Role of Heme Iron Polypeptide (HIP) for Preventing & Treating Anemia

Dr Nupur Gupta, Consultant Gynecologist

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

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

Prevalence of Anemia - Global

Iron deficiency Heavy blood lossMenorrhagia

Parasite infections

Acute and chronic

infections

Pregnancy

Deficiencies Haemoglob- inopathies

General Causes of Anemia

Severity of Anemia

Mild 10 to 10.9gm%

Moderate 7 to 9.9gm%

Severe <7gm%

Very severe <4gm%

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)

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

Severe Anemia In pregnancy

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

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

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

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

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

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.

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

Causes of Anemia in Pregnancy

2) Hereditary

-Thalassaemias

- Sickle cell

- Haemoglobinopathies

- Other haemoglobinopathies

- Hereditary haemolytic anemias

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 & ThyroxineLetsky E. 1995

Prasad AS. J. Am. Coll. Nutr. 1996

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

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 Haematol, 1972

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

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

Causes of high prevalence of

Iron deficiency Anemia

1. Dietary habits

2. Worm infestations

3. Repeated pregnancies at short intervals

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

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

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

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

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

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

Side effects of iron

Nausea

Vomiting

Constipation

Abdominal cramping

Diarrhoea

The tablet can be given with meals or

different brand may be tried

For better patient compliance

twice weekly or weekly iron

supplements

have also been recommended

Ridwan et al Am. J. Clin Nutr. 1996

Compliance Issues

Reasons for failure to respond

1. Non compliance2. Concomitant folate deficiency3. Continuous loss of blood through hookworm

infestation or bleeding haemorrhoids4. Co-existing infection5. Faulty iron absorption6. Inaccurate diagnosis

Non iron deficiency microcytic anaemiaa. Thalassaemiab. Pyridoxine deficiencyc. Lead poisoningd. Sideroblastic anaemiae. Atransferrinaemia

Prema K. Obst. & Gynaecol 1992

Sharma JB, In Progress in Obst. &

Gynaec, 2002

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

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

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

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

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

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.

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 babySharma JB, The Obstetic Protocol, 1998

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

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

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

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

HEME IRON POLYPEPTIDE– PP26

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

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

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

04/15/2023

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

49

Oral administration 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

04/15/2023

Ferrous Sulfate Therapy

Heme Iron Polypeptide

1. Serum iron 2. Transferrrin

saturation (TSAT) 3. Non-transferrin-

bound iron (NTBI)

51

Iron & Oxidative Stress Trial

04/15/2023

Baseline Hb Hb after 4 weeks Hb after 8 weeks Hb after 12 weeks 0

2

4

6

8

10

12

9.37 9.6310.29

11.26Hb rise using 0.3mg BD (0.26, 0.66, 0.97)

Series1 Linear (Series1)Week

Hb

Leve

l (gm

/dL)

Efficacy of Heme Iron Polypeptide

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.

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

Making Pregnancy SaferTargeting Anemia Eradication during Adolescence