OBGYN.net: The Universe of Women's Health

Sometimes it seems that the best science results come from keen observation rather than factual knowledge or experimentation. You remember the story of Jenner, don't you? He observed that milkmaids who contracted cowpox seemed not to become infected with smallpox. His observation of a natural phenomenon led him to the hypothesis that prior infection with cowpox provided an immunity to the lethal smallpox. Or, what about Semmelweis? Same thing. Careful and skillful observation led to the realization that the doctor's unwashed hands were responsible for the increases in puerperal fever.

If you explain to my 10 year old daughter that unwashed hands can transmit disease, you are likely to receive a response like, "Well, duh!" Sometimes it is with the light of retrospection that we can have the "Aha" reaction, or as my daughter would put it, "Well, duh!"

This, too, is the story of folic acid (also called folate) supplementation in pregnancy and its role in reducing the frequency of certain birth defects. Today we can look back, armed with the knowledge of folate metabolism by the placenta and fetus, and realize that it should have been obvious how important this vitamin is.

The story begins with the first malignancy to be deemed curable: choriocarcinoma. The first chemotherapeutic agent used successfully on choriocarcinoma was methotrexate. Methotrexate is known to inhibit an enzyme (folate reductase) found in abundance in the placenta. Folate reductase uses folic acid to help make proteins for the developing tissue. Since choriocarcinoma is a malignant form of placental tissue, and since placental tissue is dependent upon folate for its rapid growth and protein synthesis, it was natural to try methotrexate as a treatment. It worked.

In the 1960's, some physicians wondered if methotrexate could be used to induce abortions medically. It turned out not to work. A normal healthy placenta would not always be destroyed by methotrexate. The fetuses continued to live in many cases. They were born with a variety of birth defects, which, not infrequently, included neural tube defects. Neural tube defects, such as anencephaly, spina bifida and meningomyelocele, are failures of an embryonic structure (the neural tube) to fuse closed. The neural tube usually closes by 28 - 30 days after fertilization.

Fast forward to the 1980's. It becomes known through careful epidemiology and observation that the British Isles have significantly more cases of neural tube defects than the United States. A number of researchers wondered if there was a folic acid connection, insofar as it was previously shown that a folic acid blocker (methotrexate) could artificially increase the rate of neural tube defects. Tests would show that the folic acid levels in the blood of women of the British Isles were substantially lower than those in women of the United States. This was the moment of the "Aha" reaction.

Mothers of babies with neural tube defects had diets poor in folate and seldom took vitamin supplements prior to pregnancy. Mothers of babies that did not have neural tube defects reported greater intake of foods high in folate and increased frequency of taking vitamin supplements prior to pregnancy. The lower the folic acid in the diet the higher the rate of neural tube defects in the population, and vice versa.

Trials were begun to see if what was being observed in nature could be used to prevent neural tube defects. The rest, as the saying goes, is history. Women who get at least 400 mcg (.4 mg) of folate daily, through diet or vitamin supplement, have fewer offspring with neural tube defects than women who don't. Furthermore, if a woman who had a child with a neural tube defect takes 4000 mcg (4mg) of folate daily prior to pregnancy and during the first three months, the chances are reduced she'll have another baby with the same condition.

This overwhelming evidence has led many nutrition experts to recommend that folic acid be added to foods we regularly consume, such as bread and orange juice. While this has not caught on universally, there is growing awareness of the importance of this vitamin in preventing certain birth defects.

Folic acid is found naturally in most green leafy vegetables, especially the cruciferous ones: lettuce, cabbage, broccoli and Brussel sprouts. As mentioned earlier, some common foods that usually lack folate have been supplemented with tiny amounts. Folic acid can also be purchased as a vitamin supplement. The US Food and Drug Administration restricts folic acid sales without prescription to a maximum of 400 mcg (.4mg) per tablet. This is because larger doses of folate can mask symptoms of pernicious anemia, a vitamin B12 deficiency. Most prescription formulations of prenatal vitamins
contain at least 1000 mcg (1mg) of folic acid, in addition to many other vitamins and minerals essential to pregnancy.

For most women contemplating pregnancy, it is recommended to get at least 400 mcg (.4mg) of folic acid daily. Smoking and stress can lower a person's folic acid levels. So can malnutrition or malabsorption. For these women, increased folic acid supplementation is recommended.

When taking a multivitamin, be careful not to take excess amounts of Vitamin A while trying to meet the minimum folic acid dose. Excessive amounts of Vitamin A may cause certain birth defects. If one is anticipating pregnancy, probably the best all -around vitamin supplement are prenatal vitamins. These vitamins are specially compounded to provide the proper amounts of each vitamin and mineral during pregnancy, while avoiding potential toxicities.

Unfortunately, there is no magic pill. Folic acid supplementation can help reduce the incidence of neural tube defects. We are still investigating other nutritional issues, looking once more for the "Aha" reaction.