IRON DEFISIENSI ANEMIA IN PREGANANCY TIPE 1.doc

8/14/2019 IRON DEFISIENSI ANEMIA IN PREGANANCY TIPE 1.doc

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ABSTRACT

Nutritional iron-deficiency anaemia (IDA) is the most common disorder in the world,

affecting more than two billion people. The orld !ealth "rgani#ation$s global database on

anaemia has estimated a pre%alence of &' based on a regression-based analysis. ecent data

show that the pre%alence of IDA in pregnant women in industriali#ed countries is &*.' while

the incidence of IDA in de%eloping countries increases significantly up to + . Although oral

iron supplementation is widely used for the treatment of IDA, not all patients respond ade uately

to oral iron therapy. This is due to se%eral factors including the side effects of oral iron which

lead to poor compliance and lac of efficacy. The side effects, predominantly gastrointestinal

discomfort, occur in a large cohort of patients ta ing oral iron preparations. /re%iously, the use

of intra%enous iron had been associated with undesirable and sometimes serious side effects and

therefore was underutilised. !owe%er, in recent years, new type II and III iron comple0es ha%e

been de%eloped, which offer better compliance and toleration as well as high efficacy with a

good safety profile. In summary, intra%enous iron can be used safely for a rapid repletion of iron

stores and correction of anaemia during and after pregnancy.

1. Iron Deficiency in Women Nutritional

Iron deficiency is the most common deficiency disorder in the world, affecting more thantwo billion people worldwide, with pregnant women at particular ris . orld !ealth

"rgani#ation ( !") data show that iron deficiency anaemia (IDA) in pregnancy is a significant

problem throughout the world with a pre%alence ranging from an a%erage of &' of pregnant

women in industriali#ed countries to an a%erage of + (range 1+2*+ ) in de%eloping countries.

3urthermore, IDA not only affects a large number of women and children in the de%eloping

world, but is also considered the only nutrient deficiency that is significantly pre%alent in the

de%eloped world also. The number of patients with ID and IDA is o%erwhelming as more than 4

billion people, appro0imately 15 of the world$s population, are iron deficient with %ariable

pre%alence, distribution, and contributing factors in different parts of the world.

Iron deficiency affects more women than any other condition, constituting an epidemic public

health crisis. It is usually present with subtle manifestations and should be considered as a

chronic slowly progressing disease that is often underestimated and untreated worldwide despite


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se%eral warnings and awareness campaigned by the !". The high pre%alence of IDA in

women has substantial health conse uences with subse uent socioeconomic ha#ards, including

poor pregnancy outcome, impaired educational performance, and decreased wor capacity and

producti%ity. 6ecause of the magnitude and conse uences of iron deficiency anaemia in the

world, especially in women in their childbearing period, se%eral international conferences on

nutrition ha%e addressed this issue in order to reduce the pre%alence of iron deficiency in women

of childbearing age without ma7or success. The conse uences of IDA ha%e been widely studied.

!owe%er, there remains a lac of data about its effects on patient$s wellbeing.Targeted iron

supplementation, an iron-rich diet, or both, can impro%e iron deficiency. !owe%er, the %ariability

of bioa%ailable iron compounds limits its %alue against nutritional iron deficiency. Therefore,

laboratory measures of iron stores should be utilised to determine iron deficiency and monitor

therapy.This re%iew highlights the importance of IDA in pregnancy and discusses appropriatetreatment in order to a%oid serious complications of anaemia.

2. Iron Metabolism

The balance of iron metabolism in healthy indi%iduals predominantly reflects three

%ariables8 nutritional inta e, iron loss, and current demand. The nutritional iron inta e relates to

the amount of digested iron in food and the ability to absorb iron from the digesti%e tract. The

amount of iron absorbed depends largely on the presence or absence of pathology of the

gastrointestinal tract or a comorbidity (such as chronic inflammatory diseases) that may result in

e0pression of the iron regulatory proteins and a peptide called hepcidin, which ultimately bloc s

iron absorption. The main source of iron in humans comes from the destruction of erythrocytes

by macrophages of the reticuloendothelial system including the spleen or in other words, a

recycled internal iron supply. ecent studies ha%e shown how the human body up- and

downregulates iron absorption in response to changing iron status %ia intestinal and hepatic

proteins.

2.1. Iron Metabolism in Pre nancy

During pregnancy, fetal hepcidin controls the placental transfer of iron from

maternal plasma to the fetal circulation. hen hepcidin concentrations are low, iron

enters blood plasma at a high rate. hen hepcidin concentrations are high, ferroportin is


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internali#ed, and iron is trapped in enterocytes, macrophages, and hepatocytes. The daily

re uirement of e0ternal iron remains as little as between & to 9 mg daily :& ;. !owe%er,

more e0ternal iron is re uired to balance increased demand for iron especially with

physiological re uirements during growth, pregnancy, and lactation.This significant

increased demand for iron is re uired to de%elop the fetus and placenta in addition to

support mother$s blood %olume. 3urthermore, pregnant women are sub7ect to iron loss

during and after deli%ery. The total iron loss associated with pregnancy and lactation is

appro0imately &555 mg. Therefore the recommended daily dietary allowance for iron in

pregnancy is 4* mg instead of 9 mg in the adult nonpregnant population.


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apply for most patients. @easurement of both soluble transferrin receptor and serum

ferritin pro%ides a tool for accurate diagnosis of IDA. !owe%er, transferrin receptor is

not a well-standardi#ed test that can be reliably reproduced with high precision in most

laboratories worldwide. In the meantime, ferritin estimation is an easy automated test to

perform in most laboratories in the world howe%er, its use is limited in cases of

inflammation or infection as it is considered to be influenced by acute phase responses

and hence negati%ely influences its %alue in clinical interpretation of the test results.

The commonly a%ailable laboratory tests that determine iron status, namely,

serum iron, transferrin, total iron-binding capacity (TI6B), transferrin saturation, and

ferritin are widely used in worldwide clinical practice. Coluble Tf (sTf ) is present in

human plasma and is considered as a truncated form of the tissue receptor that e0ists as a

transferrin-receptor comple0 and therefore it reflects tissue iron deficiency. Another protein that plays a crucial role in iron metabolism is hepcidin, which is primarily made

by hepatocytes and secreted into the blood circulation. !epcidin is a small-si#ed

molecule composed of 4+-amino acid peptide, which is renally e0creted and therefore can

be detected and measured in urine. 3urthermore, hepcidins rapid e0cretion suggests that it

is regulation triggered at the le%el of production sites. !epcidin circulates in the

ferroportins plasma and responds to %arious stimuli that regulate iron stores and serum

iron. ecent studies demonstrate that hepcidin le%els are reduced in iron deficiency.

@easurement of blood or urine hepcidin le%els can be achie%ed by mass spectrometry

and immunoassays in serum, plasma, and urine.

!owe%er, the diagnostic utility of serum hepcidin in iron deficiency has not yet

been defined in clinical application. Ne%ertheless, hepcidin estimation seems a potentially

accurate test that reflects the actual iron status with less limitations.Altogether, new

technology such as hypochromic reticulocytes and reticulocyte haemoglobin testing,

sTf , and hepcidin ha%e reportedly been de%eloped with higher sensiti%ity, specificity,

reproducibility, and cost effecti%eness. This may offer a reliable screening tool for iron

deficiency in the future. It is worth noting that there are no specific data addressing the

difference of these mar ers in the pregnant %ersus nonpregnant population. !owe%er, in

principle, no essential change should occur in iron metabolism in the pregnant %ersus

non-pregnant population e0cept for the increased iron demand as discussed before.


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!.!. Current Strate y to Assess Iron Deficiency $urin Pre nancy

3ull blood count and @B %alue allowing the diagnosis of microcytic anaemia is

considered a good screening tool for IDA. !owe%er, in areas of the world where

haemoglobinopathies are pre%alent and these may be associated with microcytosis, iron

studies, in particular ferritin le%el remains the surrogate mar er for IDA. According to the

ferritin le%el, iron deficiency can be classified as se%ere ID when the ferritin le%el is =15

?g>< or mild-moderate ID if ferritin =&55 ?g>< and E15 ?g>< (there is a wide normal

range between 45 and ' ' and is laboratory and method specific). In cases of ele%ated

ferritin E&55 ?g>< with a concurrent anaemia, a reacti%e common cause such as infection

should be e0cluded and other causes of anaemia should be e0amined accordingly. "ther

complementary tests in iron studies such as serum iron, iron binding capacity, and

transferrin saturation are helpful in confirming the diagnosis of IDA.

(. )ral *ersus Intra*enous Iron for Treatment of Iron Deficiency in Women orRe%ro$ucti*e A e an$ Pre nancy

"ral iron therapy is the most widely prescribed treatment for iron deficiency anaemia,

howe%er, there are many issues that may pre%ent oral iron supplementation from successfully

managing IDA. 3or instance, many patients do not respond ade uately to oral iron therapy due to

difficulties associated with ingestion of the tablets and their side effects. Cide effects may play a

significant role in rates of compliance. 3urthermore, the presence of bowel disease may affect the

absorption of iron and thereby minimi#e the benefit recei%ed from oral iron therapy.

The side effects of oral iron therapy include gastrointestinal disturbances characteri#ed by

colic y pain, nausea, %omiting, diarrhoea, and>or constipation, and occur in about +5 of

patients ta ing iron preparations.

3urthermore, the most widely prescribed oral iron is mainly composed of ferrous salts.3errous salt is characteri#ed by low and %ariable absorption rates. Its absorption can be limited

by ingestion of certain foods as well as mucosal luminal damage. Therefore, ferric compounds

were introduced to a%oid such obstacles. !owe%er, these compounds are generally less soluble

and ha%e poor bioa%ailability.


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The usual recommended oral iron sulphate dose for the treatment of iron deficiency is at least 95

mg daily of elemental iron, which is e ui%alent to 4+5 mg of oral iron sulphate tablets (Abbott,

Australasia /ty


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gluconate reported. There were no life-threatening reactions recorded as a result of iron

gluconate infusion. "n the other hand, there were 1& fatalities among &F

allergic>anaphylactic reactions, which were reported for iron de0tran. The high incidence

of ad%erse reactions to iron de0tran, including serious ad%erse e%ents ha%e limited its

application in pregnancy. hilst the application of iron gluconate is considered safe, it

remains impractical in theory as it re uires multiple infusions with huge implications on

the often limited health system resources as well as on patientsG compliance. @ore

recently new forms of intra%enous iron that ha%e been de%eloped and are a%ailable, are

permitting treating physicians to safely administer relati%ely high doses of iron in a single

dose treatment.

(.2. Intra*enous *ersus )ral Iron T-era%y in Pre nancy

Intra%enous iron, including iron sucrose, was employed in randomised controlled

trials with impro%ed effecti%eness of intra%enous iron only or in combination with oral

iron, compared to oral iron only, based on !b le%els. A single I iron sucrose dose has

been reported to be associated with an increased incidence of thrombosis (F>'&, 44 ). In

contrast, small doses of intra%enous iron sucrose administered o%er a three-wee period

were without infusion-associated thrombosis, with intra%enous iron sucrose administered

in + daily doses to '+ pregnant women, also well tolerated. In the first study utilising

intra%enous iron sucrose, there was no significant difference in !b le%els at any time

measured at days 9, &+, 4&, and 15 and at deli%ery between intra%enous iron sucrose or

oral iron sulphate. In contrast, in another trial, with small doses of iron sucrose, there

was a significant difference in !b le%els in fa%our of the intra%enous iron sucrose group

as measured at 4 and ' wee s after administration of I iron and at deli%ery. !owe%er,

both trials administered I iron sucrose at the e0pense of a %astly greater effort from the

patients to present to the hospital for infusions in a short period of time as well as the

e0tra demands on hospital resources.

3urthermore, relati%ely older and established iron preparations such as

intra%enous iron polymaltose (3errosig, Cigma /harmaceuticals, Australia) demonstrated

a high safety profile in the treatment of IDA in both obstetric and general populations

without a ma0imum dose of treatment. The total dose of I iron polymaltose is


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calculated according to the patientGs body weight and entry !b le%el with reference to the

product guidelines as follows8 iron dose in mg (+5 mg per & m< constant factor (5.4') K iron

depot (+55). Iron polymaltose infusion showed high efficacy and safety profile during

pregnancy in the largest, recently published trial.

In this study, two hundred Baucasian pregnant women aged &9 years or abo%e

were identified with moderate IDA, defined as !b L&&+ g>< (reference range ( ) &452

& 5 g>< ( 152''5 g>


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5.5') in those women who had recei%ed I iron polymaltose %ersus oral iron. omen

with better iron status were less downhearted ( P H 5.55+) and less li ely to de%elop

postnatal clinical depression ( P H 5.551). This would indicate that it is worthwhile

considering the !b and iron status as a surrogate mar er for assessment of womenGs

wellbeing, not only during pregnancy but also during the postnatal period. !owe%er,

further studies are warranted to confirm and e0tend these findings.

3urthermore, recent reports demonstrate the feasibility of rapid iron polymaltose

infusion o%er 4 hours. !owe%er, a test dose of iron polymaltose (&55 mg) should be first

administered o%er 15 minutes, and premedication with antihistamine and>or low-dose

steroids is recommended prior to iron treatment for better toleration. A recent

comprehensi%e meta-analysis and re%iew by e%ei# et al. of the literature between &F*5

till present on different treatments for IDA of pregnancy showed paucity of good ualitytrials assessing clinical maternal and neonatal effects of iron administration in women

with IDA in spite of the high incidence and burden of disease associated with IDA.

During this period, there was only one prospecti%e randomi#ed trial of the effect of I

iron %ersus oral iron in the treatment of IDA during pregnancy that fulfils the stringent

independent re%iewer uality criteria.


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. Recent Data on Treatment of IDA in t-e Post%artum Perio$

The new preparations of intra%enous iron are see ing appro%al for use during pregnancy

in phase II and III clinical trials from the authorised organisational bodies in Murope and the

CA. Ne%ertheless, they can be potentially used currently in the non-pregnant female populationfor the treatment of postpartum, pre-further, and postmenopausal iron deficiency anaemia

according to the regional health authority appro%al.

Table 1

ecently a%ailable intra%enous (I ) iron preparations.

Name of the IV ironpreparation

Status ofregistration

Indications Testdose

Duration of

infusion

Max dosein singleinfusion

Ferumoxytol(Feraheme, AMAGPharmaceuticals, Inc.,USA)

FDA appro e!

"reatment o#iron$!e#iciencyanaemia in a!ultpatients %ith&'D

one * minute +* m-

Ferric car oxymaltose(Ferin/ect, 0i#orPharma, Glatt ru--,S%it1erlan!)

Appro e! in2urope,FDA$appro al issou-ht

"reatment o#iron$!e#iciencyanaemia in a!ultpatients

one*+

minutes

3 m-45-%ith max

!ose o#* m-

Iron isomaltosi!e(MonoFer,Pharmacosmos A4S,6ol ae5, Denmar5)

Appro e! in2urope FDA$appro al issou-ht

"reatment o#iron$!e#iciencyanaemia in a!ultpatients %ith&'D

one7

minutes

o max!ose -i en

at rate o#3 m-45-

3DA, 3ood and Drug Administration BOD, chronic idney disease @a0, ma0imum. No a%ailable data in pregnancy howe%er, if the benefit of treatment is 7udged to outweigh the

potential ris to the fetus, the treatment should be confined to second and third trimester of

pregnancy. M0tended appro%al is sought.


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In a randomised trial to assess safety and efficacy of intra%enous ferric carbo0ymaltose in

the treatment of postpartum IDA, 44* women were assigned to I ferric carbo0ymaltose with

&555 mg ma0imum dose (up to 1 wee ly doses) %ersus &&* women who recei%ed oral ferrous

sulphate &55 mg twice daily. Intra%enous iron carbo0ymaltose was as effecti%e as oral ferrous

sulfate with no statistically significant differences between groups at any time point despite the

shorter treatment period and a lower total dose of iron (mean &.1 g I iron %ersus & .9 g oral

iron). 3urthermore, in the I iron carbo0ymaltose group, the increases in ferritin le%els were

significantly greater than in the ferrous sulphate ( P = 5.555&) indicating a successful repletion of

iron stores and accessibility for erythropoiesis.

In a multicenter randomi#ed, controlled study, 4F& women directly after deli%ery with

haemoglobin L&55 g>< were randomi#ed to recei%e &555 mg I iron carbo0ymaltose (&'1

women), repeated wee ly to a calculated replacement dose (ma0imum dose 4.+ g), or ferroussulfate (&'9 women) 14+ mg orally three times daily for wee s (total dose '5.F g). 3erric

carbo0ymaltose-treated women achie%ed a haemoglobin E&45 g>< in a shorter period of time

with a sustained haemoglobin E&45 g>< at day '4. 3urthermore, the achie%ed haemoglobin rise of

P15 g>< was significantly more rapid in the I iron group than the oral group in achie%ing higher

serum ferritin le%els. Drug-related ad%erse e%ents occurred less fre uently with ferric

carbo0ymaltose. In a phase 1 randomised trial &*' women who recei%ed I ferric

carbo0ymaltose with a mean total dose of &.' g %ersus &*9 women who recei%ed 14+ mg ferrous

sulfate three times daily for wee s (total dose '5.F g) were assessed. /atients assigned to I

ferric carbo0ymaltose achie%ed a haemoglobin rise E45 g>< faster than the oral iron group (*

days compared with &' days in the oral iron group, P = 5.55&). The I iron group significantly

achie%ed a haemoglobin rise E15 g>< at any time (9 .1 compared with 5.' in the oral iron

group, P = 5.55&), and were more li ely to achie%e a haemoglobin E&45 g>< (F5.+ compared

with 9. , P = 5.55&). In the meantime, there were no serious ad%erse drug reactions in both

groups.

In a large randomi#ed, controlled phase 1 multicentre trial, '** women with IDA and

hea%y uterine bleeding were assigned to recei%e either I ferric carbo0ymaltose (415 women)

with a ma0imum dose of &555 mg repeated wee ly to achie%e a total calculated replacement

dose, or 14+ mg of oral ferrous sulphate ( + mg elemental iron) three times daily for wee s

with a total dose of '5.F g in 44 women. Twenty-one patients did not recei%e the assigned


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treatment in this study. About 94 of the I iron arm achie%ed haemoglobin rise P45 g>< %ersus

4 in the oral iron P = 5.55&. omen who achie%ed a haemoglobin rise P15 g>< were +1 in

the I iron group %ersus 1 in the oral iron group ( P = 5.55&). Also, more women (*1 )

achie%ed normal haemoglobin E&45 g>< in the I iron group compared to +5 in the oral iron

group ( P = 5.55&). There were no serious ad%erse drug e%ents. This trial demonstrated that

patients with IDA due to hea%y uterine bleeding who recei%ed I iron carbo0ymaltose, are more

li ely to ha%e normal haemoglobin with replenished iron stores.

Altogether, the new intra%enous iron preparations represent a medical re%olution in

effecti%e, rapid, and safe iron repletion in the management of iron deficiency anaemia. This will

positi%ely reflect on the treatment of IDA in different populations by application of a single high-

dose intra%enous iron treatment with effecti%e subse uent repletion of iron stores and hence

impro%ement of sub7ecti%e and ob7ecti%e outcomes of the IDA. Although iron deficiency is a precursor of IDA, many clinical studies treat it similarly to IDA.

/. A*oi$in Bloo$ Transfusion

In the case of se%ere IDA, a blood transfusion has been the traditional efficient approach

to correct anaemia, especially if patients did not respond to oral iron therapy or when a rapid

correction of anaemia is clinically re uired. Although there is a lac of data regarding thea%oidance of blood transfusion during pregnancy, a recent trial in%estigating treatment of IDA

with oral %ersus I iron in pregnancy demonstrated that none of both treatment arm participants

recei%ed blood transfusion for correction of anaemia during pregnancy. !owe%er two patients

(5.F ) in the oral iron arm recei%ed blood transfusion in the postpartum period.

Burrently, the de%elopment of new intra%enous iron formulations that offer higher doses

in a single administration has pro%ided the treating physicians with the opportunity to employ

intra%enous iron as an effecti%e, rapid, and safe treatment for IDA, a%oiding the use of blood

transfusion with its nown ha#ards. There is increasing e%idence-based research that supports the

safety and efficacy of I iron in IDA. There is also increasing e%idence for inade uacy of oral

iron in terms of ad%erse effects, lac of compliance as well as lac of absorption and slow and

often uestionable effect in IDA patients.


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A common re uirement across the range of clinical situations is the need for safe, effecti%e,

higher, and less fre uent doses to achie%e optimal clinical outcomes. The ma7or goals of such

strategies include o%erall cost reduction, relief to o%erstretched health system(s), impro%ed

patient con%enience, impro%ed compliance, preser%ation of %enous access, and reduced blood

transfusion. This will ultimately reduce the demand for blood transfusions, especially in the case

of short supply. 3urthermore, some of the new iron preparations such as ferric carbo0ymaltose

and iron isomaltoside do not re uire a test dose and therefore, ease the application of intra%enous

iron in a timely and cost-effecti%e fashion. This certainly will enhance the use of intra%enous iron

in clinical practice.

0. Summary

The !" has recognised the problem of IDA in the general population as the most debilitatingnutritional deficiency worldwide in the twenty-first century, noting women to be at particularly

high ris . Cuch a problem, if ignored and not addressed properly, can ha%e a de%astating effect

on entire populations with serious conse uences. Therefore, the use of intra%enous iron should

be considered as an effecti%e, rapid, and safe treatment option in some clinical situations. An

algorithm for the treatment of iron deficiency anaemia in pregnancy and postpartum period based

on different prospecti%e randomised trials is proposed in. The intra%enous iron is increasingly

employed to a%oid or reduce the demand for blood transfusions or for effecti%e rapid repletion of

iron stores. Treatment options for IDA should consider the recently de%eloped intra%enous iron

formulations, which are considered a milestone in the management of IDA ( 3igure &).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389687/figure/fig1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389687/figure/fig1/


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i ure 1

/roposed treatment for anaemia in pregnancy and postpartum period based on different

randomi#ed and non-randomi#ed trials

"%erall, the de%eloping world is most %ulnerable, especially the poorest and the least

educated populations that are disproportionately affected by iron deficiency, and therefore ha%e

the most to gain by eradication of IDA. 3urthermore, awareness of the magnitude and scale of

the IDA problem during pregnancy and also in the non-pregnant female population will help

health practitioners in recognising the most appropriate methods of diagnosis and treatment,which are crucial in o%ercoming such a de%astating health problem. A consensus guideline set by

world e0perts in managing IDA in women and in the general population, incorporating new

intra%enous iron therapies with a global approach of the health and economy aspects of IDA,

should be considered. It is worthwhile considering a uni%ersal comprehensi%e IDA management

algorithm that offers different e%idence-based treatment options and addresses local conditions.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389687/figure/fig1/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389687/figure/fig1/


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!owe%er, de%eloping countries with pre%alent IDA often ha%e lac of resources. Therefore, it is

crucial to adapt a %iable programme with the aim of utilising the local a%ailable resources

effecti%ely. /erhaps prioritising the treatment of IDA and increasing the awareness among the

community of such a chronic de%astating problem of paramount importance is the ey for

success and sustainability of such a programme. Bertainly, successful eradication of IDA will

result in huge benefits for community health and producti%ity with a ma7or health sa%ing not

only in the de%eloping world but also in de%eloped nations.


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References

&. orld !ealth "rgani#ation : !"; The /re%alence of Anaemia in omen8 a tabulation

of a%ailable information. Di%ision of 3amily !ealth, @aternal !ealth and Cafe

@otherhood /rogramme, Di%ision of !ealth /rotection and /romotion, Nutrition/rogramme !", 4nd ed. orld !ealth "rgani#ation, Qene%a, Cwit#erland, &FF4.

4. ABB>CBN ( nited Nations Administrati%e Bommittee on Boordination>Ctanding

Bommittee on Nutrition) 3ifth report on the world nutrition situation8 Nutrition for

impro%ed de%elopment outcomes. Qene%a, Cwit#erland, accscnRwho.org, 455'.

1. @aberly Q3, Trowbridge 3

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IRON DEFISIENSI ANEMIA IN PREGANANCY TIPE 1.doc