Folic acid in pregnancy

2013.9.3주산기 전임의 이민영

Folic Acid

Folic acid/ folate ??

INTRODUCTION

Folic (Pteroyl-L-Glutamic) Acid

Pteri-dine

p-Aminobenzoic acid

L-Glutamic acidFolate ; Polyglutamyl Tetrahydro-

folates

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 sup-

plements and food fortifi-cation

Only form that can be transported across mem-branes

Absorption : ~93%

Folic acid

Folic Acid

INTRODUCTION

Functions of folic acid

Amino acid/Nucleic acid metabolism– Essential for synthesis of serine, methionine, ATP, GTP, thymidy-

late

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 preg-

nancy

Folic Acid

Dietary Fo-late

Feces

PGn

PG1

Pancreatic juice

Bile Pool A(Plasma)

Pool B(Tissues)

Urine(Folates & Catabo-

lites)

METABOLISM

Folate bioavailability

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

Folic Acid

METABOLISM

Metabolic pathway

SAM

Demethyla-tionMTHER.

B12

MS,B1

2

CBS ,B6

Remethylation pathway

Transsulfura-tion

Folic Acid

Homocysteine (Hcy)

• Sulfur-containing, highly reactive amino acid that is synthesized during protein catabolism by the conver-sion of methionine to cysteine

• Homocysteine is metabolized by

Transsulfuration, depending on VitB6 and Remethylation, depending on folate & Vit B12

METABOLISM

Folic Acid

What is homocysteine risks?

METABOLISM

Folate Vit B6 &B12

Total plasmaHomocysteine

(>15µmol/L)

Endothelial dysfunctionAlteration in hemostatisOxidation of low-density llipoproteinActivation inflammatory responseAltered cholesterol and triglyceride metabolism in vascular cells Atherosclerosis

CAD MI Stroke Thromboembolism Peripheral vascular disease

Arterioscler Thromb Vasc Biol. 2001;21:1385–1386

Folic Acid

Homocysteine and CAD

METABOLISM

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

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

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 de-

fect)– Folds in on itself and forms a tube within first month of preg-

nancy– NTDs result when the neural tube doesn’t properly close.

Folic Acid

BIRTH DEFECT

Which NTDs are most common?

Anterior neural pole

Posterior Neural pole

Failure to close =A-

nencephaly

Failure to close

=Spina bifida

Folic Acid

BIRTH DEFECT

Neural tube development

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

Folic Acid

Who is at risk for NTDs?

• All women capable of becom-ing pregnant

• 95% of NTDs occur in women with no family history of NTDs

BIRTH DEFECT

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

Folic Acid

MRC Vitamin study --- in UK

BIRTH DEFECT

MRC Vitamin Study Research Group. Lancet 1991

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

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.

Folic Acid

CURRENT

Folic acid behavior

March of Dimes Folic Acid Survey conducted by The Gallup Organization, August 2003

Awar

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folic

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30%60%90%

79%

10%

21%

2003 Folic acid knowledge (All women 18-45)

Folic Acid

Folic acid knowledge of women

March of Dimes Folic Acid Survey conducted by The Gallup Organization, August 2003

1997 1998 2000 2001 2002 200324%

25%

26%

27%

28%

29%

30%

31%

32%

33%

34%

30% 30%

27%

2003 Daily use of Vit containg Folic acid

29%

32% 31

%

CURRENT

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

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 deliver-

ies 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

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

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

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

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

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 rec-ommended daily value

100% = 400 mcg

Sample food label

RECOMMEND

Folic Acid

RECOMMEND

Fortified foods?

• The FDA ruled that starting January 1, 1998, all cereal grain products labeled “ En-riched” 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

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

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 dur-ing 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