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The Right
Supplementation during
Pregnancy.
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What is the right suplemntation?
Ca
Iron B1
Zinc
Vit C
Niacin
B2
Biotin
Vit E
DHA
Iodine B12 B6
Folic Acid
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Recommended folate intake of 400 µg not possible through diet alone!
Average intake due to nutrition: 50% of European recommended values.
Additionally, requirements increase throughout pregnancy!
Dietary Sources “folate”
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1
3
5
2
4
Low birth weight1
Preterm birth2
Congenital heart defects3
Perinatal mortality1
Neural tube defects
Folate supplementation during pregnancy Avoiding pregnancy complications
1. Scholl TO, Johnson WG. Am J Clin Nutr 2000, 71(5):1295s-1303s.
2. Bukowski R, et al. PLoS Medicine 2009; 6(5):1-11.
3. Van Beynum IM, et al. Eur Heart J. 2010; 31(4):464-71.
A good folate supply is beneficial for the normal course of pregnancy!
Folic acid deficiency has been linked to adverse outcomes of pregnancy:
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• The prevalence of NTDs at birth varies considerably by country,
geographic zone, ethnic and racial group; it ranges from as high as 1
case in 100 births in some regions of China to about 1 case in 2000
or less in some Scandinavian countries. In many countries the
prevalence is approximately 1 in 1000 births 2
• Previous studies on NTDs have been carried out in some parts
of the Islamic Republic of Iran.
In Tehran (1969–78), 1.76/1000 new born had NTDs.
In Hamadan (1991–97) 5.1/1000 and
In Kordestan 5.5/1000 new born had NTDs 2
• Between 1998 and 2003. The prevalence at birth of NTDs during the
6-year period was therefore 2.87 per 1000 births 2
Prevalence data in Iran
1. Verma, I. C. High frequency of neural tube defects in North India. Lancet 1, 879–880 (1978).
2. La Revue de Sante de la Mediterranee orientale, Vol. 13, N3, 2007
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Let start with folic acid!!!!
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Folate?
Folic acid?
Metafolin???
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Terminology is a basic(Clinic Pharmacokinet, 2010, AJCN,
2010, REVIEWS IN OBSTETRICS & GYNECOLOGY, 11)
Folate: Generic of group- related compounds
• Essential vit
• Diet/supp
Folic acid
• Synthetic
• Enriched food/pharma vit
Metafolin
• LMTHF (L-Methylfolate)
• Active folate form (FA-DHF-THF- LMF)
• Plasma/active
MTHFR main in biological processes
Dietary folate: Naturally occurring nutrient found in foods such as leafy green
vegetables, legumes, egg yolk, liver, and citrus fruit
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8 17Modified from Obeid R, et al, Am J Clin Nutr 2010; 92(6):1416-22.
5-MTHF
5-MTHF
0%
20%
40%
60%
80%
100%
maternal blood umbilical cord blood
tota
l fo
late
5-MTHF
THF
Formyl-THF
5,10-Methenyl-THF
Folic acid
Increased availability of L-5-MTHF in prenatal phase
• L-5-MTHF is the main folate form in maternal blood & umbilical cord
blood
• About 82% of total folate in maternal blood and even 90% in umbilical
cord blood account for L-5-MTHF
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Folate metabolism
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Polyglutamates
Monoglutamates
Food folates
Folic acid Folic acid
Dihydrofolate
L-5-methyl-THF
Tetrahydrofolate (THF)
5,10-methylene-THF
L-5-methyl-THF Metafolin
Folic acid
>200 µg
16Pietrzik K, et al. Clin Pharmacokinet 2010; 49:535-548.
Folate metabolism
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T enzyme polymorphism
homozygous TT: Enzyme activity reduced by approx. 70%
heterozygous CT: Enzyme activity reduced by approx. 30%
wildtype CC: Enzyme activity not reduced
• The methylenetetrahydrofolate reductase (MTHFR) 677C˃T
polymorphism is a risk factor for neural tube defects.
• The T allele produces an enzyme with reduced folate-processing ability.
• The prevalence of the MTHFR 677TT genotype varies across ethnic
groups and regions, ranging from:
• < 2% in West African and American populations18,19 to
• ˃ 35% in northern Chinese and individuals of Mexican decent.18-20
• ≈ 50% in Europe
• Meta-analysis data has shown that mothers or infants with the TT
genotype are at greated odds of having a pregnancy affected by an NTDs
than do those with the CC genotype.21-23
18Gue´ant-Rodriguez RM, et al. Am J Clin Nutr 2006; 83:701–7. 19Botto LD, Yang Q. Am J Epidemiol 2000; 151:862–77. 20Ogino S, Wilson RB. J Hum Genet 2003; 48:1–7. 21Yan L, et al. PLoS ONE 2012; 7:e41689. 22Zhang T, et al. PLoS ONE 2013; 8:e59570. 23Yadav U, et al. Metab Brain Dis 2015; 30(1):7–24.
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24Botto LD, et al. Am J Epidemiol 2000; 151:852 – 77; 25Wilcken B. et al. J Med Genet 2003; 40:619–625; 26Sadewa AH, et al. Kobe J. Med. Sci. 2002,
Vol. 48:137-144; 27Khaled K, et al. P. Arch Pathol Lab Med. 2003; 127:1349–1352.
Metafolin® – Global MTHFR polymorphism
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RBC folate level (nmol/L)
Results:
The lower the folate level in the red
blood cells, the higher the risk of
developing a neural tube defect.
Optimal red blood cell folate level:
906 nmol/L
12Daly LE, et al. JAMA 1995; 274:1698-1702.
Case control study in Ireland:
- Collection of blood samples from March
1986 – March 1990 (56046 samples, 23
week of pregnancy or more)
- Stored samples (84 cases, 266 controls,
median gestational age of 15 weeks)
Folate levels in red blood cells
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However,...
women do not start taking supplements at the right time1
of mothers of infants with NTDs did not take folic acid 3 months
prior to pregnancy, as per epidemiological studies in Middle East 2
Only 2% of mothers received preconception folic acid, as per
epidemiological study conducted in Middle East 3
women can metabolise folic acid optimally 4
pregnancies are unplanned 5
1. Family and health: Documentation for kick-off meeting on pregnancy and childbirth, Mainz, 3 March
2005.
2. Essam Al Shail et al.Saudi Med J 2014 (35)-s1.
3. Mohammad Z Seidahmed et al.Saudi Med J 2014 (35)-s1
4. Crider KS et al, Am J Clin Nutr 2011; 93 (6): 1365–1372.
5. German Federal Institute for Risk Assessment (BfR), eds.: Weisenborn, et al: “Folic acid intake of the
German population”, Berlin 2005.
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• The risk of premature birth decreases the longer that supplements are taken1
• Insufficient folate intake during the second trimester increases the risk of premature birth
by 80 %2.
1. Bukowski R et al, PLOS Medicine 2009; 6: 1-11.
2. Siega-Riz AM et al, Am J Obst Gyn 2004; 191: 1851-7.
So This can Explain…….
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HEALTHCARE Consumer Health
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Objective:
To study the effect of Metafolin vs. folic acid supplementation on folate level
Design:
Double-blind, randomized, placebo-controlled intervention trial
- 144 healthy women aged 19–33 y
Study medication:
3-arm study:
- 400 µg folic acid, 2) 416 µg Metafolin or 3) placebo daily for 24 weeks
Measurement:
RBC folate concentrations were measured at baseline and at 4-week intervals
28Lamers Y, et al. Am J Clin Nutr 2006; 84:156-161.
RBC folate level – Lamers 2006
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19 28Lamers Y, et al. Am J Clin Nutr 2006; 84:156-161.
The increase in
RBC folate was significantly
higher in the group receiving
Metafolin ® than in the groups
receiving folic acid
(P < 0.001) – from week 8.
Higher RBC folate level with Metafolin®
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Folic Acid Study overview
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That is why, all Guidelines (WHO and AMERICAN ACADEMY OF PEDIATRICS) recommended
“Women planning a pregnancy or even all women of child-
bearing age should supplement 400 µg of folic acid per day at
least 4 weeks prior to conception and should continue
through the first trimester of pregnancy”
Furthermore because folate could potentially promote tumor cell growth, high blood folate levels might be associated with an
increased risk of Breast Cancer.
: Zhang Y-F, Shi W-W, Gao H-F, Zhou L, Hou A-J, et al. (2014) Folate Intake and the Risk of Breast Cancer: A Dose-Response
Meta-Analysis of Prospective Studies. PLoS ONE 9(6): e100044. doi:10.1371/journal.pone.0100044
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J Obstet Gynaecol Can 2015;37(6):534–549 22
May 2015
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Title of Presentation | DD.MM.YYYY 23
J Obstet Gynaecol Can 2015;37(6):534–549
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Conclusion
1.In case of normal population where No known NTD risk factor and
no prior pregnancy affected with Folate sensitivity a daily 0.4
mg/day folic acid 3 months prior to pregnancy.
2.Only in case of previous pregnancy affected with NTDs or
personal history of NTDs the recommended dose is 5mg/day folic
acid.
J Obstet Gynaecol Can 2015;37(6):534–549
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Guideline
s
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26 http://www.who.int/elena/titles/daily_iron_pregnancy_malaria/en/
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What is Metafolin®?
Metafolin® is the calcium salt of the biologically active form of folate 5-MTHF.
Metafolin® dissociates into calcium and the biologically active folate form 5-MTHF, the
main folate form in maternal and cord blood.
Unlike folic acid, Metafolin® is directly available without metabolisation.
Metafolin® is particularly useful in women who cannot optimally metabolise folic acid
due to the MTHFR C677T polymorphism.
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What More!!!!!!!!????
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HEALTHCARE Consumer Health
DHA Docosahexaenoic acid
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25Adapted from Serhan CN, et al. Annu Rev Pathol 2008; 3:279–312.
DHA content in forebrains of fetuses & infants (n=34, preterm and postnatal up to 2 years)
From approx. the 22nd week of
pregnancy there is a rapid brain
growth and large amounts of
DHA need to be deposited in the
child’s growing tissues, which
depends on maternal DHA
supply.
DHA supply to the foetus and infant
33Koletzko B, et al. Acta Paediatr. 2011; 100:1405-15.
35Jensen et al. Am J Clin Nutr 2000: 71:S292-9S.
Placebo-controlled study during
lactation:
DHA content of breast milk
increased up to 90% with DHA
supplementation whereas the
DHA content in the control group
decreased by 17%.
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France
Japan
Global Recommendations