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Indian Pediatr 2009;46: 665-667 |
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Neural Tube Defects: A Neglected Problem |
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Ashok Kumar
Professor, Division of Neonatology, Department of
Pediatrics, Institute of Medical Sciences, Banaras Hindu University,
Varanasi 221 005, India.
E-mail:
[email protected]
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N
eural tube defects (NTDs) are the
most common congenital malformations affecting the brain and spinal cord.
They assume significance by virtue of their morbidity, mortality, health
care expenditure, and human suffering. The incidence of NTDs ranges from
0.5-11/1000 births in different regions of India(1). The true incidence of
NTDs is difficult to ascertain as affected pregnancies may end up in
spontaneous abortions, or may be medically terminated. Neural tube
formation (neurulation) is a highly complicated biological process
controlled by a number of genes, growth factors, adhesion molecules and
receptors(2). By third week of postconceptional age, human embryo has
three distinct primary germ layers- ectoderm, mesoderm and endoderm which
subsequently develop into various tissues and organs. The formation of
neural tube begins during third week when midline ectoderm, under the
inductive influence of the underlying mesoderm, becomes the neural plate
that further develops into the neural groove, then the neural tube. Neural
tube closes during the fourth week, and failure to do so results in
NTDs(3).
The main NTDs are anencephaly, encephalocele, and spina
bifida (including meningocele and meningomyelocele).
The incidence of NTDs shows wide variation, being
influenced by race, ethnicity, nutritional status, geographic location,
and socioeconomic conditions(3). The exact cause of NTDs is not clear in
most cases. Both genetic and environmental factors have been implicated in
the etiopathogenesis of NTDs. Polymorphism of genes involved in folic acid
metabolism significantly increase the risk(2). Other well described
factors associated with NTDs include folic acid deficiency, prenatal
exposure to drugs including antiepileptics, maternal hyperthermia and
maternal diabetes. There are also single gene disorders and chromosomal
abnormalities associated with NTDs. However, they constitute only a
minority of cases. The risk of NTDs after exposure to valproate during
early pregnancy is 1-2%. The risk of recurrence of NTDs after one affected
pregnancy is 2-3% and may approach 10% with two previous abnormal
pregnancies.
Nutritional status of pregnant women may influence
their vulnerability to NTDs. Folate deficiency is a well known cause of
NTDs. The search for other etiological factors, particularly nutritional
factors, continues. In recent years, zinc and vitamin B 12
have attracted the attention of researchers. Zinc is essential for fetal
growth and development and plays a critical role in many cellular
reactions including gene transcription, cell division and differentiation.
Inadequate zinc intake is associated with NTDs in both animals and
humans(4). The essentiality of zinc in neural tube formation is further
supported by the observation that women with acrodermatitis enteropathica,
a disorder of impaired zinc absorption from the intestine, are at high
risk for babies with NTDs(5).
In this issue of Indian Pediatrics, Zeyrek,
et al.(6) report that low maternal zinc and high copper during
pregnancy may be responsible for NTDs. However, the case-control design of
the present study precludes such a conclusion. What this study shows is
that NTD-affected pregnancies are associated with low zinc and high copper
levels. It is not possible to conclude from this study that the observed
association is causal in nature. Only a randomized controlled trial of
zinc supplementation in periconceptional period can settle the issue of
causative link between zinc and NTDs. The authors assessed micronutrient
status of pregnant women during the third trimester or at delivery and
then correlated this with the occurrence of NTDs. They assumed that
similar state of micronutrient status must have prevailed at the time of
formation of neural tube, i.e. during third and fourth weeks of
postconceptional age. This assumption is not valid.
Nutrient status changes with the stage of pregnancy,
and may be influenced by a number of factors, including nutrient-nutrient
interactions. Zinc levels are known to decline with advancing pregnancy.
Another confounding variable to be considered is the prenatal iron
supplementation which can reduce zinc bioavailability(7). Generally
pregnant women are given iron in the later part of pregnancy. The present
study does not provide any information on this important aspect. Thus low
zinc levels observed in later part of pregnancy does not necessarily mean
that similar state existed in the beginning of pregnancy. In the present
study, case and control mothers also differed with regard to age, the
former being of higher age group. Older mothers tend to have lower zinc
levels than the younger age group. Thus difference in zinc levels in cases
and controls in this study has to confront many confounding variables. In
the discussion, the authors make a contradictory statement that low zinc
and high copper levels were due to NTD-induced inflammation. In the
remaining text they maintain that low zinc and high copper possibly
resulted in NTDs. One is left wondering what came first: NTD, or low zinc
and high copper levels.
NTDs constitute the most disabling birth defect in
humans. Therapeutic options are limited in resource poor settings.
Therefore, high priority should be accorded to preventive strategies. The
role of folate in preventing NTDs is well established by several
prospective trials. Periconceptional folate supplementation reduces the
incidence of NTDs significantly (relative risk 0.28, 95% confidence
interval 0.13 to 0.58)(8). It is recommended that all women capable of
becoming pregnant consume 0.4 mg of folic acid daily on an ongoing basis
to prevent NTDs (primary prevention). For high risk (previous NTD-affected
pregnancy) women planning a pregnancy, the recommended intake of folic
acid is 4 mg daily beginning at least one month before conception and
continuing through the first trimester (secondary prevention). The timing
of folate supplementation is critical. As NTDs arise very early in
embryonic life (third or fourth weeks of gestation), before many women
realize they are pregnant, supplementation needs to be started even before
conception to ensure adequate blood and tissue folate levels at the time
of neural tube formation. Given that most of the pregnancies in India are
not planned, timely supplementation presents a formidable challenge to
health professionals and policy planners. Another approach is the
fortification of food with folate as is being done in western countries.
There is a need for public awareness campaign on a large scale to reach
out to the eligible women. Professional organizations like FOGSI, IAP, and
NNF can play a vital role on this front. We also need a public health
agency similar to the US Public Health Service (USPHS) which can act as a
nodal centre to frame and disseminate guidelines to professionals and
general public on issues of public health significance.
Folate-NTD connection illustrates the best example
where a debilitating birth defect can be easily prevented by simple means.
The birth of babies with NTDs in present scenario is a greatly missed
opportunity. In view of wide prevalence and high social costs of these
defects, there is an urgent need to have a national neural tube defects
prevention program in India.
Funding: Nil.
Competing interests: None stated.
References
1. Sharma AK, Upreti M, Kamboj M, Mehra P, Das K,
Mishra A, et al. Incidence of neural tube defects in Lucknow over a
10 yr period from 1982-1991. Indian J Med Res 1994; 99: 223-226.
2. Padmanabhan R. Etiology, pathogenesis and prevention
of neural tube effects. Congenit Anom (Kyoto) 2006; 42: 55-67.
3. Chen CP. Syndromes, disorders and maternal risk
factors associated with neural tube defects. Taiwan J Obstet Gynecol 2008;
47: 267-275.
4. Tamura T, Goldenberg R. Zinc nutriture and pregnancy
outcome. Nutr Res 1996; 16: 139-181.
5. Hambidge KM, Neldner KH, Walravens PA. Zinc,
acrodermatitis enteropathica and congenital malformations. Lancet 1975; 1:
577-578.
6. Zeyrek D, Soran M, Cakmak A, Kocyigit A, Iscan A.
Serum copper and zinc levels in mothers and their newborn infants with
neural tube defects: a case-control study. Indian Pediatr 2009; 46:
675-680.
7. O’Brien Ko, Zavaleta N, Caulfield Le, Wen J, Abrams
SA. Prenatal iron supplements impair zinc absorption in pregnant Peruvian
women. J Nutr 2000; 130: 2251-2255.
8. Lumley J, Watson L, Watson M, Bower C.
Periconceptional supplementation with folate and/or multivitamins for
preventing neural tube defects. Cochrane Database Syst Rev 2000; 2:
CD001056.
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