The Role of Folate Supplementation in Spina Bifida Occulta

12 The Role of Folate Supplementation in Spina Bifida Occulta

Elias Rizk and Bermans J. Iskandar

Epidemiology of Spina Bifida Occulta

The incidence of spina bifida occulta (SBO) in the general population is unknown. Unlike the open neural tube defects (NTDs), namely anencephaly and myelomeningocele (spina bifida aperta or SBA), which are clinically obvious, detecting the closed defects requires imaging studies, and only recently have we truly appreciated that the finding of a subtle cutaneous anomaly in the newborn may be crucial to its future neurological, urological, as well as musculoskeletal development.1 The incidence of bony anomalies that can be seen on radiographs, such as nonfusion of the laminae, is well known, but it is clear that the majority of patients with such lesions do not have spinal involvement.^2–4 Although the incidence of open NTDs is declining, such conclusions cannot be made with regard to the closed spinal defects because of the higher detection rate seen in recent years as a result of improved imaging.⁵

Familial Relationship between Open and Closed Neural Tube Defects

Open spinal defects (OSDs) have been associated with multiple maternal risk factors, such as diabetes, anticonvulsant use, and family history.⁶ However, there is only limited information available on risk factors associated with the closed dysraphic states. There is, however, some evidence that open and closed NTDs may be genetically related.⁵ This suggests that these different abnormalities may share some of the same risk factors. And until studies of risk factors in spina bifida occulta are conducted, this presumption may help guide health care providers with regard to prenatal screening, genetic counseling, and the use of periconceptional medications. In a region of Britain endemic for NTDs (prevalence of 0.8% or 10-fold higher than the current prevalence in the United States), Carter et al studied 364 siblings of 207 patients with all forms of OSD and found that there was a 4.12% prevalence of myelomeningocele or anencephaly in the series. This ratio was found to be similar to that of siblings of patients with open tube defects (4.45% and 5.18% in two major studies), and is approximately fivefold higher than the general prevalence in that region.⁵ Recently, in a study of 52 families with a lipomyelomeningocele proband, the NTD Collaborative Group showed that the estimated sibling recurrence risk for open NTDs is 4%, which is not inconsistent with the generally recognized open NTD recurrence risk of 2 to 5% in families with an open NTD proband.⁷ Further, Myers et al showed that periconceptional folate supplementation does decrease the risk of imperforate anus in the offspring,⁸ and it is well recognized that there is a strong association between imperforate anus (and other manifestations of caudal agenesis) and spina bifida occulta.⁹

Periconceptional Folic Acid Supplementation in Open Neural Tube Defects

Although Smithells et al 10 in the 1980s made the first observation that periconceptional folate supplementation may reduce the risk of NTD recurrence, the correlation between NTD and folate was first suspected by Hibbard in 1964; in the past 2 decades, a series of well-designed studies in multiple countries confirmed that periconceptional folic acid supplementation in women with 0.4 to 0.8 mg/day results in a reduction in the prevalence of open NTD by at least 70%^11–14; furthermore, supplementing women with a previous NTD-affected pregnancy with 4 mg of folic acid per day causes a 72% reduction in the NTD recurrence rate.^12,15–17 This persuaded the Public Health Service to recommend that any woman of child-bearing age who is sexually active should take a daily dose of 0.4 mg folic acid per day; similarly, women in the high-risk group (i.e., those who fit the latter criteria but who have also had a previous NTD-affected pregnancy) should take 4 mg of folic acid per day.¹⁸ Since then, many countries have instituted similar policies¹⁹ while initiating a flour fortification system, the results of which remain controversial.²⁰

Periconceptional Folic Acid Supplementation in Spina Bifida Occulta

Currently, there are no data to support or dispute the use of high-dose (4 mg) periconceptional folate in families that have a child with SBO. However, because of the observation already discussed that a genetic relationship may well exist between the open and closed spinal defects, it has been the practice of some centers to recommend the 4 mg dose in mothers of SBO-affected children. That said, three points of contention arise: First, it is equally well established that folate supplementation decreases the risk of other malformations, namely craniofacial, urological, and cardiac.²¹ Does this mean that women with a prior pregnancy affected by a craniofacial disorder should also be on the high folate dose? Second, although the 4 mg dose has had a positive effect on NTD prevalence, there are no data to suggest that this is the optimal dose, and that 0.4 mg is insufficient. The problem is that running an NTD folate dose-response study at this time would require the inclusion of thousands of subjects, and the cost of such a trial would be prohibitive (Berry RJ, CDC, personal communication). Third, although no folate toxicity has ever been reported, it is well established that folate supplementation, when not accompanied by B12, may mask pernicious anemia,²² and there have been discussions in the recent literature about the possibility that overmethylation caused by high doses of folate may shut down the activity of certain genes²³; however, this epigenetic phenomenon is still not well understood, and to this day, no negative consequences have been demonstrated in the dose ranges currently used in NTD prevention. Thus the folic acid dose (0.4 mg vs 4 mg) to be recommended in women with a previous SBO-affected pregnancy remains controversial and hinges on individual preferences.