Title: Folate, B vitamin and other micronutrient needs in women of childbearing age
Key words: neural tube defects, folate, vitamin B, folic acid, supplementation, homocysteine, methylation, serine, vitamins, B12, B6, zinc, magnesium, choline, taurine, cysteine, methionine, hyperhomocysteinemia, antioxidant, cardiovascular disease, CVD, cancer, Alzheimer’s, obesity, undernutrition, vegans, vegetarians, alcohol, cigarette, liver function, polycystic ovary syndrome, infertility, gastrointestinal disease, coeliac disease, H. pylori, foetal, miscarriage, preeclampsia, premature, Down’s syndrome, cancer, colorectal cancer, breast cancer, alcohol, smoking
Date: Sept 2006
Category: Micronutrients, Reproduction
Author: Morgan, G
Folate, B vitamin and other micronutrient needs in women of childbearing age
Recent reports (Wise 2001) of a lowering of the incidence of neural tube defects (NTDs) in the newborn in the US as a result of government sponsored folic acid supplementation of the food chain has highlighted the prevalence of nutrient deficiencies in women of childbearing age. This review will look at the role played by folate, B vitamins, and other essential micronutrients in homocysteine metabolism, which has been shown to be associated with a range of health issues in women and their offspring.
Homocysteine-associated metabolic pathways are linked to the provision of methyl groups, methylation reactions being vital in over 100 reactions in the body involving nucleic acid, protein and fat metabolism (Bailey 2001). The methylgroups are largely donated by the amino acids serine, S- adenosylmethionine (SAMe) and betaine (trimethyl glycine or TMG). Folate, vitamins B2, B6, B12, zinc and magnesium act as key cofactors in enzymatic reactions involved in the pathways depicted below:
The key indicated enzymes and their associated cofactors for these pathways are the following:
1. Methionine synthase : vitamin B12
2. S-adenosylmethionine synthase : ATP/Magnesium
3. Betaine:homocysteine methyltransferase : folate, vitamin B12
4. Serine hydoxymethyltransferase : vitamin B6
5. 5,10-Methylene THF reductase (MTHFR) : folate
6. Cystathionine beta-synthase : vitamin B2, B6, zinc
7. Cystathionine lyase : Vitamin B6, zinc
The following points can be made:
a) Homocysteine is a toxic metabolite, and is removed by either methylation to methionine or transsulphuration to metabolites including glutathione.
b) Methyl groups for methylation reactions are supplied by serine, TMG and SAMe.
c) Methylation of homocysteine to methionine can occur via two pathways, both B12 dependent.
d) MTHFR deficiency, a polymorphism present in 10-12% of the population, in the presence of folate deficiency, leads to methyl THF deficiency and more pronounced hyperhomocysteinemia (Ashfield-Watt 2002).
e) Hyperhomocysteinemia leads to disruption of transsulphuration and reduced glutathione levels. Glutathione is the major antioxidant in the body; impaired antioxidant activity helps to explain the common associations between hyperhomocysteinemia, impaired antioxidant status and degenerative diseases such as cardiovascular, cancer and Alzheimer’s disease (Fenech 1998,Vollset 2001).
Folate,B vitamin and micronutrient status of women of childbearing age
Obesity and undernutrition are the salient findings of recent nutritional surveys (Gregory 2000). Poor dietary practices, especially among lower socio-economic groups, are associated with all the key cofactors involved in homocysteine metabolism. Amongst 15-18 year old girls in the UK, levels of the cofactors vitamins B2, B6, B12, folate, zinc and magnesium falling in the lower range of nutritional intake have been reported as 21, 5, 2, 4, 10 and 53% respectively (Gregory 2000). These figures undoubtedly underestimate the size of the problem as synergism between these cofactors lead to more pronounced homocysteine elevations (Kato 1999); thus low normal values for vitamin B12, for example, in vegans and vegetarians, who comprise around 10% of this group (Gregory 2000), are likely to be significant. Dietary habits acquired in childhood are known to track into adult life (Buttriss 2002).
Magnesium deficiency is of especial concern due to its prevalence, its association with hyperhomocysteinemia and cardiovascular disease, and its ability to block the efficacy of folate and other cofactors therapeutically (Li 1999). Other variables associated with raised homocysteine levels include alcohol (Jacques 2001) and cigarette consumption (Stein 2002) and need to be considered in young women as they impact on liver function and cardiovascular disease, especially in the case of combined MTHFR and folate deficiency (de la Vega 2001).
Fertility and homocysteine
Obesity is a known cause of infertility. The recent association of obesity, the polycystic ovary syndrome, and elevated homocysteine levels (Loverro 2002), suggests nutritional factors may play a role in infertility, given that homocysteine is a sensitive marker of folate and B vitamin status (Green 1995). The same argument may apply to gastrointestinal disease (Coll 1999), particularly coeliac disease and H. pylori infection, both of which are prevalent and underdiagnosed in the female population; hyperhomocysteinemia and associated deficiencies of vitamin B12, folate, zinc and magnesium are common in such patients.
Foetal consequences of maternal dietary deficiencies
Normal pregnancy has been associated with vitamin B6, B12 and folate deficiency due to increased demand (Cikot 2001). Folate deficiency is of special concern due to its association with neural tube defects (NTDs) (MRC 1991). Although normal pregnancy has not been associated with hyperhomocysteinemia (Cikot 2001), a subgroup of patients show rises in homocysteine levels that have been linked to a range of foetal complications. These include miscarriage (Vollset 2001), abruptio placentae (Owen 1997, Eskes 2001), preeclampsia (Ray 1999, Vollset 2000), low birth weight and premature delivery (Leeda 1998, Vollset 2000). MTHFR and folate deficiency have been shown to be significant factors in such complications (Nelen 1997, Sohda 1997, Kumar 2003). Similar associations have been reported with NTD (Sheilds 1999), Down’s syndromes (James 1999) and other congenital disorders (Botto 2000). In the case of NTD, a combination of folate deficiency and homocysteine toxicity, secondary to MTHFR deficiency, has been hypothesised to affect specific receptors involved in neural tube development (Rosenquist 2000).
Homocysteine-related diseases in premenopausal women Cardiovascular disease
The Framingham study (Selhub 1995) showed that homocysteine levels above 11.4 micromol/L were associated with increased rates of cardiovascular disease (CVD), the top quintile being associated with a doubling of the rate (Graham 1997). Every 1 micromol/L elevation of homocysteine is associated with a 5% increased risk of CVD (Danesh 1998). A recent meta-analysis of 92 studies (Wald 2002) has confirmed a direct link between CVD and homocysteine levels, homocysteine being an independent risk factor for the disease (Refsum 1998, Wald 2002). Diminished levels of vitamins B2, B6, B12, folate and magnesium are also present (Shimakawa 1997, Vollset 2001). The MTHFR polymorphism, associated with higher homocysteine levels and hypertension, is another significant factor (Klerk 2002).
It is estimated that by treating this group alone, some 50,000 lives a year could be saved a year in the US (Perry 1999). Increasing dietary folate, associated with the MTHFR polymorphism, both lowers homocysteine levels and the incidence of CVD (Klerk 2002). Other MTHFR deficiency cases are associated with vitamin B2 deficiency, levels being 28% lower in cases of CVD (McNulty 2002). Vitamin B6 has also been found to reduce homocysteine levels in B2/folate replete individuals (McKinley 2001) as does magnesium in magnesium depleted cases (Li 1999). Magnesium depletion is associated with hypertension, vasospasm and ischaemic events (Altura 1995) and may account for the high incidence of migraine in MTHFR deficient individuals with raised homocysteine levels (Kowa 2000). These studies confirm the close interaction of homocysteine with its cofactors and the MTHFR polymorphism.
Folate deficiency is strongly correlated with both colorectal and breast cancer(Choi 2000). In the case of breast cancer this appears to be associated with alcohol consumption (Zhang 1999), and, in the case of colorectal cancer, with the MTHFR polymorhism (Chen 1998) Osteoporosis Though thought of as a metabolic disease, recent research has shown an association between the MTHFR polymorphism, hyperhomocysteinemia and osteoporosis (Miyao 2002). Further research needs to be carried out to elucidate whether this correlates to folate, magnesium and other homocysteine co-factors in the diet, as poor fruit and vegetable intake has been found to be associated with osteoporosis (New 2003).
The place of supplementation for premenopausal women Folate deficiency remains the major nutritional concern for women in their reproductive years. Both poor dietary intake and bioavailability are related to the poor response of NTDs to purely dietary measures (Cuskelly 1996). The bioavailability of dietary folates has been estimated to be only 50% of that of folic acid (Bailey 1998). Given the marginal dietary status of this vitamin and the prevalence of the MTHFR polymorphism and NTDs, there is a strong case for adding folic acid to the food chain and/or taking regular supplements (Czeizel 1992). A similar case can be made for vitamin B2, B6, B12, zinc and magnesium, given the presence of cardiovascular and gastrointestinal disease in this group and the synergism between the homocysteine cofactors (McCarty 2000, Koyama 2002). Such supplementation has been associated with beneficial results both gestational and post-gestational (Scholl 1997, Fawzi 1998, Bouchey 1995, Malinow 1998, Schnyder 2002). Non-dietary factors associated with homocysteine, such as stress, obesity, lack of exercise and smoking also need to be addressed in order to improve the wellbeing of childbearing women and their offspring.
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