Transcript Folic acid in preconception care., Down

Folic acid in preconception care
2008. 9. 23
고려대학교 산부인과학 교실
홍순철
1
Contents

Introduction: Birth Defects

Folate and Folic Acid

Folate and Birth Defects

Prevention of Neural Tube Defects

Canada: Preconceptional vitamin/folic acid
supplementation 2007

Summary
Evidence-based Preconception Interventions
(ACOG, AAP)
검사 및 조치
3
증명된 효과
엽산제 공급
신경관 결손증을 2/3이상 감소시킨다.
풍진 예방접종
선천성 풍진 증후군을 예방한다.
당뇨 관리
당뇨를 앓고 있는 임신부에서 기형확률이 3배정도 증가하므로
임신전 혈당 조절을 통해 기형확률을 낮춘다.
갑상선 기능저하증
치료
적절한 갑상선 기능조절은 태아의 정상적인 신경계 발달을 돕는다.
B형 간염 예방접종
태아감염을 예방하고, 엄마또한 B형간염의 합병증(간기능부전,
간경화, 간암)으로부터 보호받을 수 있다.
AIDS(에이즈)
선별검사
환자와 보호자에게 에이즈와 관련된 치료 및 임신시기 등
적절한 정보제공
성병 선별검사 및
치료
클라미디아, 임질과 관련한 자궁외임신, 불임, 만성 골반통증을 줄이고
태아합병증 가능성을 줄인다.
항응고제 조절
Wafarin과 같은 기형유발 가능성있는 항응고제를 임신전에
다른 약제로 바꾼다.
항경련제 조절
간질(epilepsy) 여성의 경우 기형유발가능성이 적은 약제로 교환한다.
Accutane 사용 조절
기형유발물질로 알려진 여드름 치료제의 일종인 Accutane사용시
임신을 피하고, 임신전에 Accutane 사용을 중지한다.
금연 상담
임신전에 금연을 함으로서, 흡연과 관련된 조산, 저체중아 등의
임신 합병증을 예방한다.
알코올 상담
무심코 먹는 일회성 술이나 습관적인 알코올 노출을 피함으로서,
태아알콜증후군 또는 알코올 관련 기형을 예방한다.
비만 조절
임신전에 적절한 체중에 도달함으로써, 비만시 증가하는 신경관 결손증,
조산, 당뇨병, 제왕절개증가, 고혈압, 혈전증을 감소시킨다.
Birth Defects



A major deviation from normal morphology or function that
is congenital origin
Incidence: newborn 3%
Causes




Genetics
Environmental
Multifactorial
Neural tube defects


9.3% of congenital defects
Major cause of stillbirth
and neonatal and infant death
Neural Tube Defects (NTDs)

Incidence: 1-5/1,000 live births

95% of babies with NTD: no family history of these disorders

Risk of recurrence: 2-3%
Spina Bifida
(per 1,000 births)
Aencephaly
(per 1,000 births)
South Wales
4.1
3.5
South Hampton
3.2
1.9
Birmingham , UK
2.8
2.0
White
1.5
1.2
Black
0.6
0.2
0.3
0.6
Charleston
Japan
Causes of NTDs (I)

Multifactorial inheritance



Environment
Diet
Physiologic abnormalities:



Amniotic fluid nutrients



hyperthermia,
hyperglycemia
Alidomide
Aminopterin, Amethopterin
Med: valproic acid
Causes of NTDs (II)

The single greatest factor?


Deficiency of maternal serum Folic Acid
Account for about 70% of NTDs
The risk of NTD is inversely correlated with maternal
serum folic acid levels in pregnancy , with a threshold of
200 µg/L, below which the risk is very significant.
-Nussbaum RL et al.
Thompson and Thompson Genetics in Medicine, 2001, p.306
Folate (Vitamin B9)

Water-soluble B vitamin

Human can not synthesize

Extremely vulnerable to heat


Cooking and other food-processing and
preparation techniques can destroy 50
percent to 90 percent of a food's folate.
Sources of folate:
Folic acid



Man-made type of the B vitamin
Used in vitamin supplements
and added to certain foods (fortified foods)
Folic acid is used more easily by the body
than folate
Folic Acid Structure
PABA=para-aminobenzoic acid
Role of Folate
 Co-factor for enzyme
involved in DNA and
RNA
biosynthesis
 Essential for proper cell
replication and growth
 Helping the building
blocks needed for making
protein in cells
Folate Recycling Pathway
 Deficiency
•
•
•
•
•
•
Early fetal loss
Preterm labor
Abruptio placentae
NTDs
Cardiac anomalies
Orofacial clefts
Folic acid
supplementation
If homocysteine increased
PIH
IUGR
RPL
CAD
Stroke
Cancer
13
MTHFR
Folic acid
METHIONINE
NTD
HOMOCYSTEINE
Cardiac
Malformation
Folate and Embryopathy



The defect of the neural tube occurs
between the 15th and 28th
postconceptional day in humans,
The critical period for NTDs follows so
soon after conception
It is necessary to ensure increased
blood vitamin levels at the time of
closure
The most women are not even aware
of their pregnancy
History of Folate and NTDs

Folate and human embryopathy
- Hibbard and Smithells, Lancet 1965

Folic acid supplementation:
reduce of recurrence risk
70 to less than 1%
- MRC Vitamin Research Group, 1991

Fortification of cereal grain
products: 140 g/100 g
- FDA 1998

Women ingest daily an extra
200g of folic acid
– ACOG 2003
Folic Acid Intake
대부분의 사람들은 신경관 기형을 방지하는데
엽산의 중요성을 알지 못하고 있다.
Folate and Congenital Heart Diseases

Homocysteine causes dysmorphogenesis of the heart
- Osenquit TH et al. J Proc Natl Acad Sci 1996

Folate supplementation of 0.2 to 0.4 mg daily will
lower homocysteine levels in women of reproductive
age
- Daly S. QJM 2002
Folate and Orofacial Clefts

Folate is essential for cellular multiplication
and differentiation in the development of lip,
alveolus, and palate.
Folate and Orofacial Clefts
 The risk of cleft lip with or without cleft
palate seems to be substantially
reduced by folic acid supplements
during the month before pregnancy and
the first two months of pregnancy
 Similar benefits are not apparent for
cleft palate
Folic acid fortification

U.S.: Fortification of cereal grain
products: 140 g/100 g (- FDA 1998)
 NTD occurrence decreased by 27% (CDC; MMWR 2004)

Canada: Fortification with folic acid of all types of white flour,
enriched pasta, and cornmeal:
150 g/100 g of flour or cornmeal,
154-308 g/100 g of rice (1998)
 The prevalence of NTD decreased by 46% (1.58/1000 births 
0.86/1000 births) (NEJM 2007)
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Canada: Preconceptional vitamin/folic acid
supplementation 2007
 Recommendations
1. Women in the reproductive age group should be advised
about the benefits of folic acid in addition to a
multivitamin supplement (III-A)
2. Women should be advised to maintain a healthy diet, as
recommended in Eating Well With Canada's Food Guide.
 Good sources of folic acid: fortified grains, spinach, lentils,
chick peas, asparagus, broccoli, peas, Brussels sprouts, corn,
and oranges. (III-A)
3.Women taking a multivitamin containing folic acid should
be advised not to take more than one daily dose of
vitamin supplement (II-2-A)
21
Canada: Preconceptional vitamin/folic acid
supplementation 2007
 Recommendations
4. Folic acid and multivitamin supplements should be
widely available without financial or other barriers.
(III-B)
5. Folic acid 5 mg supplementation will not mask
vitamin B12 deficiency (pernicious anemia), and
investigations (examination or laboratory) are not
required prior to initiating supplementation.
22
Canada: Preconceptional vitamin/folic acid
supplementation 2007
 Recommendations
6. The recommended strategy to prevent recurrence of a
congenital anomaly (anencephaly, myelomeningocele,
meningocele, oral facial cleft, structural heart disease, limb
defect, urinary tract anomaly, hydrocephalus) :
 Planned pregnancy +/- supplementation compliance.
 A folate-supplemented diet, daily multivitamins with 5
mg folic acid should begin at least three months before
conception and continue until 10 to 12 weeks post
conception.
 From 12 weeks post-conception and continuing
throughout pregnancy and the postpartum period (4-6
weeks or as long as breastfeeding continues): a
multivitamin with folic acid (0.4-1.0 mg). (I-A)
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Canada: Preconceptional vitamin/folic acid
supplementation 2007
 Recommendations
7.The recommended strategy(ies) for primary prevention or to decrease
the incidence of fetal congenital anomalies
 OPTION A: No personal health risks, planned pregnancy, and good
compliance: a good diet of folate-rich foods, daily a multivitamin with
folic acid (0.4-1.0 mg) for at least two to three months before
conception and throughout pregnancy and the postpartum period (46 weeks and as long as breastfeeding continues). (II-2-A)
 OPTION B: Health risks (epilepsy, IDDM, obesity with BMI >35 kg/m2,
family history of NTD, belonging to a high-risk ethnic group): folaterich foods, daily a multivitamins with 5 mg folic acid, beginning at least
three months before conception and continuing until 10 to 12 weeks
post conception.
 From 12 weeks post-conception and continuing throughout
pregnancy and the postpartum period:a multivitamin with folic
acid (0.4-1.0 mg). (II-2-A)
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I. Folic acid recommendation
Daily Dose of FA
No risk ≥ 400 mcg
At risk
≥ 1mg
Indications
All women of childbearing age and pregnant
BMI ≥ 30 kg/m2
Previous baby including NTD and other
High
risk
≥ 4mg
congenital malformations
Women with anitiepileptics, MTX and
other antifolates
PGDM
25
I. Folic acid recommendation
26
Summary




27
Government should consider an evaluation process for
the benefit/risk of the national folic acid fortification.
Application of Canada recommendation.
Folic acid supplementation.
Application of preconception care in clinic
감사합니다.
Folic acid in preconception
care
2008. 9. 23
고려대학교 산부인과학 교실
홍순철
Recommendations of Folate (I)


The average daily intake of dietary folate
in adult women: 180-200 µg
The recommended dietary intake (RDI) a day is:

100 µg: children aged 1–7 years

150 µg: children aged 8–11

200 µg: children 12 and above

400 µg: adults women of childbearing age
Recommendations of Folate (II)

The time of supplementation


One month of preconception and 2 months of postconception
Type of supplementation: No consensus


Only folic acid?
Folic acid containing multivitamin is better in the prevention of NTD
recurrence than folic acid alone
- MRC Vitamin Research Group, 1991

Dose: No consensus

All women who of childbearing age: 0.4 mg/day

Higher pharmacological dose (4-8 mg): safe
Recommendations of Folate (III)

Women at low and high risk:


Prevention policy of U.S.A.
 High risk (5%): 4-5 mg/day
 Low risk (95%): 0.4 mg/day
Smithells et al (Lancet 1989): not worthwhile of high dose
 0.36 mg folate and multivitamins
Recommend the use of multivitamin containing folic
acid for both women at high and low risk.
It is reasonable to keep the daily folic acid consumption
to around 1 mg in the periconceptional period, that is,
about 0.2 mg from dietary sources and 0.8 mg from
supplementation. – Czeizel. Curr Opinion Obst Gynecol 1995
I. Folic acid recommendation
Daily Dose of FA
No risk ≥ 400 mcg
At risk
≥ 1mg
Indications
All women of childbearing age and pregnant
BMI ≥ 30 kg/m2
Previous baby including NTD and other
High
risk
≥ 4mg
congenital malformations
Women with anitiepileptics, MTX and
other antifolates
PGDM
34
I. Folic acid recommendation
35
Folate (Vitamin B9)

Human can not synthesize

Extremely vulnerable to heat


36
Cooking and other food-processing
and preparation techniques can
destroy 50 percent to 90 percent of
a food's folate.
Sources of folate:
요 약 (I)

엽산은 태아 신경관결손의 발생율을 감소시킨다.

엽산은 태아 심장기형, 입술 또는 입천장 갈림증 발생율을
감소시킬 수 있다.

대부분의 여성은 엽산 복용이 신경관 결손을 감소시키는
것을 모르고 있다.

엽산은 임신 1개월 전부터 임신 2개월까지 매일 0.4 mg 복
용한다.
요 약 (II)

신경관 결손을 예방하기 위하여 엽산을 단독으로
복용하는 것보다는 복합비타민과 같이 복용하는 것이
유용하다.

고위험군과 저위험군의 엽산 복용량에 대해서는 연구가
더 필요하다. 그러나 고위험군에서는 고용량(4 mg)을
우선 선택한다.

계획된 임신은 50%가 안되므로 가공식품에는 엽산을
첨가하는 것이 신경관 결손 예방에 도움이 된다.