Dr Sujoy Dasgupta was invited to deliver a lecture in the CME organized by Pfizer in July 2019 at Kolkata

1. Nutrition in Pregnancy
Dr Sujoy Dasgupta
MBBS (Gold Medalist, Hons)
MS (OBGY- Gold Medalist)
DNB (New Delhi)
MRCOG (London)
Advanced ART Course for Clinicians (NUHS, Singapore)
Consultant: Reproductive Medicine, Genome Fertility Centre,
Kolkata
• Managing Committee Member, Bengal Obstetric &
Gynaecological Society (BOGS)- 2019-20
• Secretary, Subfertility and Reproductive Endocrinology
Committee, BOGS- 2019-20
• Winner, Prof Geoffrey Chamberlain Award, RCOG World
Congress, London, 2019

2. Cetin, C. Berti, S. Calabrese; Role of micronutrients in the periconceptional period, Human Reproduction Update, Volume 16, Issue
1, 1 January 2010, Pages 80–95, https://doi.org/10.1093/humupd/dmp025
Different pregnancy stages

3. Nutritional Requirements
Periconception²
Pregnancy
Lactation³
1. Cetin, C. Berti, S. Calabrese; Role of micronutrients in the periconceptional period, Human Reproduction Update, Volume 16, Issue 1, 1 January 2010, Pages 80–
95, https://doi.org/10.1093/humupd/dmp025
2. WHO Standards for maternal and neonatal care. 2007. available from: http://apps.who.int/iris/bitstream/10665/69735/1/a91272.pdf [accessed on 17 Nov 2017]
3. Institute of Medicine (US) Committee on Nutritional Status During Pregnancy and Lactation. Nutrition During Lactation. Washington (DC): National Academies Press (US); 1991. 9, Meeting
Maternal Nutrient Needs During Lactation. Available from: https://www.ncbi.nlm.nih.gov/books/NBK235579/
4. Moss JL, Harris KM. Impact of maternal and paternal preconception health on birth outcomes using prospective couples’ data in Add Health. Archives of gynecology and obstetrics.
2015;291(2):287-298. doi:10.1007/s00404-014-3521-0.
Efforts to increase awareness of a healthy diet and lifestyle
should be strengthened not only during pregnancy but also
before, as pregnancies are often unplanned¹
Benefits of good preconception
health include improved pregnancy
and birth outcomes⁴
Optimal fetal growth & prepare the
mother for delivery
Lay the foundation of healthy life of
the infant

4. Nutritional Requirements
• Folic acidPericonception²
• Iron
• Folic acid
• Vitamin B6 and B12 in
hyperhomocysteinemia
• Calcium vitamin D
• DHA in last trimester
Pregnancy
• Iron
• DHA
• Calcium vitamin D
• Vit B6
Lactation³
1. Cetin, C. Berti, S. Calabrese; Role of micronutrients in the periconceptional period, Human Reproduction Update, Volume 16, Issue 1, 1 January 2010, Pages 80–
95, https://doi.org/10.1093/humupd/dmp025
2. WHO Standards for maternal and neonatal care. 2007. available from: http://apps.who.int/iris/bitstream/10665/69735/1/a91272.pdf [accessed on 17 Nov 2017]
3. Institute of Medicine (US) Committee on Nutritional Status During Pregnancy and Lactation. Nutrition During Lactation. Washington (DC): National Academies Press (US);
1991. 9, Meeting Maternal Nutrient Needs During Lactation. Available from: https://www.ncbi.nlm.nih.gov/books/NBK235579/
4. Moss JL, Harris KM. Impact of maternal and paternal preconception health on birth outcomes using prospective couples’ data in Add Health. Archives of gynecology and
obstetrics. 2015;291(2):287-298. doi:10.1007/s00404-014-3521-0.

5. Nutrition in Pregnancy
• An undernourished mother
inevitably gives birth to an
undernourished baby
perpetuating an intergenerational
cycle of undernutrition
• It is globally acknowledged that focusing on the first
1000 days of a child’s life – beginning from
conception to two years of age – is a critical window
of opportunity (5)

6. Pregnancy is characterized by different stages that
represent a continuum¹
Timing of a nutritional insult impacts differently on the
overall outcome of pregnancy¹
2nd Trimester
Cetin, C. Berti, S. Calabrese; Role of micronutrients in the periconceptional period, Human Reproduction Update, Volume 16, Issue 1, 1 January
2010, Pages 80–95, https://doi.org/10.1093/humupd/dmp025

7. Changes during pregnancy
• Plasma volume increases over the course of
pregnancy by about 50%. Dilutional anemia is
caused by rise in plasma volume
• The needs for most nutrients are increased
during pregnancy to meet the high demands of
both the growing fetus and mother
• Nausea and vomiting in early phase of
pregnancy
• Food aversions and cravings may impact the
food intake and preferences

8. Increased Nutritional Risk
• Pregnant women who are:
• Drug or alcohol abusers
• Vegetarians
• Smokers
• Anorexic or bulimic, underweight, or obese
• Pregnant women with:
• Hyperemesis
• Poor weight gain or weight loss
• Dehydration, constipation
• Pre-existing medical conditions

9. Nutritional Needs During Pregnancy
Recommend
ed intake
Non -
pregnant
Pregnant Lactation
Folate 400mcg 600mcg 500mcg
Vitamin B6 1.3mg 1.9mg 2.0mg
Vitamin B12 2.4mcg 2.6mcg 2.8mcg

10. Folic Acid (Vit B9)
Pteridine + PABA + Glutamate

11. • The parent of folate family compounds is folic acid which has
the following basic structure.
• Humans are incapable to synthesize it so the only source is
diet.
Folic Acid
Folates

24. The role of folate within the body
The various form of folate function as a single-carbon donor-acceptors in a
variety of biosynthetic reactions as shown below:
(1) Synthesis of methionine. By donation of methyl group from N-5-methyl-
tetrahydrofolate and requires vitamin B12 as a coenzyme.
(2) Pyrimidine synthesis which is a rate limiting step in DNA synthesis.
(3) Purine synthesis.
(4) Conversion of serine into glycine.
(5) Histidine catabolism.

25. Sources of folate

26. 26
 Maximal absorption
from the upper
jejunum
Folate absorption and transport

27. Daily folate requirement and storage
• Normal mixed diet may contain as much as 700 g of folate
per day
• Improper food preparation can reduce this amount close to the
minimum daily requirement
• Typical body stores of folate in a normal, healthy adult are
about 10mg and are located in liver
• If dietary folate intake or intestinal absorption ceased, the body
stores would become exhausted in about 3-4 months

28. Role of folate
• Of all the nutrients, folic acid is particularly essential in
pregnancy and pre-pregnancy phase due to its role in
synthesizing DNA¹
• Folic acid requirements are increased in pregnancy because of
the rapidly dividing cells in the fetus and elevated urinary
losses²
• During pregnancy, the daily folate requirement is increased3
– by fetal demands,
– decrease in gastrointestinal absorption of folate
• Older age and obesity in conjunction with pregnancy may also
increase folate needs3
1. Li K, Wahlqvist ML, Li D. Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review. Nutrients 2016, 8, 741; doi:10.3390.
2. WHO. Guideline: Daily iron and folic acid supplementation in pregnant women. Geneva, World Health Organization, 2012
3. 1. S. Bentley et al. Comparative Effectiveness of a Prenatal Medical Food to Prenatal Vitamins on Hemoglobin Levels and Adverse Outcomes: A Retrospective Analysis. Clin Ther.
2011;33:204–210.

29. Consequences of folate deficiency in pregnancy
• The accumulating evidence has shown that maternal folate
status is associated with increased incidence of NTD¹
• The most common birth defect in India is neural tube
defects (NTDs)²
• Presentations vary from anencephaly, encephalocoele to
spina bifida occulta or cystica²
• Birth prevalence of NTDs is 4.1 cases per 1000 total births
(95% CI 3.1–5.4 per 1000 total births)²
1. Gupta H, Gupta P. Neural Tube Defects and Folic Acid. Indian Pediatrics 2004; 41:577-586 .
2. Allagh KP, Shamanna BR, Murthy GVS, et al. Birth Prevalence of Neural Tube Defects and Orofacial Clefts in India: A Systematic Review and Meta-Analysis. Bhutta ZA, ed. PLoS ONE.
2015;10(3):e0118961. doi:10.1371/journal.pone.0118961.

30. Neural Tube Defects
• Role in Prevention:
– NTD are thought to result from a dietary
deficiency of folate and/or a genetic defect
affecting folate metabolism.
– During pregnancy, the neural tube is formed
from the 18th to the 26th DAY of gestation.

31. Consequences of folate deficiency in pregnancy
• Various pregnancy complications associated with folate
deficiency are¹
– Miscarriage
– Placental abruption
– Preeclampsia
– small-for-gestational-age (SGA) infants²
– Defective one carbon metabolism³
1. S. Bentley et al. Comparative Effectiveness of a Prenatal Medical Food to Prenatal Vitamins on Hemoglobin Levels and Adverse Outcomes: A Retrospective
Analysis. Clin Ther. 2011;33:204–210.
2. Dwarkanath P et al. High folate and low vitamin B-12 intakes during pregnancy are associated with small-for-gestational age infants in South Indian women: a
prospective observational cohort study. Am J Clin Nutr December 2013; vol. 98 no. 6 1450-1458
3. Li K, Wahlqvist ML, Li D. Nutrition, One-Carbon Metabolism and Neural Tube Defects: A Review. Nutrients 2016, 8, 741; doi:10.3390.

32. Source: Homocysteine Related Vitamins and Neuropsychiatric Disorders, Christina Bolander-
Patients at Risk for Low Folate Levels

33. MTHFR
• Synthetic folic acid and dietary dihydrofolate must be converted to
L-methylfolate in a multistep process in which the MTHFR enzyme
is responsible for the final conversion to L-methylfolate.
• A common genetic variant of the MTHFR enzyme significantly
reduces the amount of available L-methylfolate and can lead to
preterm delivery and birth defects
• 1/3rd of normal Indian population have deficiency of enzyme
MTHFR that impairs the conversion of supplemental folic acid to its
active form, L-methylfolate1
• Upto 50% of folate related NTDs may be explained by MTHFR
polymorphism²*
1.Greenberg J. Bell S. Multivitamin Supplementation During Pregnancy: Emphasis on Folic Acid and L-Methylfolate. Rev Obstet
Gynecol. 2011;4(3/4):126-127
2. Kirke et al. mpact of the MTHFR C677T polymorphism on risk of neural tube defects: case-control study. BMJ 2004;328:1535–6 .
* This study was done in Irish population.

34. Science of L-methylfolate
L Methyl
Folate

35. L Methyl Folate- Advantages
• Higher bioavailability than plain folic acid
• Remains active in body for longer duration-
– Lesser first pass metabolism
– Effective distribution throughout the body,
– Better reabsorption through kidney
• Active even in presence of MTHFR polymorphism
• Does not mask Vitamin B12 deficiency

36. Masking of Vit B12 deficiency-
Significance
• Megaloblastic anemia- caused by both B12 and B9
deficiency
• In severe vitamin B12 deficiency, the B12-dependent
methionine synthase enzyme is inactive, and cytosolic folate
is ‘trapped’ as L-5-methyl-THF (secondary folate
deficiency)
• Other forms of folate are used in defective DNA synthesis
• high concentrations of folic acid can cause a hematological
response in patients with megaloblastic anaemia caused by
vitamin B12 deficiency, allowing the associated
neurological complications to progress (defective DNA
synthesis)
• In frank Vit B12 deficiency, 5-methyl-THF would be
metabolically inert and would not be able to supply the
other folate coenzymes required for thymidylate synthesis

39. • 400 mcg/day from at least 1 month before conception
to 1st 3 months of pregnancy- All pregnant women
• High risk women- 5 mg/ day from at least 3 months
before pregnancy
• Given the relatively low prevalence in affected
pregnancies, screening for MTHFR is only likely to
have a marginal effect on NTD reduction.
• folate deficiency could have a direct effect on neural
epithelium, which, unlike most embryonic cells,
expresses very high levels of folate receptor.

40. Red blood cell folate concentrations increase more after
supplementation with [6S]-5-methyltetrahydrofolate than with
folic acid in women of childbearing age
• Objective:
– To investigate effect of supplementation with [6S]5-MTHF
compared with that of folic acid on red blood cell folate
concentration, an indicator of folate status
• Study design:
– Double-blind, randomized, placebo-controlled intervention trial
– N= 144 (19-33 yrs)
– Received: 400μg folic acid, equimolar amount of [6S]-5-
MTHF(416μg), 208μg[6S]-5-MTHF,or placebo daily for 24 wk
• Results:
– Increases in RBC and plasma folate concentrations were
significantly higher in the group receiving [6S]-5-MTHF compared
with the folic acid group
Lamers et al. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in
women of childbearing age. Am J Clin Nutr 2006;84:156–61

41. • Objective:
– To evaluate the tHcy-lowering potential of low dose FA and of
MTHF with respect to the MTHFR genotype
• Study design:
– randomized, placebo-controlled, double-blind study,
– N=160 women
– Received 400μg FA, equimolar amount of MTHF (480μg, racemic
mixture), or a placebo daily during an 8-wk treatment period.
– Blood samples were collected at baseline and at 4 and 8 wk
• Results:
– Folate plasma concentrations were significantly higher in the 5-
MTHF group compared with the folic acid group and placebo
5,10-Methylenetetrahydrofolate reductase genotype
determines the plasma homocysteine-lowering effect of
supplementation with 5-methyltetrahydrofolate or folic acid in
healthy young women
Fohr et al. 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-
methyltetrahydrofolate or folic acid in healthy young women. Am J Clin Nutr 2002;75:275–82.

42. Cobalamine (Vit B12)

43.  3 different forms:
cyanocobalamin
hydroxycobalamin
methylcobalamin--- Active
 Vitamin B12 and folate depend on each other for activation
 Very important for DNA synthesis, cell replication
 Individual roles of vitamin B12
 Maintains myelin sheath, promotes normal growth of nerve
cells
 Involved in bone cell metabolism/activity
Vitamin B12 is synthesized exclusively by microorganisms (bacteria, fungi
and algae) and not by animals and is found in the liver of animals bound to
protein as methycobalamin or 5'-deoxyadenosylcobalamin.

44. Enterohepatic
pathway
continuously
recycles B12
secreted from
pariental cells of
stomach

45. • Pernicious anemia in humans
(inability to absorb B12 because
of lack of gastric intrinsic factor).
• Neurological disorders–
– due to progressive
demyelination of nerve cells.
• Sources
– Synthesized only by
microorganisms, so traces
only are present in plants;
liver is a rich source.
– B12 is found in organ and
muscle meats, fish, shellfish,
dairy products, eggs and in
fortified foods like breakfast
cereals.
Deficiency symptoms

46. Progressive decline of Vitamin B12 levels
reaching marginal or even deficient levels
 The progressive decline of vitamin B12 concentrations by about
100 pmol/l during pregnancy has been reported
 Low or deficient serum and amniotic fluid concentrations of
vitamin B12 have been associated with neural-tube defects.

47. Vitamin B12
 Deficiency causes
 Lack of hydrochloric acid or
intrinsic factor
 Older adults: atrophic gastritis
 Lack of animal foods
 Vegans
 Those with anemia of folate
deficiency
 Symptoms
 Megaloblastic anemia
Inadequate absorption of
B12
Inadequate intake of
B12
Combined deficiency
state

48. Anemia of B12 or Folate Deficiency
Pfizer confidential. For Internal Use only. Do not circulate
All references at the last

49. Pyridoxine (Vit B6)

50. Vitamin B6
• Three forms
– Pyridoxal, Pyridoxine, and Pyridoxamine
– All converted to coenzyme Pyridoxal
Phosphate (PLP)
• Stored extensively in muscle tissue
• Requirements:
– The requirement for vitamin B6 in the diet is
proportional to the level of protein consumption
ranging from 1.4 - 2.0 mg/day for a normal adult.
– During pregnancy and lactation the requirement for
vitamin B6 increases approximately 0.6 mg/day.

51. Active form
Pyridoxal
phosphate (PLP)
• Active functional form is pyridoxal phosphate (PLP) and
pyridoxamine phosphate (PMP).
• For absorption, the “phosphorylated” form must be
hydrolyzed to “dephosphorylated” form by the enzyme
alkaline phosphatase in the intestine.

52. Food Sources of B6

53. FunctionsB6 is involved in:
 Amino acid metabolism
Transamination reactions required for the synthesis and catabolism of
the
amino acids.
Decarboxylation reactions.
 Breakdown of glycogen Glycogenolysis (cofactor for glycogen phosphorylase).
80-90% of body vit B6 is present in the muscles, most of it in PLP
(coenzyme) form bound to glycogen phosphorylase. Only 1 mol or less is
present in the blood
 Synthesis of epinephrine (adrenaline) and norepinephrine (noradrenaline)
 Synthesis of niacin (vitamin B3) from the amino acid tryptophan.

54. Pyridoxal-5-phosphate levels gradually decline
during pregnancy
 There is maternal vitamin B6 depletion during pregnancy, with
preferential tissue store depletion.(8)
 RDA for vitamin B6 in pregnancy is 1.9 mg/day, an increase
of 0.6 mg/day over the non-pregnant requirement(9)

55. Vitamin B6
 Deficiency –
 Impacts amino acid metabolism
 Abnormal compounds made from tryptophan accumulate in brain
 Early signs: depression, confusion
 Advanced symptoms: abnormal brain wave patterns, convulsions
 Alcohol: increases breakdown and excretion of PLP
 Isoniazid (anti-tuberculosis med): B6 antagonist
 In food
 Small amounts in lots of foods
 Lost when food is heated
Deficiencies are rare and usually are related to an
overall deficiency of all the B-complex vitamins.

56. Hyper-HomoCysteinaemia

57. Homocysteine
Homocysteine is a sulphur containing amino acid produced by
conversion of methionine, an essential amino acid present in
foods regularly consumed within diet¹
• Structure²:
1. Suchitra S. Acharya, Susmita N. Sarangi, Chapter 15 - Disorders of Coagulation, Editor(s): Philip Lanzkowsky, Jeffrey M. Lipton, Jonathan D. Fish,
Lanzkowsky's Manual of Pediatric Hematology and Oncology (Sixth Edition), Academic Press, 2016, Pages 279-333.
2. Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006 Jun;136(6 Suppl):1636S-1640S. doi: 10.1093/jn/136.6.1636S.

58. Homocysteine Plasma levels
Fasting plasma homocysteine:
 Normal levels: 4- 12 μmol/L
 Moderate hyperhomocysteinaemia : 15 – 30 μmol/L
 Intermediate hyperhomocysteinaemia : 30- 100 μmol/L
 Severe hyperhomocysteinaemia : >100 μmol/L
Wedro B. Homocysteine (Blood Test). Emedicinehealth. Available from: https://www.emedicinehealth.com/homocysteine/article_em.htm#what_is_homocysteine_and_why_measure_it
[accessed on 25July 2018]

59. Genetic factors
Physiological factors
Lifestyle
Clinical
Conditions
Drugs
Folate deficiency ↑ ↑
Vitamin B12 deficiency ↑ ↑
Vitamin B6 deficiency ↑
Pregnancy ↓
Renal failure ↑
Hypothyroidism ↑
Determinants of Plasma homocysteine
Graeme J hankey et al. MJA 2004; 181: 314–318

60. Hyperhomocysteinemia Complications
• Elevated levels of circulating homocysteine increase risk for
– Atherothrombotic coronary artery disease (CAD)
– Peripheral vascular disease
– Myocardial infarction (MI)
– Stroke
– Premature diabetic retinopathy
– Osteoporosis-induced bone fractures
– Dementia-type disorders
– ADVERSE PREGNANCY OUTCOMES
Bradley A. Maron et al. Annu Rev Med. 2009; 60: 39–54
NE Bergen et al. BJOG 2012;119:739-751

61. Hyperhomocysteinemia : Pathophysiology in
Pregnancy
• Vascular-related pregnancy complications are a major cause of
maternal and fetal morbidity and mortality¹
• Hyperhomocysteinemia causes derangement in placental
vascularization contributing to various adverse pregnancy
outcomes²
– Hyperhomocysteinemia causes vascular disease by causing endothelial
dysfunction, smooth muscle cell proliferation, and abnormalities of
coagulation
– Hyperhomocysteinemia generates reactive oxygen species such as
H2O2 that induce oxidative stress¹
1. Steegers-Theunissen RP et al. Obstet Gynecol. 2004 Aug;104(2):336-43
2. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutrition Journal. 2015;14:6. doi:10.1186/1475-
2891-14-6.

62. Hyperhomocysteinemia in Pregnancy- Outcomes
• Low birth weight
• Premature delivery
• Neural tube defects
• Pregnancy-induced hypertension
• Preeclampsia
• Hemolysis, elevated liver enzymes, low platelets (HELLP)
syndrome
• Recurrent pregnancy loss
• Abruptio placentae
• Intrauterine growth restriction
• Intrauterine fetal death
Stein Emil Vollset et al. Am J Clin Nutr 2000;71:962–8
Steegers-Theunissen RP et al. Obstet Gynecol. 2004 Aug;104(2):336-43

63. The Hordaland Homocysteine Study
Objective : Done to investigate associations between tHcy and
complications and adverse outcomes of pregnancy
Design : Plasma tHcy values measured in 1992–1993 in 5883
women aged 40–42 y were compared with outcomes and
complications of 14492 pregnancies in the same women that were
reported to the Medical Birth Registry of Norway from 1967 to
1996.
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

64. Pre-eclampsia
• Preeclampsia was reported in 451 of the pregnancies
• 60 pregnancies were of < 37 wk duration
• Weak but highly significant positive association between
preeclampsia and tHcy concentration
• Association stronger in subgroup that delivered prematurely (<
37 wk)
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

65. Placental abruption
• Placental abruption was reported in 0.5% of pregnancies
• A strongly elevated risk of placental abruption, was seen in
women with high tHcy concentrations
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

66. Premature delivery
• There was a significant association of plasma tHcy with
premature delivery both of < 37 wk and < 32 wk gestation
• In the latter period, the OR when comparing upper with lower
tHcy quartile for premature delivery (<32 wk gestation) was
1.93 (95% CI: 0.96, 3.93; P for trend = 0.03)
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

67. Low Birth Weight
• A strong association found between low birth weight (< 2500
g) and tHcy concentrations.
• The relation was strengthened with very low birth weight (<
1500 g) as the outcome, and was particularly strong for the
group weighing 500–1000 g
• In pregnancies occurring in 1980 or later, OR for very low
birth weight when comparing upper with lower tHcy quartile
was 2.07 (95% CI: 1.02, 4.22; P for trend = 0.02)
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

68. Still birth and Neonatal mortality
• Prevalence of stillbirth was 1.2% (> 16 wk gestation) and
mortality during first week of life was 0.4%
• There was a weak and non significant overall association
between plasma tHcy and stillbirth but no association of
plasma tHcy with neonatal mortality
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

69. The Hordaland Homocysteine Study
• In conclusion, data suggest an important role of tHcy as a
marker of pregnancy complications and adverse pregnancy
outcomes
Vollset SE et al. Plasma total homocysteine, pregnancy complications, and adverse pregnancy outcomes: the Hordaland Homocysteine Study. Am J
Clin Nutr 2000;71:962–8

70. Homocysteine –Vitamin Interaction
Remethylation
Cycle
Demethylation
CycleDiet
Methionine
Homocysteine
Tetra hydrofolate
Methyl
tetrahydrofolate
Cystathionine
Cysteine
Glutathione
Vitamin B6
Folic acid
MTHFR
Vitamin B 12
MS
MS – Methionine synthase
MTHFR – Methyl tetrahydro folate reductase
C BS – Cystathionine beta synthase
Sen U & Tyagi SC. PPAR Research 2010. doi:10.1155/2010/806538
CBS

71. Fate of Homocysteine
Homocysteine can be used in one of two ways:
a) In case of methionine deficiency, homocysteine can be re-
methylated to form methionine (requiring Vitamin B12 and
Folic acid)
b) In presence of sufficient methionine, homocysteine is instead
used to produce cysteine (requiring Vitamin B6)
Paul Ganguly et al. Nutrition Journal 2015; 14(6):1-10
Sen U & Tyagi SC. PPAR Research 2010. doi:10.1155/2010/806538

72. Vitamins and Hyperhomocysteinemia
• BBB* vitamins are determinants of plasma Homocysteine concentrations
• Studies show inverse relationships of blood homocysteine concentrations
with serum levels of folic acid, vitamin B6 and vitamin B12
• Vitamin deficiency is dominant
cause of hyperhomocysteinemia
– Primary cause of 2/3rd of
cases of hyperhomocysteinemia
Sandesh P Kamdi et al. Bioinformation. 2013; 9(4): 193–196
M. Rene´ Malinow et al. American Heart Association. Circulation. 1999;99:178-182
Selhub J, et.al. JAMA 1993; 270: 2693-2698
* BBB- B6B9B12 vitamins

73. Vitamins and Pregnancy
• BBB vitamins are determinants of plasma Homocysteine
concentrations
• Prevalence of subclinical deficiencies of folate, vitamins B12,
B6 high in Indian population
• During pregnancy blood concentrations of folate, cobalamin,
and pyridoxal 5-phosphate decrease further
Sandesh P Kamdi et al. Bioinformation. 2013; 9(4): 193–196
Steegers-Theunissen RP et al. Obstet Gynecol. 2004 Aug;104(2):336-43
Aline Barnabé et al. Nutrition Journal .2015; 14:19
Krishnaswamy K et al. J Assoc Physicians India. 2002 May;50 Suppl:36-42.

74. Folate + Vitamin B12 & B6 supplementation reduce
S.Hcy in Pregnant Women
14.6
17.9
19.1
17.1 17.1
9.1
12.6
10
11.1 11.1
0
5
10
15
20
25
Healthy Pre-eclampsia Eclampsia Abruptio Total
Pre-supplementation
serum Hcy mcm/L
Post-supplementation
serum Hcy mcm/L
P=0.02*
P= 0.12
P=0.004*
P=0.02* P<0.001*
* P value is statistically significant (n = 30).
In a cohort of 30 pregnant women, with S. homocysteine level >8.2 mcm/l were given folate, 5 mg/day, 1000
mcg/day each of vitamin B12 and B6 for 6 weeks, in addition to conventional therapy necessary for
underlying clinical conditions. Serum hcy levels were analyzed at baseline & at 6 weeks.
Qureshi BS et al. JPMA 2010; 60:741.
Conclusion : folate, vitamin B12 and B6 lower hcy levels in hyperhomocysteinaemic women

75. DHA

76. Essential Fatty Acids
• Linoleic Acid
• Alpha-Linoleneic Acid

80. Cervonic Acid
Decosahexenioic acid (DHA)
(22 C, ∆ 4,7,10,13,16,19)
Omega 3 FA
Produced from Alpha-linolenic acid
NOT Essential FA

81. Food sources
• Primary source: Seafood such
as fish, fish oils
• Nuts – walnuts
• Seeds – flax seed / linseed,
chia seeds
• Dark leafy vegetables – fresh
basil, spinach, broccoli
http://www.omegathreebenefits.com/dha-food-sources/
https://thehealthreportertv.files.wordpress.com/2015/01/omega-3-
foods_dollarphotoclub_71010660.jpg

82. A period of dynamic structural neural growth occurs in the
fetal brain during the third trimester of pregnancy¹
Need for Additional supplements
Adequate consumption of omega-3 fatty acids is vital during
pregnancy as they are critical building blocks of fetal brain
and retina²
DHA is the critical component of cell membranes in the brain
and retina² which become available for placental transfer in
late pregnancy³
Dietary sources of DHA are insufficient to fulfil the
requirement in pregnancy
Consensus guidelines have recommended that pregnant
women consume at least 200 mg of DHA per day²
1. Rees, A., Sirois, S. and Wearden, A. (2014), Maternal Docosahexaenoic Acid Intake Levels During Pregnancy and Infant Performance on a
Novel Object Search Task at 22 Months. Child Dev, 85: 2131–2139. doi:10.1111/cdev.12280
2. Coletta JM, Bell SJ, Roman AS. Omega-3 Fatty Acids and Pregnancy. Reviews in Obstetrics and Gynecology. 2010;3(4):163-171.
3. Bergmann RL, Haschke-Becher E, Klassen-Wigger P, Bergmann KE, Richter R, Dudenhausen JW, Grathwohl D, Haschke F.
Supplementation with 200 mg/day docosahexaenoic acid from mid-pregnancy through lactation improves the docosahexaenoic acid status
of mothers with a habitually low fish intake and of their infants. Ann Nutr Metab. 2008;52(2):157-66. doi: 10.1159/000129651. Epub 2008

83. Need for Additional supplements
After birth, human milk provides DHA to the breastfed infant
with a rapid rise towards adult levels of DHA in brain within
the first two years of life³
In the second half of pregnancy maternal DHA stores
decrease, which results in a suboptimal DHA supply of the
fetus and the neonate²
The accumulation of DHA begins in utero and is derived
predominantly through placental transfer¹
Maternal DHA intake during lactation affect infant visual
function and neurodevelopment³
1. Coletta JM, Bell SJ, Roman AS. Omega-3 Fatty Acids and Pregnancy. Reviews in Obstetrics and Gynecology. 2010;3(4):163-171.
2. Bergmann RL, Haschke-Becher E, Klassen-Wigger P, Bergmann KE, Richter R, Dudenhausen JW, Grathwohl D, Haschke F.
Supplementation with 200 mg/day docosahexaenoic acid from mid-pregnancy through lactation improves the docosahexaenoic acid status of
mothers with a habitually low fish intake and of their infants. Ann Nutr Metab. 2008;52(2):157-66. doi: 10.1159/000129651. Epub 2008 Apr
29. PubMed PMID: 18446020; PubMed Central PMCID: PMC2790529.
3. Craig L. Jensen, Alexandre Lapillonne, Docosahexaenoic acid and lactation, In Prostaglandins, Leukotrienes and Essential Fatty Acids,

84. DHA in brain
• Brain has the largest amount of lipids (60% dry weight),
compared to other organs in the body¹
• DHA constitute about 10-15% of total fatty acids in the brain,
and this represents more than 97% of total n-3 PUFA¹
• Fetus accrues up to 70 mg DHA per day during the last trimester,
specifically in the brain, and white adipose tissues, demonstrating
the significance of maternal DHA status on fetal health¹
• Depletion of DHA from the brain and retina results in reduced
visual function, cognitive and behavioral abnormalities¹
Olatunji Anthony Akerele, Sukhinder Kaur Cheema, A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in
pregnancy, In Journal of Nutrition & Intermediary Metabolism, Volume 5, 2016, Pages 23-33, ISSN 2352-3859,
https://doi.org/10.1016/j.jnim.2016.04.008.(http://www.sciencedirect.com/science/article/pii/S235238591530027X)Keywords:
Cytokines; Pregnancy; Implantation; Labour; Polyunsaturated fatty acids; Birth outcomes

85. DHA in lactation
• Human milk contains long chain polyunsaturated
fatty acids (LCPUFA) (20–22 carbons) of both
omega-3 and omega-6 classes¹
• In infants who are breast fed, supply of these fatty
acids is dependent on the maternal diet ¹
• Breastmilk has been shown to be a main
contributor to the DHA content in infant RBC²
1. Esther Granot, Einat Jakobovich, Ruth Rabinowitz, Paloma Levy, and Michael
Schlesinger, “DHA Supplementation during Pregnancy and Lactation Affects Infants'
Cellular but Not Humoral Immune Response,” Mediators of Inflammation, vol. 2011,
Article ID 493925, 6 pages, 2011. doi:10.1155/2011/493925
2. Lauritzen L et al. DHA Effects in Brain Development and Function.

86. DHA in lactation
• Supplementation during pregnancy and lactation, appears to
be more effective in raising breast milk DHA content¹
• Milk DHA content appears to be closely linked to maternal
dietary DHA intake
• Dose dependent linear increases in breast-milk
concentrations with increased maternal intake²
• After birth, human milk provides DHA to the breastfed
infant with a rapid rise towards adult levels of DHA in brain
within the first two years of life³
1. Craig L. Jensen, Alexandre Lapillonne, Docosahexaenoic acid and lactation, In Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 81, Issues 2–3, 2009, Pages 175-
178, ISSN 0952-3278, https://doi.org/10.1016/j.plefa.2009.05.006.(http://www.sciencedirect.com/science/article/pii/S0952327809000970)
2. Brenna JT, Varamini B, Jensen RG, Diersen-Schade DA, Boettcher JA, Arterburn LM. Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide. Am
J Clin Nutr. 2007 Jun;85(6):1457-64. PubMed PMID: 17556680
3. Hadley KB, Ryan AS, Forsyth S, Gautier S, Salem N. The Essentiality of Arachidonic Acid in Infant Development. Nutrients. 2016;8(4):216. doi:10.3390/nu8040216..

87. Possible role in immune function
and preterm birth
• DHA has a possible role in reducing the
inflammatory markers and boosting the immunity
of the infant¹
• Protection against necrotising enterocolitis,
bronchopulmonary dysplasia¹
• Reduction in the recurrence of PTB, especially in
women with history of pre-term or low baseline
n-3 PUFA intake²
1. Valentine CJ. Maternal Dietary DHA Supplementation to Improve Inflammatory Outcomes in the Preterm Infant. Advances in Nutrition.
2012;3(3):370-376. doi:10.3945/an.111.001248.
2. Akerele O, Cheema S. A balance of omega-3 and omega-6 polyunsaturated fatty acids is important in pregnancy. Journal of Nutrition &
Intermediary Metabolism 5 (2016) 23-33

88. Conclusion
• Folate is essential micronutrient to be
supplemented in pregnancy
• L-Methyl Folate has many advantages over the
conventional folate
• Vitamin B12 and B6, both in small amount, are
required to reduce the harmful effects of
hyperhomocysteinaemia
• DHA is essential for brain development in late
pregnancy and early infancy