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Blood Physiology :

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Structure of RBCs :

• RBCs : Red Blood Cells/Erythrocytes are Biconcave (Concave on both surfaces) in shape

• As they mature, they acquire hemoglobin

RBCs/Erythrocyte

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Hemoglobin :

• Hemoglobin is iron (in ferrous form) containing protein in Erythrocytes

Hemoglobin

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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

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Erythropoesis :

• Erythropoiesis is the process by which red blood cells (erythrocytes) are produced

• Erythro : Erythrocytes Poiesis : Formation

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Life cycle of Erythrocytes :

Life span of RBCs - 120 days

Sequestration (Destruction) of old RBCs

Erythropoiesis

New RBCs

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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

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Anemia :

Definition : It is decreased oxygen carrying capacity of blood

Less than normal (Decreased) Erythrocyte number andLess than normal ( Decreased )Amount of hemoglobin

In pregnancy, anemia is diagnosed as lower than 11 gram% Hb

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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_Pregnancy

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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 *

(DLHS RCH Survey )

* Journal of Pregnancy Volume 2012(2012), Article ID 630519, 1-10

• Besides Anemia, High Risk Pregnancy incidences are also rising in India

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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 fibroids

• Anemia management and high risk pregnancy require special attention….

….in order to ensure healthy pregnancy outcome

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Introducing first time in india

Innovative solution for Anemia management & healthy pregnancy outcome

Cpink TotalMore Than Just Iron

CompositionEach 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

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Ferrous ascorbate is a superior molecule amongst all irons..

Technology further advances...

Sustained release formulation scores over conventional ( immediate release) iron

1919

stable ferrousascorbate complex

No Dissociation

No action of Inhibitors

No chelation with inhibitors

Unlike other irons,Ferrous ascorbate…

2020

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+

Ferrous ascorbate is better absorbed, hence superior …

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In-vitro (Dissolution) study showed

Hours Absorption of Ferrous Ascorbate SR (%)

1 38.6

3 76.5

5 97.9

Data on file

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Technology further Advances….

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

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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

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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

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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)

• 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

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Folic acid

Tetrahydrofolate

5,10 Methylenetetrahydrofolate

LMF

MTHFR enzyme

Folic acid requires 4 step process to become active metabolite- LMF

MTHFR enzyme- required for converting synthetic folic acid to active form LMF

Dihydrofolate

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Body converts Folic acid into LMF if MTHFR enzyme is in normal quantity,

However…

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5,10 Methylenetetrahydrofolate

LMF

MTHFR enzyme

Prone to undergo genetic polymorphism

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

Incidence,40-50%

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MTHFR Genetic polymorphism means,

Genes producing MTHFR enzyme change their structure (undergo mutation)

in MTHFR enzyme

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Inadequate erythropoiesis

Reduction in LMF formation

MTHFR Polymorphism

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• Also, besides erythropoiesis, LMF, methylcobalamin are required for managing hyperhomocysteinemia which is independent causal factor for pregnancy complications

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The Lancet, 2005 Sep; 366 (9489):930-931. Experimental Neurology 2008 May; 212:515-521.

Hyperhomocysteinemia (High homocysteine levels )

High Incidence in Indian population

AIIMS Study confirms….AIIMS Study confirms….

Eur J Nutr, 2002; 41:68–77

…

in 84% Indian population

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Homocysteinemethionine

cysteine

re-methylation(by L-methylfolate and Methylcobalamin)

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)

( Pyridoxal-5-phosphate)

Homocysteinemethionine

cysteine

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Homocysteine

methionine

cysteine

Pregnancy Complications

IUGR

Placental abruption

Intrauterine Fetal Death

Pre-Eclampsia

Pre-term Labor

re-methylation (Methylcobalamine: 1500 mcg

& L-methylfolate: 1 mg)

trans-sulfuration (pyridoxal-5-

phospahte: 0.5 mg)

L-methylfolate, Methylcobalamin,& L-methylfolate, Methylcobalamin,& Pyridoxal-5-phosphate keep Pyridoxal-5-phosphate keep

homocysteine normal 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

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Hyperhomocysteinemia

IUGR

Pre-eclampsiaplacental abruption

Pre-term labour

Intrauterine fetal death

Clin. lab. 2011;57:933-938Indian J of Human Genet, 2010 Sep- Dec, 16 (3), 159-163. Van Driel LM et al, Obstet Gynecol, 2008 Aug;112(2 Pt 1):277-83Archives of Perinatal Medicine 2007;13 (1):27-29.

• 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)

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Hyperhomocysteinemia

Atherosclerosis & Thrombosis

Reduce blood flow to fetus

IUGR

Hyperhomocysteinemialeads to IUGR

• Indian study confirms…

– Study on 180 pregnant subjects confirms

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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

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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 )

Hyperhomocysteinemia link to IUGR;Hyperhomocysteinemia link to IUGR;Endorsed by…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.J Obstet Gynaecol India. 2012 Aug;62(4):406-8** ** Open Journal of Obstetrics and Gynecology 2011  Dec;1(4):191-196

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• 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

46Am J Clin Nutr. 2012 Jan;95(1):130-6

Study done by St.John’s National Academy of Health Science Bangalore 2006

• International study confirms methylcobalamin deficiency in pregnancy*

• Study done in 478 Indian pregnant women showed methylcobalamin deficiency in pregnancy- strongly linked to IUGR

47*Eur J Clin Nutr. 2006 Jun;60(6):791-801

Hyperhomocysteinemia

Endothelial dysfunction,Atherosclerosis & clot formation

Preeclampsia

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Hyperhomocysteinemia link to Pre-Hyperhomocysteinemia link to Pre-Eclampsia;Eclampsia;Endorsed by…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

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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

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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

525252

Vitamin D3 deficiency ..linked to preeclampsia

•Eur J Endocrinol 1998; 138 (5) : 543-7.

•Am J Physiol Renal Physiol 1979; 236: F311-9.

•The Journal of Clinical Endocrinology & Metabolism 2001;80 (4) : 1633-37

Parathyroid Hormone

Angiotensin

Hypertension

Blood Calcium

Calcium absorption

Vitamin D3 deficiency

Renin

Aldosterone

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

53Horm Metab Res. 2013 Sep;45(9):682-7

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

54. Am J Obstet Gynecol 2010 May;202(5):429.e1-129e9

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

55J Clin Endocrinol Metab. 2013 Aug;98(8):3165-73

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)

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Vitamin D3

Insulin resistance

Reduces GDM

Vitamin D3 deficiency linked to IUGR

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Vitamin D3

Calcium and phosphate absorption & deposition

Fetal bone and thereby overall growth

Curr Opin Obstet Gynecol 2011 Dec;23(6):422-6

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

58. Am J Obstet Gynecol 2010 May;202(5):429.e1-129e9

Vitamin D3 deficiency in pregnancy

Randomized controlled trials of vitamin D3 supplementation in pregnant women suggest

• 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

59. Am J Obstet Gynecol 2010 May;202(5):429.e1-129e9

• Recent evidence support vitamin D3 in modulating risk of pregnancy complications and in sustaining fetal growth, bone development .

60Curr Opin Obstet Gynecol 2011;23(6);422-6

• 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)

61International journal of Womwn’s Helath 2013:5 523-531

• 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…….

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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/m2

JAMA. 1995 Aug 9;274(6):463-8

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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

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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

• 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.

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• 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

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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

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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

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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

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

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Indication

• For Anemia and High risk pregnancy

Dosage

• One tablet once daily 2 hours after food from 2nd

trimester onwards, continue during Lactation