prevention of neural tube defects.

Neural tube defects and oral clefts are among the most common congenital malformations with prevalences of 10-15 per 10 000 and 20 per 10 000 live births, Periconceptional supplementation with folic acid reduces the risk of neural tube defects. What has been less defined is the effect of folic arid supplementation on other birth defects, such as cleft lip. with or without cleft palate.
, Wilcox and colleagues report a population based case-control study from Norway, which shows that supplementation with folic acid in the periconceptional period reduces the risk of cleft lip, with or without cleft palate, in newborn. Supplementation with 100 ug of folic acid for three months around conception was associated with a 40% reduction in the prevalence of cleft lip, with or without cleft palate, at birth. . The study supports findings from other recent studies, including a large meta-analysis.’
400 ug folic acid per day may well prevent a large proportion ot neural rube defects. even suboptimal fortification (for example. 180 ug/day in the US) greatly reduces neural tube defect rates.’
Three public health policies have been suggested.
1. for women to eat a diet rich in naturaJ folates. However, it is difficult to reach this dose with diet alone, and folate in the diet has lower bio-availability than synthetic folic acid.
2. The second is for women to take supplements of folic acid in the periconceptual period. But low compliance and high rates of unplanned pregnancy limit this approach, fewer than 50% of women followed the recommendations.
3. The third fortification of staple foods (such as wheat, corn flour, or rice).
The World Health Organization has recommended supplementation with 400 ug of folic acid in the peri-conceptual period. Fortification of food is mandatory in an increasing number of countries Countries differ substantially ) in their choices of preventive strategy.
”Further support for mandatory fortification of food comes from a cohort study showing that simply recommending women planning pregnancy to take folic acid is not enough to substantially reduce the prevalence of neural tube defects at birth.
However, in many European countries mandatory fortification has been limited by theoretical concerns. These include the potential of masking symptoms of vitamin B12 deficiency, interactions with certain drugs (amifolales). and other unrecognised adverse effects such as idiosyncratic reactions to folic acid even in small amounts
But mandatory folic acid fortification to achieve around 180 rig/day on average and 1000 pg/day at maximum appears to holds little risk of complications.
Fortification could also reduce the burden of major disorders such as cardiovascular diseases and dementia. The risks of these disorders increase with high plasma concentrations of homo-cysteine, which folic acid supplementation can reduce in humans. The definitive evidence in large long standing controlled trials studying the benefits of supplements in cardiovascular disease and dementia have yet to be obtained .
The underlying problem is a lack of knowledge of what basic defect is involved in the aetiology of these birth defects. Karen Liu has shown that in mice with a glycogen synthase kinase ( GSK-3β) defect developed defective fusion of the palate and sternum. Giving Rapamycin at an early stage in development prevented cleft palate.and later in the pregnancy the sternal defects. Rapamycin stabilizes the glycogen synthase kinase.
Another problem is the population at risk. The potential mother of a wanted baby is likely to follow this advise.
Nature 2007, vol 446, pp xi and 79
BMJ 2007, vol 334, pp433-4
Wilcox et al BMJ 2007 , vol 334, 464-467

Martin Eastwood
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