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Public HealthNutrition
Robin de Bree
1
,Lecture 1: Health effects of folate: current evidence
Folate and folic acid - vitamin B-11
- Folate present in food → Main food sources: vegetables, fruit, grains
- Recommended daily intake: 300 μg/day, Folic acid supplement 400 μg/day for 4
weeks before -> 8 weeks after conception
- Upper limit (NL): 1000 μg/day
- Intake folate equivalents diet: 258 μg/day (male 284 μg/day, female 231 μg/day)
Functions of folate
• DNA metabolism
• Amino acid metabolism
Folate metabolism
THF is essential for various cellular functions:
1. Conversion to Active Form: Folate from the diet is converted to THF, the active form,
through a series of enzymatic reactions.
2. One-Carbon Metabolism: THF plays a central role in one-carbon metabolism,
transferring one-carbon units for DNA, RNA, and amino acid synthesis.
3. DNA Synthesis and Repair: Folate supports DNA synthesis and repair, crucial for
genetic stability.
4. Methylation Reactions: Folate provides methyl groups for methylation reactions,
impacting gene expression and other cellular processes.
5. Homocysteine Metabolism: Folate helps convert homocysteine into methionine,
affecting cardiovascular health.
6. Regeneration of Folate: THF can be regenerated for further use.
7. Excretion: Excess folate is excreted in urine.
Folate is essential for DNA synthesis.
When there's a deficiency, DNA synthesis is impaired, leading to disrupted cell division.
- In the case of red blood cells, this can result in megaloblastic anemia, a condition
characterized by larger, immature red blood cells.
2
,Folate and neural tube defects (NTD)
• During embryo development cell division is extremely rapid.
• Neural tube develops from day 21-27 post conception
• Inadequate folate = lower cell division = neural tube development
Main NTD forms
1. Spina bifida: incomplete closing of the backbone and membranes around the spinal cord
Consequence: children are affected with life-long morbidity and disability, and have a 10-fold
higher risk of mortality
2. Anencephaly: rostral (head) end of the neural tube fails to close
Consequence: children generally die during or shortly after birth
In Europe, the prevalence of NTDs is 8.16 per 10,000 births. Among these cases:
- Live births account for 2.22 per 10,000 births
- Fetal deaths or stillbirths occur in 0.37 per 10,000 births.
- Termination of pregnancy following prenatal diagnosis is performed in 5.57 per
10,000 births.
Estimated lifetime expenditures for a child born with spina bifida include:
1. Total lifetime direct cost of care, which covers medical and treatment expenses.
2. Emotional costs, referring to the psychological and emotional toll on the child and
their family.
In the United States, around 3,000 pregnancies are affected by neural tube defects annually,
with over 300,000 affected worldwide. These figures highlight the significant impact and
financial burden associated with caring for children born with these conditions.
The history of NTDs (Neural Tube Defects) suggests a common etiology with increased
risk of recurrence. This is attributed to both genetic and environmental factors:
- Genetic factors include the recurrence rate of NTDs, differences in risk among ethnic
groups, and findings from twin studies, indicating a genetic component.
- Environmental factors may not have a constant NTD rate over time, raising questions
about the role of nutrition.
Hibbard's 1964 study found that women with pregnancies affected by NTDs had higher
urinary formiminoglutamic acid levels than the normal population. This suggested that folate,
a B-vitamin, is involved in the breakdown of formiminoglutamic acid and is relevant to NTD
development.
These studies investigate the relationship between NTD (Neural Tube Defects) and folate
interventions:
1. Smithells (1980):
- Intervention: Multivitamin (n=178)
- Control: Unsupplemented women not recruited for the trial (n=260)
NTD rates:
1 child in the intervention group (0.6%)
13 children in unsupplemented women (5%)
Conclusion: Multivitamin supplementation significantly reduced NTD rates.
3
, 2. Laurence (1981):
- Intervention: 4 mg/d folic acid (n=60)
- Control: Placebo (n=51)
NTD rates:
2 children in the intervention group
4 children in the control group
Initial conclusion: No significant effect of folic acid on NTD recurrence.
3. Laurence (1981, taking compliance into account):
- Intervention: 4 mg/d folic acid (n=60) (Compliance intervention: n=44 (74%))
- Control: Placebo (n=51)
NTD rates:
0 children in mothers who took the supplement
6 children in mothers who did not receive/take the supplement
Revised conclusion: Folic acid may prevent NTD when compliance is considered.
4. NTD and folate - MRC study:
Multicenter study involving 1,817 women with previous NTD-affected pregnancies.
Four groups: Folic acid, Folic acid + multivitamin, Multivitamin, and Placebo.
Out of 1,195 completed pregnancies, NTD rates were significantly lower in the folic acid
groups (6 children) compared to the other groups (21 children). The relative risk (RR) was
0.28, indicating a strong protective effect of folic acid.
Conclusion
Folic acid supplementation prevents NTD
Advice to take folic acid supplements periconceptional:
– Normally: 400-500 μg/d folic acid from 4 weeks before conception until 8 weeks after
– For women with history of NTD-affected pregnancy: 4,000-5,000 μg/d
Strategies to optimize folate status
- Diet: Increased intake of ‘natural foods’ high in folate (liver, vegetables). Limitations:
1. Major dietary changes needed to increase folate intake substantially
2. Bioavailability
- Supplements: easy & effective. Limitations:
1. Not effective on population level (compliance/unplanned pregnancies)
- Fortification. Benefits:
1. Population-wide impact, including those who may not actively seek out dietary
changes or supplements.
2. It ensures a consistent and controlled intake of folate
Strategies to optimize folate status: Fortification of grain foods with folic acid
- Since 1998, the US and Canada have mandated adding 140 μg of folic acid per 100g
of grain product, resulting in an average additional daily intake of about 100 μg.
- Reaching the target population: This method effectively reaches the entire
population, including women of childbearing age who benefit most from increased
folate intake.
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