NEURAL TUBE DEFECTS ETIOLOGY
Category: Child Health
Abstract : ETIOLOGY Over the last century, teratogens implicated in the etiology of NTD
in experimental animals and in humans include potato blight, hyperthermia, low
economic status, antihistamine and sulfonamide use, nutritional deficiencies,
vitamin deficiencies, and anticonvulsant use. Of all the suspected teratogens,
carbamazepine, valproic acid, and folate deficiency have been most strongly
ETIOLOGY
Over the last century, teratogens implicated in the etiology of NTD
in experimental animals and in humans include potato blight, hyperthermia, low
economic status, antihistamine and sulfonamide use, nutritional deficiencies,
vitamin deficiencies, and anticonvulsant use. Of all the suspected teratogens,
carbamazepine, valproic acid, and folate deficiency have been most strongly tied
to the development of NTD.
In humans, carbamazepine and valproic acid have been
definitively identified as teratogens. Valproic acid is a known folate
antagonist and may work through that action. A woman taking valproic acid during
pregnancy has an estimated risk of 1-2% of having a child with an NTD.
Therefore, women taking antiepileptic drugs during pregnancy are advised to
undergo routine prenatal screening with AFP.
Smithells first advanced the
concept that nutrition may be related to the development of NTD in the 1970s. He
noted that a low erythrocyte folate and leukocyte ascorbic acid during the first
trimester resulted in more pregnancies affected by NTDs than in controls. His
early work led to 2 important randomized controlled studies on the use of
periconception folate by British and Hungarian research groups.
The
Medical Research Council in Britain performed a prospective, randomized,
double-blind, multicenter trial to see if women who previously gave birth to
children with NTDs could lower the recurrence rate with multivitamins or folate
(4 mg/d). Thus, 1817 women who had had a previous child with an NTD and 1195
women who had not were randomized into 4 groups. One group received
multivitamins, another group received folate, the third group received both, and
the fourth group received neither. The study was terminated early when a
significant protective effect was observed in the groups that received folic
acid but not in the groups that did not. Multivitamins alone had no significant
protective effect. Folic acid ingestion in the preconception period prevented an
estimated 72% of recurrent NTDs. The article with this conclusion was published
in Lancet in 1991.
Hungarian investigators performed a randomized,
double-blind, multicenter trial of folic acid to see if it had a protective
effect for a first occurrence of NTD. One group of 2104 women received 0.8 mg of
folic acid with their multivitamins, while the second group of 2052 women
received no folic acid with their multivitamins. The folic acid group had no
cases of NTD, while the non–folic-acid group had 6 cases. This finding,
published in the New England Journal of Medicine in 1992, indicated that
ingestion of preconception folic acid significantly decreased the first
occurrence of NTD. For this reason, the US Public Health Service issued their
strongly worded recommendation to women of childbearing age to take folic acid
supplements.
However, several important issues have been raised. Since
only 50% or fewer of the pregnancies in the United States are planned,
compliance with the request to ingest preconception folic acid is not always
easy to achieve. Folic acid is not protective unless ingested in the
periconception period. The NTD occurs before day 26 postfertilization, often
before many women have discovered their pregnancy. The precise minimal dose of
folate required to be protective against an NTD has not been determined, thus
making routine food fortification a difficult issue. Furthermore, folic acid can
mask a vitamin B-12 deficiency that can cause neurologic damage. For these
reasons, ingesting daily folic acid in the form of a multivitamin tablet has
become the preferred recommendation. Finally, the precise mechanism in which
folic acid is protective is unclear.
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