Blood Physiology :
1
Structure of RBCs :
• RBCs : Red Blood Cells/Erythrocytes are Biconcave
(Concave on both surfaces) in shape
• As they mature, they acquire hemoglobin
RBCs/Erythrocyte
2
Hemoglobin :
• Hemoglobin is iron (in ferrous form) containing
protein in Erythrocytes
Hemoglobin
3
Function of Hemoglobin :
• Hemoglobin combines with Oxygen in lung and is
carried to all tissues throughout body ;
Thus Oxygen is delivered to tissues
• Carbon dioxide which is produced in tissues is carried
back to lungs with help of Hemoglobin
• Thus, Hemoglobin plays a vital role in the transport
of respiratory gases in the body
4
Erythropoesis :
• Erythropoiesis is the process by which red blood cells
(erythrocytes) are produced
• Erythro : Erythrocytes
Poiesis : Formation
5
Life cycle of Erythrocytes :
Life span of RBCs - 120 days
Sequestration (Destruction) of old RBCs
Erythropoiesis
New RBCs
6
7
Erythropoiesis process..
• In process of erythropoiesis, first multiplication of
stem cells and precurssor cells takes place ( goes on
for 10-14 days)
• Followed by iron uptake which goes on for 5-7 days
8
Anemia :
Definition :
It is decreased oxygen carrying capacity of blood
Less than normal (Decreased) Erythrocyte number
and
Less than normal ( Decreased )Amount of hemoglobin
In pregnancy, anemia is diagnosed as lower than 11
gram% Hb
9
Anemia of Pregnancy :
• Pregnancy doubles the amount of iron required by a
woman’s body.
• Extra iron is needed to make hemoglobin for the extra
volume of blood produced during pregnancy and to
provide iron to the developing fetus
• Supply of iron in the body is not sufficient to produce
the required hemoglobin, the result is anemia.
• Hence, iron supplements are recommended from
second trimester of pregnancy
http://wikiparenting.parentsconnect.com/wiki/Anemia_during_Pregnancy10
9 out of 10 pregnant women in India are anemic, as
not all patients respond adequately to Iron oral
therapy due to side effects (gastrointestinal
discomfort) of oral iron which lead to poor
compliance and lack of efficacy *
* Journal of Pregnancy Volume 2012(2012), Article ID 630519, 1-10
(DLHS RCH Survey )
11
• Besides Anemia, High Risk Pregnancy
incidences are also rising in India
12
High Risk Pregnancy
• Any of the below…
• Previous pregnancy – with complication (such as
IUGR, preeclampsia)
• Pregnancy at age of 35 years or above
• Pregnancy with more than one baby
• Diabetes, hypertension, asthma
• Abnormalities of reproductive tract, Uterine fibroids13
• Anemia management and high risk pregnancy
require special attention….
….in order to ensure healthy pregnancy
outcome
14
Introducing first time in india
Innovative solution for Anemia management &
healthy pregnancy outcome
Cpink Total
More Than Just Iron
Composition
Each film coated tablet contains:
• Ferorus Ascorbate Eqv. to
• Elemental iron……………………………………….....100mg
• (in sustained release form)
• L Methyl folate …………………………………...…….0.5mg
• Methylcobalamin JP…………….……………..…........1500mcg
• (Stabilized)
• Pyridoxal 5 phosphate………………………………....0.5 mg
• Cholecalciferol………………………………………….1000 IU
• Zinc as Zinc Sulphate Monohydrate IP………..…….25mg
• Biotin………………………………………………..…...0.6mg
• Nickel as Nickel Sulphate IP……………………..…..80mcg
• Iodine as Potassium Iodide IP...………….………..…35mcg
• Manganese as Manganese Sulphate IP………..……0.4mg
• Copper as Copper Sulphate Pentahydrate USP……0.3mg
• Silicon as Colloidal Slicon Dioxide IP………………...2mg
• Vanadium as Sodium Vanadate……………………...10mcg
• Chromium as Chromium Picolinate USP……………10mcg
• Molybdenum as Sodium Molybdate Dihydrate……...15mcg
Ferrous ascorbate is a superior molecule
amongst all irons..
Technology further advances...
Sustained release formulation scores over
conventional ( immediate release) iron
18
Unlike other irons,
Ferrous ascorbate…
stable ferrous
ascorbate complex
No Dissociation
No action of
Inhibitors
No chelation with inhibitors
19
19
Ferrous ascorbate is
better absorbed,
hence superior …
Ascorbate is a reducing agent
and prevents Oxidation. Thus
maintains Iron in highly
soluble ferrous form.
Fe2+
No oxidation of Fe2+
to Fe3+
High Concentration of Fe2+
20
20
21
In-vitro (Dissolution) study showed
Data on file
Hours
Absorption of Ferrous
Ascorbate SR (%)
1
38.6
3
76.5
5
97.9
22
Technology further Advances….
23
Benefits of Sustained Release Iron
• In terms of efficacy related to rise in hemoglobin,
sustained release iron is more potent than
conventional iron
• After 12 weeks of treatment, 80 mg elemental iron
given in sustained release form is equivalent to 105
mg elemental iron given in conventional release iron
in terms of hemoglobin rise
• Eur J Nutr. 2012 Mar, 51(2):221-9
24
Benefits of Sustained Release Iron
• Systemic review of 106 studies including data from
10515 patients showed that sustained release ferrous
salt showed 88.29% reduction ( came down to 3.7 %
from 31.6% ) in gastrointestinal adverse effects as
compared to immediate release ferrous salt
• Sustained release ferrous salt is better tolerated than
immediate release ferrous salt
• The Scientific World Journal, 2012;2012:846824
25
Sustained release iron (ferrous ascorbate) is
superior to immediate release
formulations
• More potent Hb rise
• 88 % reduction in GI adverse effects
• Ensures better patient compliance
Eur J Nutr. 2012 Mar, 51(2):221-9
There are two important ingredients
Which play significant role in
Erythropoiesis
LMF ( L Methyl Folate – active form of folic acid )
and
Methylcobalamin
(Acitve form of vitamin B12)
27
• LMF & methylcobalamin help in
- Multiplication of stem cells and precurssor cells
required for erythropoiesis (RBC formation)
* Baillieres Clin Haematol. 1995 Sep;8(3)441-59
** Annual Review of Nutrition.2004 July Vol.24 105-131
LMF rather than folic acid is a better choice in
anemia management and in high risk
pregnancy
29
Folic acid requires 4 step process to become
active metabolite- LMF
Folic acid
Dihydrofolate
Tetrahydrofolate
5,10 Methylenetetrahydrofolate
MTHFR enzyme
LMF
MTHFR enzyme- required for converting synthetic folic acid
to active form LMF
30
Body converts Folic acid into LMF if MTHFR
enzyme is in normal quantity,
However…
31
5,10 Methylenetetrahydrofolate
MTHFR enzyme
LMF
Prone to undergo
genetic polymorphism
Incidence,
40-50%
1) Saussele T. et al, Med monatsschr Pharm. 2008 Dec; 31 (12):469-72,
2) Thomas P et al., Vitam Horm. 2008;79:375-92. 3) Wounds. 2006;18(4):101-116
32
MTHFR Genetic polymorphism means,
Genes producing MTHFR enzyme change their
structure (undergo mutation)
in MTHFR enzyme
33
MTHFR Polymorphism
Reduction in LMF formation
Inadequate erythropoiesis
34
• Also, besides erythropoiesis, LMF,
methylcobalamin are required for managing
hyperhomocysteinemia which is independent
causal factor for pregnancy complications
The Lancet, 2005 Sep; 366 (9489):930-931.
Experimental Neurology 2008 May; 212:515-521.
35
Hyperhomocysteinemia (High homocysteine levels )
High Incidence in Indian population
AIIMS Study confirms….
…
in 84% Indian population
Eur J Nutr, 2002; 41:68–77
36
re-methylation
(by L-methylfolate and Methylcobalamin)
methionine
Homocysteine
cysteine
trans-sulfuration
(by Pyridoxal-5-phosphate)
2) Eur J Obstet Gynaecol Reprod Biol;2003, Apr 25, 107 (2):125-34
9) Food Nutr. Bull.2008 Jun; 29(2 suppl): S116-25
37
( L-methylfolate & Methylcobalamin)
methionine
Homocysteine
cysteine
( Pyridoxal-5-phosphate)
38
re-methylation
(Methylcobalamine: 1500 mcg
& L-methylfolate: 1 mg)
Pregnancy Complications
IUGR
Placental abruption
methionine
Homocysteine
cysteine
Intrauterine Fetal Death
Pre-Eclampsia
Pre-term Labor
trans-sulfuration
(pyridoxal-5phospahte: 0.5 mg)
L-methylfolate, Methylcobalamin,& Pyridoxal-5-phosphate
keep homocysteine normal
Eur J Obstet Gynaecol Reprod Biol;2003, Apr 25, 107 (2):125-34
Food Nutr Bull, 2008 Jun; 29(2 Suppl): S116-25
39
Pre-term labour
Intrauterine fetal death
IUGR
Hyperhomocysteinemia
placental abruption
Clin. lab. 2011;57:933-938
Indian J of Human Genet, 2010 Sep- Dec, 16 (3), 159-163.
Van
Driel LM et al, Obstet Gynecol, 2008 Aug;112(2 Pt 1):277-83
.
Archives of Perinatal Medicine 2007;13 (1):27-29
Pre-eclampsia
40
• In second and third trimester of pregnancy there can
be pregnancy complications such as
– IUGR (Intra Uterine Growth Retardation)
– Intrauterine fetal death (fetal death after 20th
week of gestation)
– Placental abruption (detachment of placenta
from uterus)
– Pre-eclampsia (Hypertension)
– Pre-term labour (birth before 37th week of
gestation)
41
Hyperhomocysteinemia
Hyperhomocysteinemia
leads to IUGR
Atherosclerosis
& Thrombosis
Reduce blood flow to fetus
IUGR
42
• Indian study confirms…
– Study on 180 pregnant subjects confirms
In women with
Serum Homocysteine levels
Normal Pregnancies
7.4 micromol/litre
IUGR fetuses
11.1 micromol/litre
Clin Lab. 2011;57(11-12):933-8
43
King Edward Memorial Hospital, Pune ……Asia Pac J Clin
Nutr 2005
Methylcobalamin deficiency related to hyper
homocysteinemia contributes to small size of Indian
babies ( IUGR )
44
Hyperhomocysteinemia link to IUGR;
Endorsed by…
• Hyperhomocysteinemia is associated with IUGR and
should be identified as a risk factor as correction favors
pregnancy outcome*
• Increased levels of homocysteine are involved in
pathogenesis of IUGR and dysfunction observed in
pregnancy disorders**
* J Obstet Gynaecol India. 2012 Aug;62(4):406-8
** Open Journal of Obstetrics and Gynecology 2011 Dec;1(4):191-196
45
• Meta-analysis of 19 studies in 21,326 pregnant
subjects showed:
1 unit rise in maternal homocysteine leads to 31 gm
decrease in fetal birth weight
Am J Clin Nutr. 2012 Jan;95(1):130-6
46
Study done by St.John’s National Academy
of Health Science Bangalore 2006
• International study confirms
deficiency in pregnancy*
methylcobalamin
• Study done in 478 Indian pregnant women showed
methylcobalamin deficiency in pregnancy- strongly
linked to IUGR
*Eur J Clin Nutr. 2006 Jun;60(6):791-801
47
Hyperhomocysteinemia
Endothelial dysfunction,Atherosclerosis & clot
formation
Preeclampsia
48
Hyperhomocysteinemia link to Pre-Eclampsia;
Endorsed by…
• Increased levels of homocysteine are involved in
pathogenesis pre-eclampsia and dysfunction observed in
the pregnancy disorders*
• Hyperhomocysteinemia along with increased blood
pressure is a risk factor for cardiovascular disease (CVD)
in preeclampsia**
* Open Journal of Obstetrics and Gynecology 2011 Dec;1(4):191-196
** Indian J Clin Biochem. 2011 Jul;26(3):257-60
49
L-methyl Folate+Methylcobalamin +
Pyridoxal-5-phosphate
• Help in erythropoiesis
• Reduce Hyperhomocysteinemia
• Prevent HHCY induced IUGR & Pre-eclampsia
Annual Review of Nutrition. 2004 July Vol.24:105-131
Link between vitamin D insufficiency and adverse
pregnancy outcome
• 1,873 pregnant women above 24 weeks' gestation with any
maternal complication
• vitamin D deficiency was significantly higher in anemia (17.1%
vs 11%) and preeclampsia (19.8% vs 11.4%) when compared
to the uncomplicated group
• Maternal vitamin D deficiency in pregnancy is significantly
associated with elevated risk for GDM ( Gestational Diabetes
Mellitus), anemia, and preeclampsia
Int J Womens Health. 2013 Sep 4;5:523-31
51
Vitamin D3 deficiency ..linked to
preeclampsia
Hypertension
Vitamin D3 deficiency
Aldosterone
Calcium absorption
Blood Calcium
•Eur J Endocrinol 1998; 138 (5) : 543-7.
Angiotensin
Renin
Parathyroid Hormone
•Am J Physiol Renal Physiol 1979; 236: F311-9.
•The Journal of Clinical Endocrinology & Metabolism 2001;80 (4) : 1633-37
52
52
Vitamin D3 deficiency & risk of
preeclampsia
• Prevalence of vitamin D3 insufficiency was very high 78% of all subjects
• Study done in 188 subjects showed risk of
developing preeclampsia increases up to 5-fold in
women with vitamin D3 insufficiency
• Supplementation of Vitamin D3 during pregnancy
recommended to decrease adverse consequences
Horm Metab Res. 2013 Sep;45(9):682-7
53
Vitamin D3 deficiency & preeclampsia
• Study in 274 pregnant women showed that vitamin
D3 deficiency at or before week 22 of gestation was
an independent predictor of preeclampsia
• Patients with 25(OH)D levels <15 ng/mL a 5-fold
increase in the risk of pre-eclampsia
. Am J Obstet Gynecol 2010 May;202(5):429.e1-129e9
54
Vitamin D3 status & risk of pre-eclampsia
• Meta-analysis on 8 relevant papers revealed an
overall significant association between vitamin D3
deficiency and risk of pre-eclampsia
J Clin Endocrinol Metab. 2013 Aug;98(8):3165-73
55
Vitamin D3 deficiency..linked to
gestational diabetes
• In gestational diabetes, underlying cause is
development of insulin resistance (the important
cause for the same is vitamin D3 deficiency)
Vitamin D3
Insulin resistance
Reduces GDM
56
Vitamin D3 deficiency linked to IUGR
Vitamin D3
Calcium and phosphate absorption & deposition
Fetal bone and thereby overall growth
Curr Opin Obstet Gynecol 2011 Dec;23(6):422-6
57
Fetal and newborn effects of gestational
vitamin D3 supplementation
• Study done in 449 pregnant women showed, higher
mean birth length at delivery in babies from mothers
who received recommended vitamin D3
• Incidence of low birthweight was significantly lower
in newborn infants from mothers who received
recommended dose of vitamin D3
. Am J Obstet Gynecol 2010 May;202(5):429.e1-129e9
58
Vitamin D3 deficiency in pregnancy
Randomized controlled trials of vitamin
supplementation in pregnant women suggest
D3
• Greater incidence of small-for-gestational-age
infants born to mothers who received placebo than
to mothers who received 1000 IU of vitamin D3 per
day during final trimester of pregnancy
. Am J Obstet Gynecol 2010 May;202(5):429.e1-129e9
59
• Recent evidence support vitamin D3 in modulating
risk of pregnancy complications and in sustaining
fetal growth, bone development .
Curr Opin Obstet Gynecol 2011;23(6);422-6
60
• Vitamin D3 has a role in erythropoiesis
• It is also important for bone marrow function
• Study done in 1873 pregnant women showed
vitamin D3 deficiency is associated with increase risk
for anemia, GDM (Gestational diabetes mellitus)
International journal of Womwn’s Helath 2013:5 523-531
61
• Vitamin D has been suggested to have effect on
erythropoiesis.
• 554 subjects were included. Anemia was present in
49% of 25-hydroxyvitamin D-deficient subjects
compared with 36% with normal 25-hydroxyvitamin D
levels (p < 0.01). 25-hydroxyvitamin D-deficient
subjects had a lower mean Hb (11.0 vs. 11.7 ).
• This study demonstrated association of vitamin
D deficiency and a greater risk of anemia, lower mean
hemoglobin.
• Ann Hematol. 2010 May;89(5):447-52.
62
Benefits of Vitamin D3
• Vitamin D3 reduces….
• The risk of pre-eclampsia by 40 %
• Gestation diabetes by 2 times
• Low birth weight by 60 %
Epidemiology. 2014 March ; 25(2): 207–214.
Am J Obstet Gynecol. 2012 September ; 207(3): 182.e1–182.e8.
Food Nutr Bull. 2009 Dec;30(4 suppl);s4777-9
Role of Biotin
• Essential for fat & carbohydrate metabolism thus
prevents Gestational diabetes
• Helps prevent hair fall during pregnancy
http://www.chatelaine.com/health/welness/biotin-can boost your-health
• Role of Minerals…….
65
Zinc supplementation on pregnancy outcome
• 580 pregnant women, 19 weeks’ gestational age
• Received 25 mg of zinc until delivery
• Zinc supplementation was associated with 126 g
greater birth weight and 0.4 cm greater head
circumference than infants in the placebo group.
• Zinc supplementation was associated with a 248-g
higher infant birth weight and a 0.7-cm larger infant
head circumference in ladies with BMI < 26 kg/m
2
JAMA. 1995 Aug 9;274(6):463-8
66
A double-blind trial of zinc supplementation in
pregnancy
• Zinc significantly reduced incidence of intrauterine
growth retardation, and most measured indices of
labour and fetal health were better in supplemented
group
Eur J Clin Nutr. 1991 Mar;45(3):139-44
67
Zinc – Mechanism of action
• Zinc acts as a cofactor for more than 70 different
enzymes. Zinc dependent enzymes are involved in
metabolism of carbohydrates, lipids, and proteins
• It also helps in development of immunity
https://www.medicineindia.org/pharmacology-for-generic/3075/iron-ferrous-ascorbate-zinc
68
• Deficiency of manganese in pregnancy can
lead to poor pregnancy outcome, including
IUGR
• Manganese plays important role in fetal
development
• Environ Res. 2015 Jan;136:47-56
• Oxidative Medicine and Cellular Longevity,Volume 2011, Article ID 841749
• Nutrition. 2009 Jan;25(1):78-84.
69
• Low nickel leads to reduced fetal growth
• Ingestion of multimicronutrient formula containing
silicon, vanadium, chromium, molybdenum led to
reduction in incidence of IUGR babies
• IARC Sci Publ.1984;(53):339-65
• Lancet. 2008;371:215-27
• Arch Pediatr Adolesc Med. 2007 Jan;161(1):58-64
70
Effect of Iodine Supplementation During
Pregnancy on Infant Neurodevelopment
• Iodine is the main constituent of thyroid hormones,
which in turn are required for fetal brain
development
• The Mental Development Index and Psychomotor
Development Index (PDI) for 691 children were
obtained
• Lower intake of iodine led to decrease in
Psychomotor Development Index (PDI)
Am J Epidemiol. 2011 Apr 1;173(7):804-12
71
Micronutrients in fetal growth and development
• Minerals are important either as central components
of the catalytic sites of enzymes (Cu and Fe, for
example) or as stabilising factors in enzymes and
transcription factors (Zn, for example)
• Iron deficiency is associated with increased risk of
maternal haemorrhage, and peri-partum blood loss
has more severe consequences for anemic mother
Br Med Bull. 1999;55(3):499-510
72
Micronutrients in fetal growth and development
• Severe copper deficiency causes fetal resorption
while milder deficiencies result in skin, neuronal and
hair abnormalities
• The lesions underlying alterations presumably occur
as a result of reduced cupro-enzyme activity
• Copper deficiencies in collagen and elastin cross
linking, due to a fall in lysyl oxidase activity, lead to
problems with lung development and with aortic
elasticity.
Br Med Bull. 1999;55(3):499-510
73
Role of Minerals
• Improve fetal birth weight
• Essential for fetal brain development
Food Nutr Bull. 2009 Dec;30(4 suppl);s4777-9
Am J Epidemiol. 2011 Apr 1;173(7)
• Thus, looking at the roles of various ingredients in
cpink Total, it is concluded that cpink Total is an
Innovative solution for Anemia management &
healthy pregnancy outcome
75
Indication
• For Anemia and High risk pregnancy
Dosage
• One tablet once daily 2 hours after food from 2nd
trimester onwards, continue during Lactation