Role of heme iron polypeptide for treating and preventing anemia

1. Role of Heme Iron Polypeptide (HIP) for
Preventing & Treating Anemia
Dr Nupur Gupta, Consultant Gynecologist

2. Is the commonest medical disorder in
pregnancy and has a varied prevalance,
aetiology and degree of severity in different
populations being much more common in non-
industrialised nations
- Schwartz et al. Clin Obstet Gynaecol 1995
ANEMIA

3. Definition of Anemia in pregnancy
Low circulating haemoglobin with Hb < 2SD of
the median of a healthy population of the same
age and stage of pregnancy
WHO: Hb < 11 g/dl (7.45 mmol/l), PCV < 0.33,
CDC < 10.5 g/dl during the second trimester

4. Prevalence of Anemia - Global

5. Iron deficiency
Heavy blood
lossMenorrhagia
Parasite
infections
Acute and
chronic
infections
Pregnancy
Deficiencies
Haemoglob-
inopathies
General Causes of Anemia

6. Severity of Anemia
Mild 10 to 10.9gm%
Moderate 7 to 9.9gm%
Severe <7gm%
Very severe <4gm%

7. Severity of Anemia
Mild to Moderate
• Decreased work capacity
• May go without any
adverse consequences
Moderate
• Substantial reduction in
work capacity
• Morbidity rates are higher
• Susceptible to infections
• Premature/LBW
• Unable to bear blood loss
(antepartum & post-partum
haemorrhage)

8. Severe Anemia
Distinct stages recognised
1. Decompensated - Cardiac decompensation due to
low Hb
2. Compensated - cardiac output is raised even at rest
3. Circulatory failure - anaerobic metabolism & lactic
acid accumulation occurs

9. Severe Anemia In pregnancy

10. Consequences of Anemia in Pregnancy
• Impaired tissue oxygenation
• Impaired organ function
• Increased susceptibility to thrombocytopenic bleeding
• Increased post operative morbidity
• Increased probability of blood transfusion
• Impaired quality of life

11. Anemia is responsible for 40-60% of maternal deaths
(developing countries)
Indirect deaths:
- Cardiac Failure
- Haemorrhage
- Infection
- Pre-eclampsia
- Viteri. Adv. Exp Med Biol 1994, Bhatt J. Obstet Gynaec Ind. 1997
Maternal effects of Anemia

12. Maternal effects of Anemia
1. There may be no effect
2. Increased weakness
3. Lack of energy
4. Fatigue
5. Poor work performance
ICMR 1989, Lops et al Am Fam Physician 1995
Severe anemia:
1. Palpitation
2. Tachycardia
3. Breathlessness
4. Cardiac Stress
5. Decompensation
6. Cardiac Failure
7. Pre-Term labour
8. Pre-eclampsia
9. Sepsis

13. Fetal effects of Anemia
Increased perinatal mortality and morbidity
- Prema et al Nutr. Rep. Int. 1981; Lozoff et al NEJM 1992
• Preterm deliveries
• Intra-uterine growth retardation (IUGR)
• Low fetal iron stores
• Fetal iron deficiency anemia
• Cognitive and affective dysfunction in the infant

14. Agarwal et al Ind. J. Med. Res. 1991; Preziosi et al Am J Clin Nutr 1997
Mean Birth Weight, Apgar & 3 months Hb
was higher
Fetal effects of Anemia
Babies of iron supplemented mothers

15. Iron Deficiency
 Most common micronutrient deficiency in
the world affecting 1.3 billion people i.e.
24% of the world population.
 Defined as hemoglobin below the 5th
percentile of healthy population.
 Iron deficiency can range from sub-clinical
state to severe iron deficiency anemia.

16. Causes of Anemia In Pregnancy
1) Acquired - Iron deficiency anemia
- Anemia caused by acute blood loss
- Anemia of inflammation or malignancy
- Megaloblastic anemia
- Acquired haemolytic anemia
- Aplastic or hypoplastic anemia
- Thalassaemias
- Sickle cell haemoglobinopathies
- Other haemoglobinopathies
- Hereditary haemolytic anemias

17. Causes of Anemia in Pregnancy
2) Hereditary
-Thalassaemias
- Sickle cell
- Haemoglobinopathies
- Other haemoglobinopathies
- Hereditary haemolytic anemias

18. Factors required for erythropoiesis
• Proteins (erythropoietin)
• Minerals (iron)
• Trace elements (Zinc, Cobalt, Copper etc)
• Vitamins : Folic acid, Cyanocobalamin (B12), Vitamin C,
Pyridoxine (B6), Riboflavin, Vitamin A
• Hormones : Androgens & Thyroxine
Letsky E. 1995
Prasad AS. J. Am. Coll. Nutr. 1996

19. Enhance Inhibit
Meat Phosphate
Fish Calcium
Poultry Tea (tannic acid)
Seafood Coffee
Gastric acid Colas
Ascorbic acid Soy protein
Malic acid High doses of minerals
Citric acid Bran/fiber
Source: Compiled from Provan D.Mechanisms and management of iron deficiency anaemia. Br
J Haematol 1999; 105 Suppl 1:19-26; Wharton B. Iron deficiency in children: detection and
prevention. Br J Haematol 1999; 106:270-280; Cook JD. The measurement of serum
transferring receptor. Am J Med Sci 1999;318:269-276.
Dietary Factors That Affect absorption

20. Bio-availability of Iron
1. High bio-availability diet
Diet rich in meat, poultry, fish
2. Intermediate bio-availability diet
Cereals, roots, tubers with some animal foods like
meat, fish and ascorbic acid.
Hallberg et al Scand J Haemat

21. 3. Low bio-availability diet
Non-industrialised countries vegetarian
diet low in ascorbic acid with excess of
inhibitors of iron absorption (phytates),
cereals, roots, tubers, maize, rice , beans,
whole wheat, flour, sorghum
Iron bio-availability

22. Iron requirements
2.5 mg/day in early pregnancy
5.5 mg/day from 20-32 weeks
6 to 8 mg/day from 32 weeks onwards
Average : 4mg/day
Sharma JB, The Obstet Protocol, 1998

23. Causes of high prevalence of
Iron deficiency Anemia
1. Dietary habits
2. Worm infestations
3. Repeated pregnancies at short intervals

24. Prevention of Iron deficiency
Ideally women should enter pregnancy
with adequate iron stores
As a public health approach, prolonged oral iron
supplementation even before pregnancy is a better
strategy (PRECONCEPTION COUNSELING)
Sloan et al Mother Care Project, 1992

25. Iron supplementation
during pregnancy
In developed countries like U.K routine Iron
supplementation is not recommended
However, it is mandatory in non-industrialized countries
WHO recommends 60 mg elemental iron with 250 mg folic
acid for 6 months in pregnancy and additional 3 months
postpartum
Sloan et al, Mother care project, 1992

26. 100 mg elemental iron with
500 mg of folic acid
for 100 days in second half of pregnancy
Govt. of India, 2000
GOI & MOH recommendation

27. Other effective strategies
1. Treatment of hookworm infestation
Albendazole (400 mg)
Mebendazole 100 mg BD for 3 days
2. Improving dietary habits
3. Food fortification
Atukorala et al. Am. J. Clin Nutr 1994
Viteri et al Am. J. Clin Nutr 1995

28. Diagnosis
1. Haemoglobin estimation (<11 g/dl)
2. Peripheral blood film : Microcytic hypochromic picture
3. Blood indices are lower
4. Low serum ferritin (<12 mg/l)
5. Elevated Total Iron Binding Capacity (TIBC) ( > 350 mg/dl)
6. Low serum iron ( < 60 mg/dl)
7. Low transferrin saturation ( < 15 % )
8. Raised Free Erythrocytic Protoporphyrin (FEP) (>50 mg/dl)
9. Raised serum transferrin receptor
10. Bone marrow examination

29. Oral Iron Therapy
• 180 mg – 200 mg elemental iron with 500
mg folic acid per day
• Reticulocyte count rises in 5 –10 days
• Hb rises 0.3 to 1 g per week

30. Side effects of iron
Nausea
Vomiting
Constipation
Abdominal cramping
Diarrhoea
The tablet can be given with meals or
different brand may be tried

31. For better patient compliance
twice weekly or weekly iron
supplements
have also been recommended
Ridwan et al Am. J. Clin Nutr. 1996
Compliance Issues

32. Reasons for failure to respond
1. Non compliance
2. Concomitant folate deficiency
3. Continuous loss of blood through hookworm
infestation or bleeding haemorrhoids
4. Co-existing infection
5. Faulty iron absorption
6. Inaccurate diagnosis
Non iron deficiency microcytic anaemia
a. Thalassaemia
b. Pyridoxine deficiency
c. Lead poisoning
d. Sideroblastic anaemia
e. Atransferrinaemia
Prema K. Obst. & Gynaecol 1992
Sharma JB, In Progress in Obst. &
Gynaec, 2002

33. In India, two or three doses of intramuscular or
IV iron at time of tetanus toxoid injection was
found to be well tolerated, safe and effective
regimen.
Bhatt J. Obstet Gynecol Ind. 1997
Sharma and Jain (MD thesis 2002)
IM Iron with Tetanus

34. Parenteral Iron therapy
• Indicated when the pregnant women is unable
to take iron due to side effects or is non
compliant
• Its main advantage is certainity of administration
• Rise in haemoglobin is similar to oral iron (upto
1gm per wk)
Sharma J.B. Progress in Obst. & Gynae. (Studd) 2003

35. Parenteral Iron Therapy
It has no advantage over oral iron if the
latter is well tolerated
Indicated only for non-compliance or
serious side effects with oral iron
Sharma JB, In Progress in Obst. & Gynaec, 2002

36. Dose calculation of Parenteral Iron
Prema K 1992
Basu J. Obstet Gynaecol Br. Cwith 1965
Elemental iron (mg) =
(Normal Hb – Patients Hb) x Wt (Kg) x 2.21 + 1000

37. 1. Carbonyl Iron (very effective and well
tolerated, better compliance)
2. Iron ascorbate
3. Iron Polymaltose complex (not used any
more due to lack of efficacy)
4. Heme Iron Polypeptide
New Therapeutic Alternatives

38. Role of blood transfusion
1. Severe anaemia beyond 36 weeks
2. Associated infection
3. To replenish blood loss due to antepartum or
postpartum haemorrhage
4. Patients not responding to oral or parenteral iron.
Packed cells are preferred.

39. Management of labour
1. Comfortable position
2. Sedation and pain relief
3. Oxygen for dyspnoea
4. Use betamimetics & steroids with caution in preterm
labour
5. Digitalisation for cardiac failure of severe anaemia
6. Aim to deliver vaginally
7. Antibiotic prophylaxis
8. Avoid prolongation of second stage
9. Active management of third stage
10. Neonatologist should attend to the baby
Sharma JB, The Obstetic Protocol, 1998

40. Puerperium
1. Adequate rest
2. Continue iron and folate for at least 3 months
3. Energetic treatment of any infection
4. Watch and energetically treat puerperal sepsis,
failing lactation, sub involution of uterus and
thromboembolism
Sharma JB, The Obstetic Protocol, 1998

41. Maternal Mortality
It can happen in severe anaemia due to cardiac
failure or pulmonary embolism at following times:
1. Last trimester (maximum blood volume)
2. During labour
3. Immediately after delivery
4. During puerperium
Sharma JB, The Obstetic Protocol, 1998

42. Contraception
Minimum spacing for 2 yrs to make up for iron
stores
Sterilization is preferred if family is complete
Intrauterine device can be inserted if no
menorrhagia
Barrier methods can be offered but high failure rate
is the disadvantage
Sharma JB, In progress in Obst & Gynae, 2002

43. Types of Iron
Heme Iron
• Animal tissue (red meat,
poultry & fish)
• More bioavailable
• Better absorption
Inorganic Iron (iron salts)
• Vegetables & cereals
• Less bioavailable (altered
absorption by food –
tannins, phytates, soy &
dairy products)
• Inadequate absorption

44. HEME IRON POLYPEPTIDE– PP26

45. HEME IRON POLYPEPTIDE
• Oral tablet containing 6/12 mg of elemental iron as
heme iron polypeptide (HIP),
– With polypeptides of varying molecular weights,
porphyrin rings
• Peptides & amino acids are cleaved during processing to
increase the concentration of the bioavailable iron.
• Heme moiety remains covalently bound to the
polypeptide chain
– Enhancing solubility in aqueous solutions at a wide
range of pH levels; pH less than 3 and pH > 6
46

46. Mechanism of Absorption & Metabolism
1. Absorbed over several hours after oral administration
2. Heme attaches to apical brush border of the absorptive
enterocyte.
3. Heme moiety binds to transferrin
4. Carried across brush border into the cytosol intact
5. Peak change in serum iron from a single dose is seen in
2 -4 hours & gently slopes thereafter for up to ten hours

47. Advantages of Heme Iron
Heme Iron Uses
• GI tolerability comparable
to IV iron,
• Reduced GI distress
• Higher Bioavailability
• Higher serum Fe, Ferritin
Recommended Use
• One tab three times daily
• With or without meals
Ideal alternative to traditional iron therapy

48. Iron & Oxidative Stress Trial
• Production of superoxide & NO plays a role in cellular
signaling & metabolic regulation
• Iron is involved in both formation & scavenging of these
species
• Iron deficiency (anemia) associated with oxidative stress
• Iron preparations also induce oxidative & nitro-sative stress
04-08-2015
49

49. Oral
administr
ation
leads
High
transferrin
saturation
levels
Formation
of non-
transferrin-
bound iron
Potentially
toxic form
of iron
Propensity
to induce
oxidative
stress
High serum
iron &
transferrin
saturation
levels
observed
Iron & Oxidative Stress Trial

50. Ferrous
Sulfate
Therapy
Heme Iron
Polypeptide
1. Serum iron
2. Transferrrin
saturation (TSAT)
3. Non-transferrin-
bound iron
(NTBI)
04-08-2015
51
Iron & Oxidative Stress Trial

51. 9.37 9.63
10.29
11.26
0
2
4
6
8
10
12
Baseline Hb Hb after 4 weeks Hb after 8 weeks Hb after 12 weeks
HbLevel(gm/dL)
Week
Hb rise using 0.3mg BD (0.26, 0.66, 0.97)
Series1 Linear (Series1)
Efficacy of Heme Iron Polypeptide
04-08-2015
52

52. Why L-methylfolate?
• It is the biologically active isomer
of folate and the primary form of
folate in circulation.
• It is the only form of folate to
cross the blood-brain barrier.
• Folic acid (Vit B9) is required for
the nucleic acid metabolism, red
blood cell maturation and for cell
division and growth.

53. Megaloblastic anemia,
Neural tube defects,
Homocysteinemia
Cleft lip & palate
Dietary supplementation with L-Methylfolate at
the time of conception is known to reduce the risk
of neural tube defects in the offspring.
Deficiency of L-methylfolate

54. Making Pregnancy Safer
Targeting Anemia Eradication during Adolescence