Anemia of Prematurity - Portal Neonatal

ETIOLOGY Section 5 of 11
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.
FETAL SURGERY FOR TREATMENT OF NEURAL TUBE
DEFECTS
Section 6 of 11
Over the past decade, fetal surgery for NTDs (specifically, myelomeningocele) has developed.
Interest in this approach to the treatment of NTDs stems from a growing body of literature that
supports the 2-hit hypothesis. Initially, most investigators believed that all the neurologic deficits seen
in NTDs resulted from the neurulation defect that occurs during days 26-28 of gestation. However,