene combinations in decreasing order of significance include compound heterozygous mutations, i.e. one C677T gene and one A2398C gene, a single C677T gene abnormality, double A2398C gene abnormalities, and least concerning is a single A2398C mutation.
In the past the common treatment for MTHFR mutations was to give patients very high doses of folic acid with the idea that if there is a lot of folic acid around even though there is a deficiency in the enzyme conversion to methyl folate, there would hopefully be enough methyl folate being produced to overcome any deficiency problems. I have equated this to the "little boy" solution. A common gift to give little boys is a little workbench that has different shaped holes and pegs that have different shapes to fit those holes. Little boys will take any peg and use the hammer to try to force it through the hole on the bench. The "little girl" solution is to find the peg that fits the hole and just put it in easily. A high dose of folic acid is the little boy solution. Utilizing methyl folate which is the desired end product of the MTHFR enzyme is the little girl solution.
In the past high doses of folic acid was the only option because folic acid was easily available and cheap whereas methyl folate was not available and is more expensive. However, methyl folate is the obvious most effective option as it bypasses the need to be converted from folic acid into methyl folate. Fifteen years ago, the first prescription prenatal vitamin containing methyl folate was marketed. Today a high percentage of prescription prenatals have methyl folate and an increasing percentage of over-the-counter prenatals as well.
Too Much Folate?
It is essentially impossible to get too much folate from food, but the question for us to explore is whether it is possible to get too much folic acid or too much methyl folate as a supplement.
Epidemiologic research attempting to uncover associations between folic acid supplementation and ASD rates has produced conflicting results. Some studies suggest a protective effect and other studies show no association or suggest a positive association between high amounts of folic acid intake and ASD prevalence.
The combination of low vitamin B12, which can occur in people eating vegan or vegetarian diets, along with high folic acid levels has been shown in animal studies to increase the risk of neurodevelopmental problems. Vitamin B12 is a required cofactor for the methionine synthase reaction in which homocystine is converted to methionine through transfer of a methyl group from methylenetetrahydrofolate. Folic acid excess can cause a decrease in functional folate availability, and this can be further exacerbated by vitamin B12 deficiency. Therefore, the combination of either low folate levels or high folic acid levels with vitamin B12 deficiency is linked to impaired neurocognitive development. As the average intake of folic acid has increased, there may be a greater potential for this combined effect to occur.
The latest research from the Boston Birth Cohort showed a positive association between maternal plasma folate levels and autism risk. Autism incidence was greatest in children born to mothers with the highest maternal plasma folate levels, exceeding the cutoff suggested by WHO (>45.3 nmol/L). Children with cord blood plasma levels of unmetabolized folic acid in the highest versus the lowest quartile had a greater risk for developing ASD. Unfortunately, the unmetabolized folic acid in the mothers was not measured.
A Swedish study testing the association of 62 different maternal blood biomarkers measured during early pregnancy with the later development of ASD identified total folate is having the highest odds ratio of 1.7. Again, the level of unmetabolized folic acid was not measured in the mothers.
Animal studies confirm the harmful effects of high folic acid levels probably due to high levels of unmetabolized folic acid, but there was not an adverse effect from high levels of methyl folate supplementation in the animal studies.
Where to Find Natural Folate
While too much synthetic folic acid in fortified processed foods and supplements may be problematic, your body needs natural folate in your diet for optimal mitochondrial function, protein metabolism and breaking down homocysteine, which can be harmful in high amounts.
Prenatal vitamins can assure you that you are getting an adequate amount of folate. We have started recommending prenatal vitamins that contain methyl folate rather than folic acid. The data suggests that methyl folate may be safe whereas high levels of folic acid may increase the likelihood for neurodevelopmental abnormalities.
There is data showing that for patients undergoing frozen embryo transfer cycles (FET) have an increasing rate of implantation as their folate supplementation levels are increased with a peak implantation rate between 2000 and 3000 mcg daily and then a decrease if folate intake is greater than 3000. Although controversial, we recommend methyl folate rather than folic acid as the preferred form of folate supplementation.
None of the studies on folate take into account the dietary intake of folate. They only look at the level of supplementation. One of the problems is that today's food supply is frequently deficient in proper nutrition including vitamins and minerals. However, the best way to naturally increase your levels of this important micronutrient is to eat foods rich in natural folate, that include asparagus, avocados, Brussels sprouts, broccoli, kale, and spinach. Meanwhile, vitamin B12-rich foods include grass fed beef, beef liver, wild rainbow trout and wild sockeye salmon.
