The Right

Supplementation during

Pregnancy.

2

What is the right suplemntation?

Ca

Iron B1

Zinc

Vit C

Niacin

B2

Biotin

Vit E

DHA

Iodine B12 B6

Folic Acid

3

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”

4

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:

5

• 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

Let start with folic acid!!!!

6

Folate?

Folic acid?

Metafolin???

7

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

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

9

Folate metabolism

10

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

12

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.

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

14

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

15

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.

16

• 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…….

HEALTHCARE Consumer Health

18

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

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®

Folic Acid Study overview

21

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

J Obstet Gynaecol Can 2015;37(6):534–549 22

May 2015

Title of Presentation | DD.MM.YYYY 23

J Obstet Gynaecol Can 2015;37(6):534–549

24

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

Guideline

s

26 http://www.who.int/elena/titles/daily_iron_pregnancy_malaria/en/

27

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.

28

What More!!!!!!!!????

HEALTHCARE Consumer Health

DHA Docosahexaenoic acid

30

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%.

31

France

Japan

Global Recommendations