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Role of Folate and DHA in Preterm
Delivery Prevention.
1
What is the right suplemntation?
Folic Acid
Niacin
B1
DHA
Iron
Ca
B6
B2
Zinc
Iodine
Biotin
B12
Vit C
Vit E
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Prevalence data in Iran
• 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
1.
2.
Verma, I. C. High frequency of neural tube defects in North India. Lancet 1, 879–880 (1978).
La Revue de Sante de la Mediterranee orientale, Vol. 13, N3, 2007
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Let start with folic acid!!!!
Folate?
Folic acid?
Metafolin???
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Terminology is a basic(Clinic Pharmacokinet, 2010, AJCN,
2010, REVIEWS IN OBSTETRICS & GYNECOLOGY, 11)
Dietary folate: Naturally occurring nutrient found in foods such as leafy green
vegetables, legumes, egg yolk, liver, and citrus fruit
Folate: Generic of grouprelated compounds
• Essential vit
• Diet/supp
Folic acid
• Synthetic
• Enriched
food/pharma vit
Metafolin
• LMTHF (LMethylfolate)
• Active folate form (FADHF-THF- LMF)
• Plasma/active
MTHFR main in biological processes
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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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T enzyme polymorphism
• 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
homozygous TT:
heterozygous CT:
wildtype CC:
Enzyme activity reduced by approx. 70%
Enzyme activity reduced by approx. 30%
Enzyme activity not reduced
18Gue´ant-Rodriguez
RM, et al. Am J Clin Nutr 2006; 83:701–7.
LD, Yang Q. Am J Epidemiol 2000; 151:862–77.
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.
19Botto
20Ogino
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Metafolin® – ME MTHFR polymorphism
"Geographical
and ethnic variation of the 677C>T allele of 5,10
methylenetetrahydrofolate reductase (MTHFR): findings from
over 7000 new-borns from 16 areas world wide"
Region
ME
CC
57%
CT
34%
J Med Genet 2003;40:619–625
TT
8%
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J Obstet Gynaecol Can 2015;37(6):534–549
Title of Presentation | DD.MM.YYYY
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DHA
Docosahexaenoic acid
DHA supply to the foetus and infant
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.
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%.
•
25Adapted
from Serhan CN, et al. Annu Rev Pathol 2008; 3:279–312.
33Koletzko
35Jensen
B, et al. Acta Paediatr. 2011; 100:1405-15.
et al. Am J Clin Nutr 2000: 71:S292-9S.
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What are these special FAs?? What is their role anyway?
• LCPUFA are Essential Fatty acids and cannot be synthesized
in the body and therefore they are required from the diet
• They serve important physiological functions in the organism
• NATO workshop: (1) have anti-inflammatory properties; (2) lower serum triglycerides
and cholesterol; and (3) decrease thrombosis and platelet aggregation (J Nut, 89)
• Grey matter expansion, cell membrane, and
neurodevelopment
LCPUFA: The argument
• Several studies has suggested that human evolved on a diet with a
Omega-6/Omega-3 ratio of approximately 1:1
• Today’s lifestyle and alimentation created an imbalance in the
Omega-6/Omega-3 ratio however in current diet it ranges from
10:1 to 25:1
• This imbalance fuels the concerns that today’s diet may be
insufficient to meet Omega-3 FA’s requirements and calls
supplementation
The argument: Pregnancy & meet the need?
• Pregnancy: Increased demand for DHA
• DHA: Preferentially transported to the infant during 3rd
trimester of gestation & coincides with later stages of brain &
retinal maturation, WITH estimated 67–75 mg/day of DHA
accumulated in utero at the same time
• More demand: Expanded RBC mass, placenta, and basic needs
(LOW dietary intake)
• Supply:
 Maternal DHA intake
 Adaptive metabolic mechanisms(increased synthetic capacity to
metabolise alpha LA to DHA
 Preferential use of the DHA stored in adipose tissue
 DHA saved from pregnancy amenorrhea
AJCN, 00, 09, J Nutr, 01, 05, Placenta, 05, Pediatrics, 08
The evidence
PTB & GA
Neurodevelopment and growth
IVF and others (maternal depression)
DHA and PTB: Biological plausibility?
• A high ratio of omega-6 to omega-3 fatty acids will result in
increased proinflammatory eicosanoid production (ie,PGE2 &
PGF2)
• More DHA in diet: Reduction in the production of
proinflammatory eicosanoids and increased production of
prostacyclin (PGI2), which may promote myometrial relaxation
• Omega-3 fatty acids downregulate the production of PGE2 &
PGF2, and may thereby inhibit the parturition process
Clinic ObGyn, 04, AJOG, 06
13 RCTs
Dosing, sources, and means!! Test your
info!!
• Pregnant and lactating: Aim to achieve at least 200-300 mg
DHA/day to support optimal visual and cognitive development
in offspring
• Women advised to achieve fish consumption equal to
200 mg/day DHA intake rather than merely relying on the
number of servings of fish
• A minority of women achieve this level of DHA: 1999-2002
National Health and Nutrition Examination (NHANES), mean
DHA intake 73 mg/day among pregnant women, and
62 mg/day among childbearing age
March of Dimes, 09, Br J Nut, 07
Global Recommendations
France
Japan
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What happens with Iod in pregnancy?
• During pregnancy, hormonal changes
and metabolic demands result in
significant changes in thyroid
function
• Increased need for iodine supply due
to: (1) Increased production of TH &
maintain euthyroidism, (2) Elevated
renal clearance of iodine, and (3) the
fetoplacental acquisition of maternal
iodine and TH
Best Pract Res Clin Endocrinol Metab , 04, Thyroid, 2000
ID & maternal neonatal child outcomes: Test your info!
• 3rd cause of developmental problems in children
• ID disorders: Range from mild to moderate to severe
• Developmental quotient: Reduction in IQ scores to cretinism
• Severe ID during pregnancy: Congenital hypothyroidism resulting
in cretinism, an irreversible form of retarded growth and mental
retardation
Biological plausibility
• MID during pregnancy: Hypothyroxinemia in the mother
and/or elevated (TSH) levels in the fetus
• Related to mild and subclinical cognitive and
psychomotor deficits in neonates, infants and children
(Journal of Trace Elements in Medicine and Biology, 13)
• Before the fetal hypothalamic–pituitary–thyroid system becomes operative,
maternal T4 transfer is crucial for the fetus
• The fetal thyroid grows between 12 and 39 weeks of gestation, becomes active
in the 2nd trimester where demand for Iodine before 12-14 weeks
Now show them the evidence…Research
& studies