August 2007 - Volume 1, Issue 4

STEPS TOWARD EBM/ GUIDELINE FOR IRAQI MEDICAL AND NURSING SCHOOLS: PREVENTION AND TREATMENT OF IRON DEFICIENCY ANAEMIA IN IRAQI PREGNANT WOMEN

Dr Thamer.K.Yousif /MBChB/FICMS/MsC Dr. Taghreed k. AI-Haidari (CABOG) Dr Emil N Azzo

1. PURPOSE AND SCOPE

Anaemia is the commonest medical disorder in pregnancy and has a varied prevalence, aetiology and degree of severity in different populations, being more common in developing countries. Iron deficiency anaemia is the commonest nutritional deficiency in pregnancy followed by folate deficiency. Over 50% of pregnant women in developing countries suffer from iron deficiency anaemia, and in these countries anaemia is frequently severe and can be expected to contribute significantly to maternal mortality and morbidity.

The aim of this guideline is to assess the evidence regarding the prevention and management of anaemia in pregnancy, particularly iron deficiency anaemia. It assesses also the advisability of routine iron supplementation during pregnancy and the adolescent girls who soon will get pregnant. The objective of this guideline is to reduce the maternal and perinatal morbidity and mortality rates.

2. IDENTIFICATION AND ASSESSMENT OF EVIDENCE

The Cochrane Database and Medline were searched using the terms - anaemia; iron deficiency; pregnancy.

Where possible, recommendations are based on, and explicitly linked to, the evidence that supports them. Areas lacking evidence are highlighted and annotated as 'Good Practice Points'.

3. BACKGROUND

Iron deficiency is defined as a condition in which there are no mobilizable iron stores, causing a compromised supply of iron to tissues (including the red blood cell). The more severe stages of iron deficiency cause anaemia. Iron deficiency is estimated as being 2-5 times more common than iron deficiency anaemia.

Iron deficiency anaemia is the main cause of microcytic hypochromic anaemia, in which mean cell volume (MCV), mean cell haemoglobin (MCH) and mean cell haemoglobin concentration (MCHC) are all reduced, and the blood film shows microcytic hypochromic red cells. Haemoglobin is more than 2 standard deviations below the mean for a population of healthy people of the same age and sex. This represents a level of less than 13 g/dl for men and less than 12 g/dl for women (less than 11 g/dl in pregnancy).

In developed countries it is most commonly due to blood loss: Menorrhagia in premenopausal women; gastrointestinal bleeding in men and postmenopausal women; other causes are iron-deficient diet and malabsorption (e.g. celiac disease).

In developing countries several factors may combine: Poor diet; Increased requirements (e.g. frequent pregnancy); blood loss due to menorrhagia and gastrointestinal bleeding (e.g. hookworm, trichuriasis, amoebiasis and schistosomiasis); and haemolysis due to malaria or haemoglobinopathies 1,2,3.

How common is it?

Iron deficiency anaemia is the most common type of anaemia in all countries. It affects up to 30% of the world's population, with prevalence in developed countries of about 8%. The most common cause in developing countries is hookworm infestation; it is estimated that a billion people are infected worldwide4.

It occurs during pregnancy in 23% of pregnant women in developed countries, and 52% of pregnant women in developing countries 1,2,.3.

4. HOW CAN THE DIAGNOSIS BE MADE?

4.1 Which symptoms may be present?

Symptoms may be few if the anaemia develops gradually, but are typically: Fatigue; Breathlessness; palpitations; headache; tinnitus; unusual dietary cravings (pica).

4.2 Which signs may be present?

Pallor of eyelids, tongue, nail beds and palms; atrophic glossitis and angular cheilosis (also signs of megaloblastic anaemia and riboflavin deficiency, respectively); brittle, longitudinally-ridged, flaking nails and koilonychia (spoon-shaped nails) in chronic cases; dysphagia (due to an oesophageal web - Plummer-Vinson syndrome); hair loss; splenomegaly; tachycardia, murmurs, cardiac enlargement, and heart failure (if severe anaemia).

4.3 Which investigations are useful in the diagnosis of iron deficiency anaemia?

Full blood count: Low haemoglobin (Hb) concentration, less than 12 g/dl for women;
low MCV, MCH, and MCHC (mean cell volume, mean cell Hb, mean cell Hb concentration) ;
reticulocyte count low for the degree of anaemia; there may be a mild thrombocytosis (raised platelet concentration).\

Blood film: microcytic hypochromic red cells, with occasional target cells and pencil-shaped poikilocytes.

Serum ferritin level: low (an indicator of reduced body-iron stores). However, as ferritin is an acute-phase protein, levels may be normal or elevated in infective, inflammatory or malignant disease despite iron deficiency. Serum ferritin level is also increased by excessive alcohol consumption.

Erythrocyte protoporphyrin: increased with iron deficiency, and correlates well with a reduced ferritin level. However, levels can also be increased by infection, inflammation, lead poisoning, and haemolytic anaemia.

Serum iron and transferring (total iron-binding capacity [TIBC]): reduced serum iron and increased transferring, with a consequent reduction in transferring saturation. However, there is a marked diurnal variation, and a considerable overlap between iron-deficient and normal people.

Serum transferring receptors: a relatively new test that is not widely available. Rose in iron deficiency. Its major advantage is that it is not affected by infection or inflammation, and does not vary with age, sex or pregnancy. It is, however, elevated by increased red-cell production or turnover (e.g. haemolytic anaemia). There is a lack of standardization of the different methods available.

Bone-marrow aspiration: rarely needed, but will show absent bone-marrow iron stores.

4.4 How are these investigations affected by pregnancy?

Full blood count: in pregnancy a physiological reduction in Hb concentration occurs, which does not represent anaemia. There is an increase in red-cell mass and plasma volume; the plasma volume increases more than the red-cell mass, causing the Hb reduction.
There is a lack of agreement on the Hb level for the diagnosis of anaemia during pregnancy:

The World Health Organization (WHO) defines anaemia as an Hb level less than 11 g/dl throughout pregnancy (this is the most widely used definition worldwide).

The American Centers for Disease Control and Prevention modified this by trimester of pregnancy: First-trimester Hb level less than 11 g/dl; second-trimester Hb level less than 10.5 g/dl; third-trimester Hb level less than 11 g/dl.

4.5 What else might it be?

Other anaemias that may be mistaken for iron deficiency anaemia:
Anaemia of chronic disorders: inhibition of release of iron from macrophages to red-cell precursors results in a normocytic or mildly microcytic anaemia (serum iron and total iron-binding capacity [TIBC] both reduced, serum ferritin normal or raised). It does not respond to iron therapy.

Other causes of impaired haemoglobin synthesis and microcytic anaemia: Sideroblastic anaemia -refractory hypochromic anaemia, with ring sideroblasts and increased iron in the bone marrow.

Thalassaemia trait (alpha or beta) - a hypochromic microcytic anaemia, the mean cell volume tends to be particularly low for the degree of anaemia 9,10.

5. HOW SHOULD WE MANAGE THE PREGNANT WOMEN WITH IRON DEFICIENCY ANAEMIA?

5.1 What are Complications and prognosis?

Complications: Increased morbidity from infectious disease, due to adverse effects on the immune system; heart failure; angina. Complications specific to pregnancy: Increased maternal mortality; increased prenatal and perinatal infant mortality; increased prematurity; and infants born to iron deficient mothers require more iron than is supplied by breast milk, and at an earlier stage, to avoid iron deficiency in the infant 3.

5.2 How can search for the cause of iron deficiency anaemia?

Difficulties in diagnosis may occur when more than one type of anaemia is present. A dimorphic blood picture may be present, and additional investigations such as vitamin B12 and folate levels may help diagnose the different causes of anaemia.

A reason for iron deficiency should always be sought. History taking should attempt to determine whether gastrointestinal (GI) blood loss, menstrual loss, malabsorption, or nutritional deficiency is likely. Drug history of non-steroidal anti-inflammatory use is particularly important, as this might point to possible GI bleeding.

In developed countries dietary deficiency, by itself, is rarely a cause of iron deficiency anaemia unless there are increased physiological demands for iron (e.g. during infancy, adolescence, pregnancy, lactation, and in menstruating women).

But iron deficiency anaemia tends to be 3-4 times higher in non-industrialized than in industrialized countries.

Both upper and lower GI investigations should be considered, because of the high incidence of pathology (except possibly in premenopausal women with heavy periods).

A study of people with iron deficiency anaemia and no obvious cause from history found that 84% had a GI cause of blood loss: 28% due to upper GI pathology alone, 27% due to lower GI pathology alone, and 29% due to dual pathology 11.

Coeliac disease has been found to be the cause in 2-3% of people presenting with iron deficiency anaemia.

The definitive test for coeliac disease is a small-bowel biopsy; these should therefore be taken during upper GI endoscopy 12.

Haematuria is an uncommon cause of iron deficiency anaemia and is usually clinically obvious.
Stool examination should be considered in people with a history of travel to the tropics, in order to exclude hookworm infestation, which is the commonest cause of iron deficiency anaemia worldwide 1,9.

5.3 How could treat iron deficiency anaemia during pregnancy?

Not enough evidence to know the best way to treat iron deficiency anaemia in pregnancy. Recommendations for the treatment of anaemia are currently based on expert opinions rather than systemic reviews of randomised clinical trials.

There is controversy around the significance for women and there babies of the physiological haemodilution of pregnancy and at what level of haemoglobin women and babies would benefit from iron treatment, some studies suggest that the physiological decrease in haemoglobins associated with improve outcomes for the baby, whilst others have identified adverse long term outcomes for the baby 13.

While an Indian study of the maternal and perinatal outcome in varying degrees of anaemia has found that: Mild anaemia fared best in maternal and perinatal outcome while severe anaemia was associated with increased low birth weight babies, induction rates, operative deliveries and prolonged labour 14.

The risk factors for preterm delivery and intrauterine growth retardation are quite similar, although relatively little is understood about the influence of maternal nutritional status on risk of preterm delivery. Several potential biological mechanisms were identified through which anaemia or iron deficiency could affect pregnancy outcome. Anaemia (by causing hypoxia) and iron deficiency (by increasing serum nor epinephrine concentrations) can induce maternal and foetal stress, which stimulates the synthesis of corticotrophin-releasing hormone (CRH). Elevated CRH concentrations are a major risk factor for preterm labour, pregnancy-induced hypertension and eclampsia, and premature rupture of the membranes. CRH also increases foetal cortisol production, and cortisol may inhibit longitudinal growth of the foetus. An alternative mechanism could be that iron deficiency increases oxidative damage to erythrocytes and the faetoplacental unit. Iron deficiency may also increase the risk of maternal infections, which can stimulate the production of CRH and are a major risk factor for preterm delivery 15.

In spite of that, it is widely accepted and is a common practice to treat with iron-replacement therapy in pregnancy and is recommended when iron deficiency anaemia is detected. But whether to treat pregnant women with mild anaemia remains controversial.

5.3.b Which treatment is recommended?

Management involves treatment of the underlying cause and oral iron-replacement therapy (e.g. with ferrous sulphate 200 mg three times a day), taken an hour before food or on an empty stomach, if oral iron is not well tolerated consider: taking with or immediately after food but absorption is reduced in such cases by about 40%, and reducing the daily dose once or twice a day - one tablet taken consistently is better than total rejection of a higher dose because of unacceptable adverse effects 3,19.

Adverse effects of oral iron are a common cause of non-compliance. They include epigastric discomfort, nausea, diarrhoea, and constipation.

Although vitamin C (e.g. in citrus fruits and fruit juices) has been shown to increase oral iron absorption, high-dose vitamin C supplements should not be given with iron as the combination frequently causes epigastric pain 3.

Failure to respond to treatment is usually due to poor compliance. It can also be due to continuing excessive blood loss, associated inflammatory disease, malabsorption, a combined deficiency state, or another cause of hypochromic anaemia such as sideroblastic anaemia or thalassaemia trait.

Intramuscular or intravenous iron-replacement therapy might be considered if the person is completely unable to tolerate oral iron, or if losses exceed the amount that can be absorbed orally. However, this therapy should rarely be used outside a specialist setting. The rise in Hb is no faster than with effective oral therapy. Injections are painful, and there is a risk of anaphylaxis.

Blood transfusion should usually be avoided. Someone with profound anaemia who has severe symptoms (e.g. severe heart failure) may require transfusion. This should be done with extreme caution, under diuretic cover, owing to the risk of precipitating or worsening heart failure 1,2,3,9.

The risk of maternal heart failure is increased at haemoglobin levels less than 7 g/dl, and discussion with an Obstetric unit is strongly recommended if the level is this low 3,6.

In addition it runs the risk of possible parasitic or viral infection transfusions such as HIV and hepatitis, despite screening. There is also possibility of bovine spongioform encephalitis (BSE) and as yet unknown viral infection 13.

In some countries, iron supplementation is routinely given with folic acid during the second half of pregnancy 20.

5.4 What follow-up is recommended?

Check the full blood count 2-4 weeks after starting iron (earlier if symptoms are sever) in order to assess response to treatment. Recheck the full blood count thereafter using clinical judgement 21.

Haemoglobin (Hb) should rise by about 0.1-0.2 g/dl per day (about 2 g/dl every 3 weeks).
Iron replacement should be continued for 3 months once the Hb has normalized, in order to replenish iron stores 3, 22.

5.5 What other advice should give the patient?

Oral iron frequently causes stool to become black and it reduces the absorption of tetracyclines, quinolones, bisphosphonates, and zinc. The absorption of oral iron is reduced by zinc, magnesium salts (e.g. in antacids), calcium (e.g. in milk and dairy products), tannins (e.g. in tea, coffee, and cocoa), and phytates (present in cereal grains, legumes, nuts, and seeds) 3.

6. HOW CAN PREVENT IRON DEFICIENCY ANAEMIA IN PREGNANCY?

6.1 The role of iron supplement?

Prophylactic iron supplementation for all pregnant women is not recommended in the UK. Likewise it is not recommended in Australia, Canada, and New Zealand; it is however recommended in France and the USA 20.

That is true for women in developed countries that are generally clinically healthy and have access to adequate nutrition, the benefits of iron supplementation are unclear, and there may be risks. Thus, a better "conservative" approach may be that such women do not require routine iron supplementation during pregnancy 24.

But in developing countries anaemia in pregnancy is high and this is attributed to poor nutrition and the high incidence of disease and it can associated with increasing problems including postpartum haemorrhage which is a major contributor to maternal mortality in many developing countries 24.

6.2 How much iron is needed:

In developing countries, supplementation should be initiated as soon as possible after conception because of the high prevalence of iron deficiency at the onset of pregnancy 29.

6.3 What other factors looked for in the prevention?
6.3.a What is the role of hookworm infection in iron deficiency anaemia?

6.3.b What is the role of diets in the prevention?

An assessment of dietary intake is required to aid in the development of relevant dietary guidelines for those population.

6.3.c What is the role of iron supplementation during adolescence?

Iron deficiency anaemia is prevalent among adolescent girls because the growth spurt and onset of menstruation increase iron requirements. Women who conceive during or shortly after adolescence are likely to enter pregnancy with low or absent iron stores or IDA.

Iron supplementation during adolescence is one of the new strategies advocated to improve iron balance in pregnancy.

Although supplementation will correct anaemia and increase iron stores in girls, the positive effect on iron status will be temporary if their diets do not contain adequate bio available iron. But iron status in early pregnancy may be improved if the period of supplementation continues up to the time of conception.

Supplementation before pregnancy should be viewed as an additional strategy to supplementation during the second and third trimesters 32.

A considerable amount of information remains to be learned about the benefits of maternal iron supplementation on the health and iron status of the mother and her child during pregnancy and postpartum. Current knowledge indicates that iron deficiency anaemia in pregnancy is a risk factor for preterm delivery and subsequent low birth weight, and possibly for inferior neonatal health. But data are inadequate to determine the extent to which maternal anaemia might contribute to maternal mortality and even for women who enter pregnancy with reasonable iron stores, iron supplements improve iron status during pregnancy and for a considerable length of time postpartum, thus providing some protection against iron deficiency in the subsequent pregnancy. Mounting evidence indicates that maternal iron deficiency in pregnancy reduces foetal iron stores, perhaps well into the first year of life. This deserves further exploration because of the tendency of infants to develop iron deficiency anaemia and because of the documented adverse consequences of this condition on infant development 33.

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APPENDIX

The evidence used in this guideline was graded using the scheme below and the recommendations formulated in a similar fashion with a standardised grading scheme.

CLASSIFICATION OF EVIDENCE LEVELS

Ia Evidence obtained from meta-analysis of randomised controlled trials.
Ib Evidence obtained from at least one randomised controlled trial.
IIa Evidence obtained from at least one well-designed controlled study without randomisation.
IIb Evidence obtained from at least one other type of well-designed quasi-experimental study.
III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.
IV Evidence obtained from expert committee reports or opinions and/or clinical experience of
respected authorities.

GRADES OF RECOMMENDATIONS

A	Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels Ia, Ib)

B	Requires the availability of well controlled clinical studies but no randomised clinical trials on the topic of recommendations. (Evidence levels IIa, IIb, III)

C	Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV)

GOOD PRACTICE POINT

G	Recommended best practice based on the clinical experience of the guideline development group.