Folic acid supplementation can help prevent neural tube defects (NTDs) like spina bifida. The CDC recommends that women planning to become pregnant take 400 micrograms of folic acid daily starting at least one month before conception through the first trimester. Women at high risk for NTDs due to family history should take 4,000 micrograms daily. Getting adequate folic acid from foods and fortified grains can also help reduce NTD risk.

1. Folic acid in pregnancy
2013.9.3
주산기 전임의 이민영

2. Folic
Acid
Folic acid/ folate ??
INTRODUCTION
Folic (Pteroyl-L-Glutamic) Acid
Pteridine
p-Aminobenzoic acid
L-Glutamic acid
Folate ; Polyglutamyl Tetrahydrofolates

3. Folic
Acid
INTRODUCTION
Folate VS
• Natural (complex) form
 Foods such as dark-
green leafy vegetables,
broccoli, asparagus,
lentils, beans, peanuts,
strawberries, kiwi, orange
juice, liver
 Can be lost throught
processing and cooking
 Absorption : 50%
• Synthetic (simple) form
 Fully oxidized form,
Pteroylmonoglutamic acid
 Have only one glutamate
molecule attached
 Used in nutritional
supplements and food
fortification
 Only form that can be
transported across
membranes
 Absorption : ~93%
Folic acid

4. Folic
Acid
INTRODUCTION
Functions of folic acid
 Amino acid/Nucleic acid metabolism
– Essential for synthesis of serine, methionine, ATP, GTP,
thymidylate
 Cell growth and division
 Formation of Red blood cells
 Reduction blood homocystein level
 Prevention of NTDs
– All NTDs occur between 17th and 30th days following conception
– Adequate folate should be obtained in the 1st trimester of
pregnancy

5. Folic
Acid
Dietary Folate
Feces
PGn
PG1
Pancreatic juice
Bile Pool A
(Plasma)
Pool B
(Tissues)
Urine
(Folates & Catabolites)
METABOLISM
Folate bioavailability

6. Folic
Acid
Drugs that interfere with folic acid
 Alcohol ,Tabacco
 Aspirin, ibuprofen, acetaminophen
 Antacids & anti-ulcer medications ;
 Cimetidine (Tagamet®)
 Some antiseizure medications ;
 Phenobarbital, Phenytoin,Primidone, Valproic acid
 Some antibiotics/antibacterials;
 Trimethoprim (Bactrim®), Sulfonamide (Septra®)
 Oral hypoglycemic agents
 HTN Tx. ;
 ß-blocer, CCB, Triamterene (Dyrenium®)
 Some anticancer drugs
 MTX
METABOLISM

7. Folic
Acid
METABOLISM
Metabolic pathway
SAM
Demethylation
MTHER. B12
MS,B12
CBS ,B6
Remethylation pathway
Transsulfuration

8. Folic
Acid
Homocysteine (Hcy)
• Sulfur-containing, highly reactive amino acid that is
synthesized during protein catabolism by the
conversion of methionine to cysteine
• Homocysteine is metabolized by
 Transsulfuration, depending on VitB6 and
Remethylation, depending on folate & Vit B12
METABOLISM

9. Folic
Acid
What is homocysteine risks?
METABOLISM
 Atherosclerosis
 CAD
 MI
 Stroke
 Thromboembolism
 Peripheral vascular disease
Arterioscler Thromb Vasc Biol. 2001;21:1385–1386

10. Folic
Acid
Homocysteine and CAD
METABOLISM

11. Folic
Acid
Causes of hyperhomocysteinemia
• Genetic defects
 Enzymes involved in homocysteine metabolism
 CBS, MS deficiency
 MTHFR deficiency
• Nutritional deficiencies
 Vitamin cofactors (folate, Vit B12, Vit B6)
• Other factor
 CKD, Hypothyroidism, Psoriasis, SLE, etc
 Drugs: Methotraxate, Phenytoin, Theophylline, Niacin,
Carbamazepine, Immumosuppressive agents , etc
 Alcohol, Smoking, coffee
METABOLISM

12. Folic
Acid
Homocysteine and other disease
 Osteoporosis
 Cognitive impairment
 Alzheimer disease
 Chronic kidney disease
 Prenatal complications to women & Fetus
 Preeclampia, placental abruption, pregnancy loss, IUGR
 NTD
METABOLISM
Circulation. 2005;111:e289–e293

13. Folic
Acid
BIRTH DEFECT
What are neural tube defects?
• Neural tube defects (NTDs) are birth defects that occur
early in pregnancy
– 1 – 2 / 1,000 live births in the United States ~ 4,000 affected
pregnancies per year
– 2nd in the cause of infant mortaility (1st : Congenital heart defect)
– Folds in on itself and forms a tube within first month of
pregnancy
– NTDs result when the neural tube doesn’t properly close.

14. Folic
Acid
BIRTH DEFECT
Which NTDs are most common?
Anterior
neural pole
Posterior
Neural pole
Failure to close
=Anencephaly
Failure to close
=Spina bifida

15. Folic
Acid
BIRTH DEFECT
Neural tube development

16. Folic
Acid
Etiology of NTDs
• Multifactorial Inheritance
 Single gene mutation
 Meckel-Gruber syndrome
• Aneuploidy
 Trisomy 16, 18
 Triploidy
• Teratogenic Drugs
 Accutane, Valproic acid, Carbamazepine
• Hyperglycemia
• Aberrations of folic acid intake / Metabolism
BIRTH DEFECT

17. Folic
Acid
Who is at risk for NTDs?
• All women capable of
becoming pregnant
• 95% of NTDs occur in women
with no family history of
NTDs
BIRTH DEFECT

18. Folic
Acid
MRC Vitamin study --- in UK
• International, multicenter, double blind randomized
control trial
 Recruit 1817 women who had a previous affected pregnancy
• 4-Treated groups
 A : Folic acid (4mg/day)
 B : Folic acid + Multivitamins
 C: Neither
 D : Multivitamins
• Evaluation of effects of folic acid or other vitamins
– Comparison of groups A+B / C+D, groups B+D / A+C
BIRTH DEFECT
MRC Vitamin Study Research Group. Lancet 1991

19. Folic
Acid
MRC Vitamin study --- in UK
BIRTH DEFECT
MRC Vitamin Study Research Group. Lancet 1991

20. Folic
Acid
MRC Vitamin study --- in UK
• Folic acid supplementation reduces the risk of an NTD
in pregnancy
• Women who had at least on previous pregnancy with a
NTD
– 4mg folic acid/day before pregnancy and thoroughout the
first trimester
– 71% protective effects
BIRTH DEFECT
MRC Vitamin Study Research Group. Lancet 1991

21. Folic
Acid
Other benefits of folic acid
• Additional birth defect
– Orofacial cleft
– Congenital heart disease
– Urinary tract anomaly
– Limb defect
• May prevent
– Cardiovascular disease
– Cancer; Colorectal cancer, Colorectal adenoma
– Alzheimer disease
BIRTH DEFECT
Hernandez-Diaz S, et al. NEJM 2000
Centers for Disease Control and Prevention and March of Dimes
T. Bottiglieri and L. Wallock.

22. Folic
Acid
CURRENT
Folic acid behavior
March of Dimes Folic Acid Survey conducted by The Gallup Organization, August 2003
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Aware of folic acid Know it prevents
birth defects
Know to take it
before pregnancy
79%
10%
21%
2003 Folic acid knowledge (All women 18-45)

23. Folic
Acid
Folic acid knowledge of women
March of Dimes Folic Acid Survey conducted by The Gallup Organization, August 2003
24%
25%
26%
27%
28%
29%
30%
31%
32%
33%
34%
1997 1998 2000 2001 2002 2003
30% 30%
27%
2003 Daily use of Vit containg Folic acid
29%
32%
31%
CURRENT

24. Folic
Acid
The challenge
• NTDs happen in the first month of pregnancy----
Before most women know they are pregnant !!!
• Half of all pregnancies in the US are not planned !!
Be prepared!
CURRENT

25. Folic
Acid
PREVENTION
CDC recommends for US women
• How much?
– 400㎍/day; All women in childbearing age low risk women
– 1 mg/day ;Pregnant women
– 4 mg/day ; Women with history of neural tube defect
deliveries take folic acid 1 month prior to conception and
during first trimester
• When ?
– 1~3 months before and continuing through the first months
of pregnancy
Nutrition and Micronutrients in Pregnancy - Prof.S.N.Panda

26. Folic
Acid
PREVENTION
Recommends
• High risk for NTD recurrence
– Daily 4.0mg of folic acid
– At least 50~72% ↓
• Low risk pregnancy
– Daily 0.4mg of folic acid
– The incideince rates of NTDs by 40~60% ↓
Maternal-Fetal Toxicology. 2001

27. Folic
Acid
Who is at high risk for NTDs?
• Women who…
 Have a previous pregnancy affected by an NTD
 Have a family history of NTDs
 Use certain anti-seizure medication
 Have insulin-dependent diabetes
 Been diagnosed as clinically obese
 Abuse alcohol
PREVENTION
FDA 1996

28. Folic
Acid
• Folic acid is added to
some grains as:
 Pasta
 Breads
 Cereals
 Rice
• Folate is naturally found
in:
 Leafy green vegetables
 Cooked dry edible beans
 Broccoli
 Peanuts
 Citrus fruits
What foods contain folate/folic acid?
RECOMMEND

29. Folic
Acid
RECOMMEND
Best sources of folate
 1/4 cup peanuts: 207 mcg
 3 oz. beef liver: 185 mcg
 1/2 cup garbanzo beans: 134 mcg
 1 cup navy beans: 129 mcg
 1/2 cup pinto beans: 117 mcg
 1/2 cup lentils, split peas, black beans, or kidney beans: 114 mcg
 1/2 cup black-eyed peas: 105 mcg
 1/2 cup cooked spinach: 100 mcg
 1/2 cup corn: 88 mcg
 4 spears of asparagus: 85 mcg

30. Folic
Acid
• Look for “Folic Acid” or
“Folate” in the left column
• Check value in the right
column – this number is
the percent of your
recommended daily value
100% = 400 mcg
Sample food label
RECOMMEND

31. Folic
Acid
RECOMMEND
Fortified foods?
• The FDA ruled that starting
January 1, 1998, all cereal
grain products labeled
“ Enriched” must be fortified
with folic acid.
 140 mcg FA per 100 gram of
flour
 Observed NTD redution :18%
National Center for Health Statistics.
Trends in spinal bifida and anencephalus in
the United States 1991-1999

32. Folic
Acid
RECOMMEND
How much is “too much”?
• 1000mcg is the upper limit for folic acid
• Too much folic acid may hide Vitamin B12 deficiency
– Do not correct the changes in the nervous system that result
from Vit B12 deficiency
– Nerve damage could theoretically occur due to such masking

33. Folic
Acid
RECOMMEND
Take home message
• More than 4,000 babies in the United States are born each year
with Neural Tube Defects (NTDs).
• Taking folic acid at least one month before and during the
first trimester of pregnancy can help prevent NTDs.
• Women of child bearing age with no history of NTDs should
take 400mcg of Folic acid daily.
• Women of child bearing age with a personal or family history
of NTDs should take 4,000mcg of Folic Acid