The role of nutrition in mammalian development and the risk of congenital anomalies is also one of the many questions that nutritional genomics is trying to answer.
The maternal diet and wellness, both before and during pregnancy are crucial to the prospects of the offspring's. All expecting women need a good mixed diet that provides both adequate calories and nutrition. However socio-economic and cultural barriers are established causes that interfere with the well being of pregnant women. Annually 500000 women die of pregnancy related causes worldwide, of which 43% casualties are contributed by developing countries such as: Bangladesh, Bhutan, India, Nepal, Pakistan and Sri Lanka. 1 in 21 women in rural Africa die of pregnancy related causes, the count is 1 in 38 in south Asia and 1 in 73 in Latin America, compared to ratios of 1 in 6366 in America and 1 in 9850 in north Europe. The obvious reasons for such stark differences are malnutrition, poverty, lack of sanitation and poor education76.
Abundant experimental and epidemiological data demonstrate the association of congenital malformation and disease with maternal nutrition and genetic factors. The growth of the developing fetus is entirely dependant on the provision of nutrition via maternal blood supply. Based on the vulnerable period hypothesis the effect of restrictive stresses can be more profound during early pregnancy and the development of the baby's brain and neurological system is at risk during the vulnerable period76.
Essential micronutrients are now established to be important precursors and cofactors of several vital metabolic pathways and therefore believed to be imperative to fetal development. Malnutrition in individuals from poor agrarian societies at and around birth makes them ten times more prone to die prematurely76.
Fetal development involves continuous cell proliferation, differentiation and the formation of tissues and organs. All of this cellular activity proceeds via dynamic changes in patterns of gene expression of a large number of developmentally regulated genes as per stages of embryonic growth. The precise regulation of gene expression, the surrounding placental environment; including the maternal nutrition state are important contributors to the completion of normal morphogenesis. When any of these processes goes awry - because of genetic mutation, disease or interference in normal progression of development - the consequences can be disastrous.
Many vitamins and micronutrients are now recognized as crucial cofactors in metabolic pathways that regulate nucleic acids synthesis and / or repair systems as well as the expression of genes3. Folic acid is one such micronutrient; deficiencies of which have been related to abnormal embryogenesis via disruption of genomic integrity and affecting gene expression through alteration in DNA methylation: a major epigenetic feature of DNA that regulates gene transcription4.
Neural tube defects (NTDs) are a range of congenital malformations associated with the failure of the neural tube to close properly during early embryonic development; they can lead to severe disability or even death
Micronutrients are nutrients: including dietary vitamins and minerals; needed throughout life in small quantities due to our inability to synthesize them within the body. Several micronutrients are known to be substrates and cofactors for enzymes in different metabolic pathways and are therefore crucial for good health.
Studies that form the basis of the development of the reference values are not free from limitations which necessitate the application of scientific judgment in the setting of the reference values.
The Indian RDA values of folic acid (in terms of free folate) as per the ICMR are:
13 years and above: 100 µg / day
Pregnant Women: 400 µg / day
Lactating females: 150 µg / day
Age
(years)
Males and Females
(μg / day)
Pregnancy
(μg / day)
Lactation
(μg / day)
1 - 3
150
NA
NA
4 - 8
200
NA
NA
9 - 13
300
NA
NA
14 - 18
400
600
500
19 +
400
600
500
Table 2.1 American RDA of vitamin B6 for Adults.
Age (years)
Men
(mg / day)
Women
(mg / day)
Pregnancy
(mg / day)
Lactation
(mg / day)
19 - 50
1.3
1.3
51+
1.7
1.5
All Ages
1.9
2.0
The Indian RDA values of vitamin B6 as per the ICMR are:
13 years and above: 2 mg / day
Pregnant Women: 2.5 mg / day
Lactating females: 2.5 mg / day
Vitamin B12 is important for the functioning of the central nervous system through its contribution in maintaining healthy nerve cells. The deficiency of vitamin B12 causes megaloblastic anemia, a hematological condition affecting red blood cell (RBC) structure and function. It is also vital to DNA synthesis and biological methylation: vitamin B12 is a cofactor of the enzyme MS
Various studies have demonstrated the lack of awareness among women of the reproductive age group about the dietary intake of micronutrients, the ideal time to initiate supplementation and the role of micronutrients in preventing birth defects. Such lack of awareness not only exists within the general population, but also amongst nurses, health professionals and pharmacists.
Homocysteine metabolism is regulated by nutritional status of folate, choline, vitamin B12123 and vitamin B6 since these micronutrients are highly interrelated in one - carbon metabolism75.
Most dietary folates are 5 - MTHF and FTHF: vitamin B12 dependent MS (Figure 2.4: Reaction 8) plays a vital role in facilitating the conversion of extracellular 5 - MTHF to polyglutamate THFs that can be readily diverted to nucleotide biosynthesis etc. In addition, vitamin B6 is necessary for the formation of cystathionine from homocysteine (Figure 2.4: Reaction 12). The demonstration of the association of cobalamin with NTDs as an independent risk factor124-125 is strongly suggestive that one or more enzymes of the biochemical pathways in which these micronutrients part take are eventually involved with the occurrence of NTDs. As with folate some studies have failed to attribute reduced MS activity in wake of vitamin B12 deficiency to the risk of NTDs126, several studies show no significant differences between serum levels of vitamin B12 or folate in NTD case versus control mothers127-128, while others show lower maternal serum vitamin B12 levels in NTD cases81, 124, 129-130. Ray and Blom131 reviewed 17 different studies and concluded that there exists a modest risk between vitamin B12 deficiency and the possibility of NTD offspring, but the significance of such an understanding is unclear if one were to include the complexity factors just as in the case of folate. Some studies examine the vitamin B12 content of amniotic fluid and have demonstrated that such lower vitamin levels are a risk of NTD offspring132-136.
Of all possible mechanisms by which one - carbon metabolism might contribute to NTDs, there is no direct evidence linking any specific metabolic perturbation in one - carbon metabolism with a specific cellular event that might results in a NTD. The situation further complexes when mutations in genes encoding proteins engaged in micronutrient uptake and transport, or enzymes partaking in one - carbon metabolism present themselves as additional variables (discussed later). But with a large numbers of association studies being carried out across the globe, some in an international collaborative fashion, such studies are evolving to become more authoritative in predicting the true risk factors which nonetheless will finally contribute to the unveiling of the mystery that now surrounds the role of micronutrients in birth defects. However until these questions are answered most of our current understanding is more of an intellectual exercise.
Since dietary factors are believed to be associated with several leading causes of disease and death worldwide, researchers and policy makers require dietary data to assess the quality and adequacy of diet in relation to health. Such data also helps to identify target groups for public health education and awareness programs and / or to evaluate one or more of the following: the impact of welfare reforms and legislations, effect of food fortification policies and outcomes of child - maternal nutrition programs.
Randomized trials have demonstrated the efficacy of folic acid in preventing NTDs more than a decade ago. Following these observations public health agencies, national committees and professional bodies in several countries have taken to promote the use of folic acid or folates: either via advocating increased consumption of folate rich food, by recommending supplementation and mandating fortification. Supplementation is obviously the best method to modulate folate status in any target population under experimental conditions, but the problem of compliance in the general population renders it unlikely to achieve substantial results by recommending supplementation. Either ways the recommendations were almost identical and mostly targeted to the prevention of NTDs.
There has been substantial continual progress in the understanding the role of folic acid in health and disease. However the issue of bioavailability needs to be addressed before we can progress into understanding which amongst supplementation, fortification or consumption of natural folates is the best to achieve ideal folate status. Increasing awareness about micronutrient supplementation and therefore the overall increase in the use of such micronutrients even in the presence of both limited and widespread fortification with time will demonstrate the beneficial and / or hazardous effects associated with such consumerism.
