Folic Acid - The biggest experiment you didn't know you were a part of.

Americans have a love affair with vitamins and minerals, those mysterious compounds that seem to be necessary for good health yet are in reality very poorly understood. Over half the population takes one or more supplements daily despite a conspicuous lack of evidence that they offer any benefit. It's not too hard to see why we are so enamored with these amazing little pills. They are cheap, harmless, and a simple google search turns up millions of websites praising the miracles they work. One of them, vitamin C (in the form of limes), cured the British navy of scurvy and played no small part in establishing the British Empire. Others were found to virtually eliminate such 19th and early twentieth century scourges as rickets (vitamin D), pellagra (niacin), and beriberi (thiamine) in the developed world.

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Even the US government has not been immune to their lure. After seeing the impact of putting iodine in salt ( dramatically decreasing goiters and hypothyroidism) and vitamin D in milk, (which essentially eliminated childhood rickets in the US) the FDA has become a proponent of adding supplements to the US food supply. The 70s saw the introduction of a number of B vitamins into the nations food supply. For the most part these were very successful efforts to treat vitamin deficiencies and the problems caused by them.

Throughout this period researchers gradually accumulated knowledge of the various bioactive substances. They began to quantify the amounts of these substances in the “average” diet and attempt to determine what minimal levels of intake were necessary to prevent the most obvious disease causing deficiencies. It became obvious that those vitamins which were fat soluble (A, D, E and K) and thus stored in fat tissue, could be over consumed and quickly become toxic, even lethal. But the rest, the water soluble vitamins were considered harmless. When I was in medical school we were taught that the you could take all the vitamin C or any of the B vitamins you wanted. Whatever was excess you simply peed out! And with few exceptions that remains the conventional wisdom in medicine today.

Folate was first isolated from Spinach in 1941 by researchers looking for a means to cure anemia. Very quickly it was discovered that folate enhanced the rate of tumor growth, which in turn led to the development of folate antagonists, the first anticancer drugs and still among the most commonly used. Folate was necessary for rapid cell growth and it was reasoned that it might be beneficial for fetal development. Clinical trials in 1991 confirmed that increasing folate intake of pregnant women decreased the rate of neural tube defects.

 

ACOG and the USPHS began recommending prenatal supplements of folate for all pregnant women beginning three months prior to pregnancy. The problem, of course, is that very few women know that they are pregnant until two to six weeks after they conceive. Even among the minority that actually does plan their pregnancy, few know three months ahead of time when that will occur. So those well meaning folk at USPHS, got together with the epidemiologists at the FDA and, beginning in 1998 had folic acid put into the flour supply of some commodities (like uncooked breakfast cereals) at a rate of 140 micrograms per hundred grams of flour. At that rate a large bowl of breakfast cereal will supply the recommended 400 micrograms of folic acid daily.

 

It worked, spectacularly. The prevalence of low folate levels in the US population dropped from 16% to 0.5% (Pfeiffer, 2005) The rate of NTD dropped as well. To be fair, the rate did not drop equally across populations. Americans of black and hispanic descent saw improvement in folate levels but not as dramatic as among whites. There is a proposal currently under study to address that discrepancy by requiring folic acid addition to the corn meal supply.

 

All was not quite as rosy as the policy makers wanted to believe however. Almost as soon as population data began to be published showing the dramatic efficacy of adding folic acid to the food supply, oncologists began publishing papers questioning the wisdom of adding folic acid to the food supply. They pointed out rightly that adding more than the Recommended Daily allowance of folate, a known promoter of tumor growth, to the food supply of a nation that was also obsessed with vitamin supplementation, ran a substantial risk of dramatically over dosing folate in some members of the population.

 

It turns out they were right to be concerned. The same study that approvingly noted the decrease in numbers of people with low folate levels also noted, without concern, that the number of people with greater than 45.3 nanomoles/liter went from 7% to 38% of the population. That corresponds roughly with the established Tolerable Upper Limit of folic acid intake of 1000 micrograms/day. The question then becomes, what is that upper limit based on?

 

It turns out that long term studies on the effects of folate at higher levels than normally found in the human body have never been done. Too little vitamin B 12 can cause severe blood disorders and neurological damage if left untreated. It was well known at the time that excess amounts of folate could mask the symptoms of vitamin B 12 deficiency. The limit of 1000 micrograms of folic acid per day was based simply on the dose that was low enough not to hide the symptoms of B12 deficiency. It had nothing to do with the potential for toxicity of high doses of folate, which were assumed to be harmless.

Nutritional surveillance studies which have been ongoing continue to report the folic acid fortification programs are a massive success story. Blood (serum to be exact) folate levels in the population of females of reproductive age have gone from 14.0 nanomoles/liter during the period from 1988 – 1994 to 37.6 nanomoles/liter between 1999 and 2010 (Pfeiffer et al, 2012). In their zeal to make sure all women who could potentially get pregnant were getting enough folate they have managed to increase the average folate content of the entire population of women between the ages of 14 and 44 to over two and a half times what used to be normal. The amazing thing is that, with very few exceptions, most researchers happily assumed this was a good thing.

 

Now, add to all of this, the current practice of the obstetric community in the US which is to automatically put all of their patients on prenatal vitamins, containing an additional 400 to 800 micrograms of folate depending on brand. Women who were born with a neural tube defect or had a previous child with a neural tube defect are often put on doses as high as 4000 micrograms, ten times the estimated average requirement, with absolutely no data that it helps or is safe. If a little is good, a lot must be better.

Fortunately, those few researchers who have been uncomfortable with employing the nations food supply to conduct a massive, uncontrolled experiment on the entire population have started to publish some data and the findings raise some significant red flags. Selhub, et al, (2009) reported significantly greater cognitive impairment in older subjects with elevated folate levels and lower B12 levels. Troen et al, (2006) reported a biphasic effect of folate levels. Both too much and too little folate impaired the function of certain immune system cells in post menopausal women.

 

The concerns for pregnant women come from two sources. First, the number of new diagnoses of autism began to sharply increase in 2000. By 2000 children children exposed to excess folate in utero in 1998 would be approaching the age at which autism is first diagnosed. In 2000 the rates of autism diagnosis were about 1 in 150 children. By November of 2015, according to the National Health Interview Survey an estimated 1 in 45 children were being diagnosed with autism, a 300% increase that just happens to correspond with the FDA folate fortification program.

 

Of course that's just a correlation and doesn't imply causality but it seems there is now direct evidence of a role for excessive folate in the genesis of autism. In preliminary results from an ongoing study of the early life determinants of autism presented at the 2016 International Meeting for Autism Research in Baltimore, researchers from Johns Hopkins have found that increased levels of folate and B12 can significantly increase the risk that a pregnant woman's offspring will develop autism. If the mother's blood folate was excessive, the risk of developing autism was doubled. If excessive B12 levels were found the risk was tripled. But if both folate and B12 levels were elevated the mother's offspring had a 17.6 times greater risk of developing autism. Ominously, the study found that 10% of women had more than 59 nanomoles/liter of folate (much higher than the recommended upper limit of 45.3) and 6% had more than 600 picomoles/liter of B12.

 

Bear in mind that these are preliminary results and more research is definitely warranted before making major changes. Certainly is it still important to get enough folate, and at the right time to impact neural tube defects. On the other hand, given the prevalence of folic acid in the food supply, in supplements, and of course in prenatal vitamins it would be wise to be cautious. What can one do?

 

Well, a survey of the foods you regularly eat and the amounts is a useful starting point. If you are inclined to eat several bowls of fortified cereal a day – stop! If you are taking vitamin supplements in addition to prenatal vitamins – stop!

 

If you have real concerns about neural tube defects or if you have neural tube defects in your family, it might be wise to have a blood folate level checked.

 

For the rest of you, probably the wisest course of action would be to keep a food diary.

For processed foods like cereal or pasta, check the amounts of folic acid on the label and multiply by the amount you eat on average. Don't forget to check the folic acid on energy bars and energy drinks, if you consume such.

 

That will give you a pretty good starting point.


Multiply the number you get by 1.7

 

That coverts folic acid to DFE – daily folate equivalents. Basically folic acid is synthetic and more bioavailable than the natural folate found in foods.

 

For unprocessed foods only a few contain significant amount of natural folate.

Liver 250 micrograms per 3 oz serving

Lentils 180 micrograms per 1/2 cup
Spinach 100 micrograms per 1/2 cup
Great Northern Beans, 90 micrograms per half cup
Aspargus 85 micrograms in four spears
Broccoli 50 micrograms per 1/2 cup
Eggs 25 micrograms per egg
Cantaloupe 25 in a quarter of a medium sized melon

 

Add up how much you eat of these then add that to the folic acid x 1.7 from above.

 

Now add the folic acid content of any vitamin supplements, prenatal vitamins – don't forget to multiply by 1.7 to convert to folate equivalents.

 

If you get less than 400 micrograms (of folate equivalents) you definitely need to be taking supplements of some sort.
If you get somewhere between 400 and 1000 total, you're probably okay, at least until more information is available.
If you get more than 1000 micrograms then you should consult your doctor about stopping your prenatal vitamin. (Or me if they aren't being helpful.)

 

Also, although most obstetricians and many midwives will tell you differently, the proper counseling for folic acid is to take it from 3 months before conception until 12 weeks after conception. That's it. After 12 weeks the neural tube should be closed and folate will have no further impact. For anyone with a relatively healthy diet I would suggest stopping prenatal vitamins altogether at 12 weeks.