Folic Acid and Neural Tube Defects
Abstract & Commentary
By John C. Hobbins, MD
Professor, Department of Obstetrics and Gynecology,
University of Colorado School of Medicine, Aurora
Dr. Hobbins reports no financial relationships relevant to this field of study.
Synopsis: In a recent case-control study involving more than 1000 patients whose fetus's had neural tube defects, analysis of their dietary intake showed a protective effect of folic acid in diabetics and in the overall population, but not in obese patients.
Source: Parker SE, et al. The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida. Am J Obstet Gynecol 2013;209:239.e1-8.
The incidence of neural tube defects (ntd) at birth has diminished somewhat over the last 20 years to
< 1 in 1000 because of an improvement in screening and diagnosing this condition and, probably, an increased emphasis on adequate intake of folic acid in pregnancy.
Diabetes represents a well-known risk factor for NTD and obesity also has been implicated. Authors from a large consortium of centers in the United States and Canada (the Epidemiology Center Birth Defects Study) have recently published a case-control study to identify whether adequate dietary/supplemental intake of folic acid was associated with a decrease in the incidence of spina bifida (SB) in pregestational diabetics and obese patients.1
Data on 1154 cases of SB were accumulated between 1976 and 2011, as well as another 9439 control patients registered during that time. Information was also filed on dietary and/or vitamin intake on all patients in the study over the month before and 1 month post-conception. In addition, any history of diabetes was documented and maternal body mass indices (BMIs) were recorded.
NTD mothers were more likely to have pre-existing diabetes (0.7% vs 0.4%) or be obese (19% vs 10.8%) than controls. Folic acid intake of < 400 ug per day had an adverse effect in both diabetics and non-diabetics. For example, in those diabetics in the low folic acid group, the risk of SB was four times higher than controls (odds ratio [OR], 3.95; 95% confidence interval [CI], 1.56-10.0). In non-diabetics, there still was a difference in the rate of SB with low intake of folic acid (OR, 1.99; 95% CI, 1.69-2.34) compared with those with adequate intake. However, while obese patients did have an increased risk of SB (OR, 1.87; 95% CI, 1.46-2.65), folic acid did not seem to lower the rate of SB in these women.
This study sends the message that folic acid does decrease the rate of SB in all patients and in pre-existing diabetics in particular — who again are shown to have a higher incidence of SB than in the overall population. It is unclear why obese patients are seemingly resistant to the protective effect of folic acid.
Years ago, Reece at al2 showed in an in vitro rat embryo model that the higher the concentration of glucose to which the embryo was exposed, the greater the chance of an NTD. The neural tube closes in human pregnancy between days 20 through 28 post-conception. Therefore, it is very important for diabetics to be in good glucose control and to have folic acid on board during this early window of time.
Folic acid also helps to protect against a recurrence of NTD. In some areas of Great Britain (for example, Liverpool) the rate of NTD had been unusually high, but Smithells et al3 showed that with folic acid supplementation the recurrence rate of SB decreased from 4% to about 1.4%.
Although diabetics and those with a previous history of NTDs are among the most vulnerable to this complication, together they still contribute only a modest percentage of cases to the overall pool of NTDs, which in part could be that many lower-risk patients are not as apt to plan for early pregnancy coverage with folic acid. For this reason, in 1982 the Public Health Service recommended intake of folic acid to be at least 400 ug per day for everyone of childbearing age. It should not be difficult to attain that goal with diet alone, but for various reasons such as malabsorption problems, a lack of dietary knowledge, or, commonly, a well entrenched fast-food mentality, it has been more effective to simply prescribe prenatal vitamins. The most commonly used prenatals generally contain 800 ug of folate, which provides a cushion by doubling the above recommendation. However, some high-risk patients may need more, such as obese mothers, patients with methylene tetrahydrofolate reductase deficiencies, those having had bariatric procedures, those being maintained on certain antiepileptic medications, and those who have already had a NTD pregnancy.
Since 1991, the Centers for Disease Control and Prevention has recommended that patients at high risk for NTD have 10 times the usual requirement of folic acid per day (4000 ug) — an intake that might only be attained through a vitamin supplement. Interestingly, in 1998 the FDA decreed that cereal grains be fortified with folic acid by adding 140 ug of it to every 100 g of grain. Frankly, the concept would be more effective if the Big Mac were targeted for fortification. The company claims to help feed 60 million people around the world, and this item (576 calories), combined with a coke and fries, tally out at 1386 calories. This combination, while providing more than half our daily requirement of calories, contains only about one-tenth of the daily requirement of folic acid.
This study alerts us to the increased risk of NTD in diabetics and how folic acid can decrease the risk in everyone — except, seemingly, obese patients who probably should be put in an increased requirement category.
- Parker SE, et al. The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida. Am J Obstet Gynecol 2013;209:239.e1-8.
- Reece EA, et al. Ultrastructural analysis of malformations in the embryonic neural axis induced by in vitro hyperglycemic conditions. Teratology 1985;32:363-373.
- Smithells RW, et al. Further experience in vitamin supplementation for prevention of neural tube defect recurrences. Lancet 1983;1:1027-1031.