Lecture notes Public Health Nutrition

PUBLIC HEALTH NUTRITION
LECTURE 1: HEALTH EFFECTS OF FOLATE

INTRODUCTION
Women who are pregnant were very tired and had a specific type of anemia, especially for women in poor
environments. Is this linked to nutrition?
At the end, folate (found in margarine) seemed to be the factor that prevented the anemia.

FOLATE, FOLIC ACID AND ADVERSE PREGNANCY OUTCOMES
Folate and folic acid - Vitamin B11
- Folate is present in food: vegetables, fruit, grains
- Recommended daily intake: 300 microgram/day
o Pregnant: supplement 400 microgram/day from 4 weeks before until 8 weeks after
conception
- Upper limit: 1000 microgram/day
- Intake folate equivalents diet: average 258 microgram/day (man 284 microgram/day, vrouw 231
microgram/day)

Functions of folate:
1. DNA metabolism (DNA synthesis)
2. Amino acid metabolism (protein metabolism)




Folate and protein intake via diet. If there is a shortage of folate, there will be an effect on DNA synthesis via
B2.
Two circles who are closely connected

Folate and DNA synthesis:
- Folate deficiency reduces DNA synthesis
- The cell division is disturbed (less red blood cell division)
- You will get megaloblastic anemia
- Whenever anemia is diagnosed, check folate levels

Folate and Neural Tube Defects (NTD):

, - During embryo development cell division is extremely rapid, all the vitamins should be in a level to
assist this development
- Neural tube develops from day 21-27 post conception (critical time)
- Inadequate folate leads to a lower cell division, which results in lower neural tube development
- In beginning of the pregnancy!

Main NTD forms:
- Spina bifida: incomplete closing of the backbone and membranes around the spinal cord
- Anencephaly: rostral (head) end of the neural tube fails to close
- Prevalence EU: 8..000 births
o Live births: 2.22
o Fetal deaths/stillbirths: 0.37
o Termination of pregnancy: 5.57

Consequences of NTD:
- Anencephaly: children die during or shortly after birth
- Spina bifida: children are affected with life-long morbidity and disability, and have a 10-fold higher risk
of mortality
- Estimated lifetime expenditures:
o Total lifetime direct cost of care for a child born with spina bifida
o Emotional costs
o US: 3000 pregnancies are affected by NTD every year (>300.000 worldwide)

NTD – history:
- All NTD’s have common etiology because of increased risk of recurrence:
o Genetics:
 Recurrence rate: second baby’s more
 Ethnic groups
 Twin studies
o Environmental:
 NTD rate is not constant over time: role of nutrition?
o Second baby’s more
- So genetic and environmental factor
- Hibbard (1964):
o Women with pregnancies with NTD had higher urinary formiminoglutamic acid than normal
population
o Folate is involved in breakdown of formiminoglutamic acid

NTD and folate - Interventions:
- Smithells (1980):
o Population:
 Intervention: Half multivitamin (n = 178)
 Control: Half no multivitamin, not recruited for the trial (n=260)
o Issue:
 Not randomized
 Not ethical
 Multivitamin, you don’t know which vitamin does the effective work
o NTD rates:
 1 child in intervention group (0.6%)
 13 children in unsupplemented women (5%)
- Laurence:
o Population:
 Intervention: 4 mg/day folic acid (n = 60)  Really high doses!
 Control: placebo (n = 51)

, o Intervention on recurrence, when they already had a baby
o Conclusion: no effect of folic acid on recurrence of NTD
o Issue: compliance!
 Intervention group did not take it;
 Exclude those women out the intervention group; compliance intervention (n = 44)
 NTD rates:
 0 children in mothers who took supplement
 6 children in mothers who did not receive/take supplement
o Conclusion: folic acid may prevent NTD events
o They did not check for the diet? Why?
 Hard
 Not necessary since the required intake was extremely high

NTD and folate - MRC study:
- Multicenter
- 1817women with previous NTD-affected pregnancy were divided into 4 groups
o Folic acid ( 4 mg/day)
o Folic acid + multivitamin
o Multivitamin
o Placebo
- 1195 had a completed pregnancy
o 6 children had NTD in folic acid groups
o 21 children had NTD in not folic acid groups
o RR = 0.28
- Conclusion: Folic acid supplementation prevents NTD
- Advice: take folic acid supplements peri-conceptionally
o Normally: 400-500 microgram/day folic acid from 4 weeks before conception until 8 weeks
after
o For women with history of NTD-affected pregnancy: 4000-5000 microgram/day

OPTIMIZING FOLATE INTAKE - STRATEGIES
Strategies to optimize folate status:
- Diet: increased intake of ‘natural foods’ high in folate (liver, vegetables)
o Limitations:
 Major dietary changes needed to increase folate intake substantially
 Bioavailability
- Supplements: easy and effective
o Limitations: not effective on population level / hard to reach the women who need it
(compliance / unplanned pregnancies)
- Fortification: in the food for everybody

Fortification:
- Folic acid fortification in grain foods
- Mandatory in US & Canada since 1998:
o 140 micrograms/100 g of product
o  mean additional intake of 100 micrograms/day
o On population level in NL, we would reach the advise
- Whole target population (women at childbearing ages) is reached
- Limitations:
o Possible other health effects?
 CVD
 Other?
o Safety issue for:
 Women not at childbearing ages

,  Men, children
 Older adults: masking of B12 deficiency. B12 deficiencies show the same symptoms
as B11 deficiencies. When everyone receives B11 in their food, the symptoms
(anemia) are cured. You will not go to the doctor, although B12 deficiency is still
there.
 Risk-benefit balance

EXPLORATION OF THE EVIDENCE ON FOLIC ACID, HOMOCYSTEINE AND CVD
What is homocysteine?
- Sulfur-containing amino acid produced from methionine
- A high homocysteine level is associated with an increased risk of CVD.

Folate and with B-12 lower homocysteine and therefore lower risk of CVD.
- Interventions:
o Folic acid (0.8 mb/day): lower homocysteine
 25% reduction in non-fortified populations
 15% reeducation in fortified populations
o Vitamin B12 adds 7% reduction
o Vitamin B6 no effect
Lot of interventions done. If you give folate compared with placebo, homocysteine is lowered.

Homocysteine and Risk of Ischemic Heart Disease and Stroke – A Meta-analysis - Paper A (2002)
1. What conclusion do you draw from this paper?
Elevated homocysteine levels are a modest predictor of IHD and stroke in healthy population.
2. What do observational studies contribute to the main research question?
The evidence was first high (only retrospective), but due to adding on (more) prospective studies, the evidence
got moderate. The RR lowers due to the adding on the prospective studies.
3. What are limitations of this study with respect to the main research question?
Usage of observational studies, which makes the evidence weaker.
Casualties are not defined.
Effect of confounders are not identified.
4. What would be a logical next step, what would you do at this stage?
Confirming conclusion by providing evidence from RCT’s.

Homocysteine and CVD: meta-analyses




By adding prospective studies, the risk lowers.

Homocysteine and CVD: the evidence
- Observational studies: lowering of plasma homocysteine by 25% (3 micromole/L) is associated with
o 11% lower risk of coronary heart disease
o 19% lower risk of stroke
- Intervention trials
o Trials with intermediate endpoints (indication for CVD)