reminiscences from indian pediatrics: A
tale of 50 years |
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Indian Pediatr 2017;54: 47-48 |
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Management of Iron Deficiency Anemia - A
Tale of 50 Years
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Piali Mandal and *Sharmila B Mukherjee
Department of Pediatrics, Lady Hardinge Medical
College, New Delhi, India.
Email: [email protected]
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With
the 1967 January issue, Indian Pediatrics embarked upon a new
journey under the stewardship of a new editor, Dr NG Mojumdar. This
issue consisted of 64 pages, with five research papers (phenylalanine
metabolism in protein calorie malnutrition, relationship of skeletal
maturation with nutrition, two studies on parenteral iron, and rectal
bleeding in childhood) as well as other regular features. As iron
deficiency is one of the most common micronutrient deficiencies
encountered by pediatricians, we discuss how the management of iron
deficiency anemia (IDA) has evolved in the last fifty years.
The Past
The study [1] entitled ‘Single dose intravenous
iron infusion in treatment of iron deficiency anemia’ was conducted by
at the Central Railway Hospital in Bombay. In those days, a few studies
in adults from Western countries had demonstrated superior results of
single intravenous iron infusions compared to the standard practice of
giving multiple injections when oral preparations were ineffective. The
authors had observed that their patients who resided outside Bombay were
less compliant with iron therapy, and were irregular in follow-up. Thus,
they felt that a single dose would be a suitable alternative therapeutic
option. Over a period of six months, children with IDA and hemoglobin (Hb)
< 7 g/dL were enrolled; initially in-patient and subsequently
out-patient. The final study population comprised of 70 children (50%
under the age of three years with equal gender ratio). Baseline
hematological investigations were performed to establish IDA. Following
a test dose, a single intravenous infusion of Iron-Dextran complex was
administered (dose according to a standard formula based on body weight
and hemoglobin deficit). Patients were monitored for 4 hours for adverse
reactions and asked to return at 6 weeks. The outcome variable was the
percentage of children demonstrating a significant ( ³3
g/dL) increment of Hb. Low- to moderate-grade fever was observed in
71.4%, allergic reactions (urticarial rash, itching, flushing and facial
puffiness) that responded to anti-histaminic drugs in 10%, local
reactions (soreness at infusion site) in 28.5%, and thrombophlebitis in
2.8% children. Once safety was established, enrolment of out-patients
began. A successful response ranging from 50% to 76.6% (stratified
according to baseline Hb levels) was observed in the children who
followed-up at 6 weeks (42.9%), and from 85.7% to 100% in the remaining
who followed-up at 12 weeks. A better response was noted in children who
had a lower pre-infusion Hb level in both groups. Authors concluded that
a single intravenous dose of iron-dextran countered the challenge of
non-compliance, showed faster hematological response, was less time
consuming and economical, and could be used safely in outpatient
settings for treatment of IDA.
Historical background and past knowledge: Iron
salts have been used therapeutically since more than 300 years. Earlier
use was based on the symbolic trans-cultural belief that iron was
associated with strength. The medicinal use of iron for treating ‘chlorosis’
(described as a condition characterized by a greenish-yellow
discoloration of the skin) by Syndenham in 1681 has been reported in the
literature [2]. In 1713, Lemery and Geoffy inferred that iron was a
constituent of blood by demonstrating its presence in the ash of burnt
blood [3]. Pierre Blaud revolutionalized iron therapy in the early
nineteenth century by developing iron pills (combinations of ferrous
sulfate and potassium carbonate) for ingestion [4]. Subsequently, many
other oral formulations emerged, but all of them had a common drawback
of being less efficacious in malabsorptive disorders, and were dependent
on compliance. The first parenteral preparation, Ferric hydroxide,
introduced in the early 20th century, was administered by both
subcutaneous and intramuscular routes, but was discontinued due to
severe toxic reactions. Subsequently, a supposedly safer intravenous
preparation – saccharated oxide of iron – was developed by Nissim in
1947, but subsequently was found to have serious adverse effects. The
preparation used in this study Iron-Dextran complex (Imferon) was
developed by Baird and Podmore in 1954. This had a surrounding
carbohydrate shell which controlled the release of free iron. Later it
also fell into disrepute due to anaphylactic reactions. The study by
Kango and Varudkar [1] also reported hypersensitivity reactions in 10%
of children.
The Present
Iron deficiency anemia remains one of the most common
causes of nutritional anemia globally, especially in low- and
middle-income nations. In India, the prevalence of nutritional anemia
remains high and largely unchanged over the last few decades despite the
implementation of many community-based strategies. The third National
Family Health Survey (NFHS) in 2005-06 reported 80% children under 2
years and 70% under 5 years as anemic, and NHFS-4 (2014-15) reported
variable prevalence of anemia in various states ranging from 23%
(Manipur) to more than 70% (Bihar) in children between 6 to 59 months
[5,6].
As the first line of treatment, oral iron is
relatively inexpensive, safe and efficacious. Till around a decade ago,
the oral dose of iron therapy in children was 4-6 mg/kg/day of elemental
iron [7]. The discovery that the duodenal absorptive capacity was
saturated by 25 mg was the basis for reducing the dose to 3 mg/kg /day
[8]. Currently there are many iron salt preparations (sulfate, fumarate,
succinate, gluconate, glutamate, lactate, ammonium citrate, amino-acid
chelates, polymaltose Complex, carbonyl, colloidal, and heme-based)
overwhelming the market, which makes it difficult for the pediatricians
to decide what to prescribe [9]. Adverse effects are gastrointestinal
side-effects (that can be minimized by administering in divided doses
between meals), staining of teeth (reduced by rinsing of mouth) and an
astringent taste (that varies among compounds). These side effects and
long duration of therapy often lead to non-compliance.
Indications for intravenous iron include conditions
that render oral iron therapy ineffective (ongoing blood loss, worm
infestation, malabsorptive syndromes and gastrointestinal cancer) and
the functional iron deficiency that arises from the increasing use of
erythropoiesis-simulating agents in patients with chronic kidney
disease. Currently used parenteral preparations are low molecular weight
(LMW) iron-dextran, iron sucrose and ferric gluconate. Recently, third
generation formulations (like ferumoxytol, ferric carboxymaltose and
iron isomaltoside 1000) have emerged, which are iron-carbohydrate
complexes that slow the release of iron resulting in more favorable
safety profiles.
Various programs have been initiated by the
Government of India with the common goal of clinically screening the
high-risk populations, and either providing prophylactic or therapeutic
supplemental iron. More recently, the National Iron Plus Initiative [10]
provides weekly/bi-weekly age-stratified iron and folic acid
supplementation to children, adolescents and women, irrespective of
their iron or hemoglobin status. With constant efforts from the
government and increasing sensitization of the community to the clinical
implications of iron deficiency, importance of prophylactic iron and
optimum nutrition; we will hopefully be able to see a uniform decline in
the prevalence of IDA nationwide by the time the next NFHS is conducted.
References
1. Kango RN, Varudkar BL. Single dose intravenous
iron infusion in treatment of iron deficiency anemia. Indian Pediatr.
1967;4:21-6.
2. Stockman R. The treatment of chlorosis by iron and
some other drugs. Br Med J. 1893;1:881-5.
3. Russell L, Haden MD. Historical aspects of iron
therapy in anemia. JAMA. 1938; 111:1059-61.
4. Blaud P. Sur les maladies chloropiques et sur un
mode de traitement specifique dones ces affections. Rev Med Fr Etrang.
1832;45:357-67.
5. International Institute of Population Sciences.
National Family Health Survey-3, 2005-06. IIPS: Mumbai, 2007.
6. International Institute of Population Sciences.
Key Findings From NFHS-4. Available from:
http://www.rchiips.org/nfhs/factsheet_nfhs-4.shtml. Accessed
December 10, 2016.
7. Glader B. Anemias of Inadequate production. In:
Kliegman RM, Jenson HB, Behrman RE, Stanton BF, editors. Nelson Textbook
of Pediatrics. 18th edition. New Delhi: Elsevier; 2008. p.2014-16.
8. Andrews NC. Disorders of Iron and Copper
Metabolism, the Sideroblastic Anemias, and Lead Toxicity In: Nathan DG,
Ginsburg D, Orkin SH, Look AT, editors. Nathan and Oski’s Hematology of
Infancy and Childhood. 8th edition. Philadelphia: WB Saunders; 2015.
p.344-81.
9. Nagpal J, Choudhury P. Iron formulations in
pediatric practice. Indian Pediatr. 2004; 41; 807-15.
10. Adolescent Division, Ministry of Health and
Family Welfare. Guidelines for Control of Iron Deficiency Anaemia.
National iron plus initiative 2013. New Delhi: National Rural health
Mission, MOHFW, 2013.
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