Introduction

In more than 80% of countries in the world, the prevalence of anaemia in pregnancy is >20%, and is a major public health problem. More than 56 million women are estimated to be affected globally, approx 32 million of them being from Asia. The global prevalence of anaemia in pregnancy is estimated to be approximately 41.8%, varying from a low of 5.7% in the USA to a high of 75% in Gambia ( Table 1 ). Some women are anaemic prior to the index pregnancy and others become progressively anaemic during pregnancy. In the USA, anaemia in pregnancy was estimated to increase from 1.8% to 8.2% and 27.4% in the first, second and third trimesters respectively.

Definition

During pregnancy, anaemia is defined as a haemoglobin concentration (Hb) <110 g/L at sea level, which is two standard deviations below the mean Hb expected. Consequent to the physiological haemodilution which is maximal during 20–24 weeks of gestation, the Hb varies with the period of gestation. The Hb increases with high altitudes and in those who smoke. In those who smoke, the decrease in plasma volume and increase of Hb, both of which adversely affects fetal growth, are adaptations to increased carboxyhaemoglobin which has no oxygen carrying capacity. Quitting smoking can reduce the Hb to its original levels within five years. Although the Hb can increase in pregnant women who smoke, a decrease of Hb with smoking and the use of smokeless tobacco have been shown. Genetic differences may also affect the Hb. A haematocrit of <33% could also be considered for the diagnosis of anaemia in pregnancy. Severe anaemia in pregnancy (Hb < 70 g/L) requires urgent medical treatment and Hb <40 g/L is an emergency carrying a risk of congestive cardiac failure, sepsis and death.

Definition

During pregnancy, anaemia is defined as a haemoglobin concentration (Hb) <110 g/L at sea level, which is two standard deviations below the mean Hb expected. Consequent to the physiological haemodilution which is maximal during 20–24 weeks of gestation, the Hb varies with the period of gestation. The Hb increases with high altitudes and in those who smoke. In those who smoke, the decrease in plasma volume and increase of Hb, both of which adversely affects fetal growth, are adaptations to increased carboxyhaemoglobin which has no oxygen carrying capacity. Quitting smoking can reduce the Hb to its original levels within five years. Although the Hb can increase in pregnant women who smoke, a decrease of Hb with smoking and the use of smokeless tobacco have been shown. Genetic differences may also affect the Hb. A haematocrit of <33% could also be considered for the diagnosis of anaemia in pregnancy. Severe anaemia in pregnancy (Hb < 70 g/L) requires urgent medical treatment and Hb <40 g/L is an emergency carrying a risk of congestive cardiac failure, sepsis and death.

Pathophysiology

Nutritional Iron Deficiency (ID), accounting for more than half the cases in non-malarial areas, is the commonest cause of anaemia during pregnancy ( Table 2 ). A woman could progress from a healthy non-anaemic iron replete status, to a state of low iron stores (latent ID), to ID with no anaemia and finally to a clinical iron deficiency anaemia (IDA). Therefore the prevalence of ID is always greater and could be 2–2.5 times the prevalence of IDA. ID per se (without IDA) can lead to functional impairment at tissue level.

A 55 kg pregnant woman is estimated to need approximately an additional 1000 mg of iron over the whole pregnancy. Iron requirements as well as iron absorption are very low in the first trimester, but progressively increase to reach a maximum in the third trimester. It has been estimated that the daily iron requirements of a 55 kg pregnant woman increases from approximately 0.8 mg in the first trimester to 4–5 mg during the second trimester and >6 mg in the third trimester.

Pre-conceptual low iron stores are associated with an increased risk of anaemia during the latter half of pregnancy as well as adverse perinatal outcomes. Ideally in order to meet the additional iron requirements of pregnancy a woman should have at least 300 mg of iron stores prior to conception. Even a European type diet with high bio availability of iron, and the increased iron absorption during the latter half of pregnancy, may not be able to meet the additional requirements of iron for the pregnancy. In the USA, >50% of women in reproductive age (WRA = 15–45 years) were found to have <300 mg of iron stores, highlighting the need to ensure adequate iron nutrition prior to pregnancy even in well-resourced settings.

Diagnosis

Tiredness, weakness, lethargy, irritability and decreased work tolerance are the well known clinical presentations of anaemia. However the majority of women with mild to moderate anaemia are asymptomatic. Rarely, a woman with severe anaemia may present with glossitis, angular stomatitis, ankle oedema and early evidence of congestive cardiac failure and may require emergency treatment. Multiple pregnancy, teenage pregnancy and high parity are associated with increased risk of anaemia in pregnancy. Reduced inter-pregnancy non-lactating intervals may also be associated.

Although Hb <110 g/L is the accepted criterion for the diagnosis of anaemia in pregnancy, considering physiological haemodilution, altitude, smoking and ethnicity, certain adjustments to this value have been suggested, although adjustments based on altitude may not be justified. Hb and the other haematological indices being defined for individual populations considering the above factors, their iron stores and patterns of diet intake, and reducing the diagnostic level in a pregnant woman to Hb <100 g/L in the first and second trimesters, have also been suggested. However, a cut off level of 110 g/L is needed to compare prevalence and effects in different communities, regions and countries.

Confirmation of ID in pregnancy is difficult. Detection of stainable iron as haemosiderin in bone marrow aspirates excludes ID, but its absence is not proof of ID. Serum ferritin (SF), transferrin saturation and bone marrow iron decrease over the course of pregnancy, even in women receiving high daily iron supplements. Serum transferrin receptor (sTfR) levels of >8.5 mg/L indicate ID. A sTfR/log10SF ratio (sTfR-SF Index) >1.8 indicates ID in non-pregnant adults but is not as effective in pregnancy. As sTfR assays are expensive and not freely available, a SF <12 μg/L is frequently used to diagnose ID. SF increases in the presence of infection or inflammation. Although assessment of C-reactive protein may not help, use of higher cut off levels of SF e.g. <30 μg/L or <50 μg/L may be indicated in the presence of chronic inflammation. Although a combination of Hb, SF, sTfR and sTfR-SF Index would enable the diagnosis of IDA, this would not be possible in low resource settings.

In IDA, a Full Blood Count should characteristically show: Mean Corpuscular Volume (MCV) <80 fl, Mean Corpuscular Haemoglobin Concentration <30%, Mean Corpuscular Haemoglobin <30 μg/L and Red Cell Count <4.1 mil/mm ³ . However haematological indices are altered during pregnancy. A combination of iron deficient microcytes, folate or B ₁₂ deficient macrocytes and pregnancy and/or iron supplementation induced macrocytes would lead to a polymorphic blood picture. The haematological indices, which are average quantities, will not indicate this. Therefore in communities where nutritional anaemia is common, the examination of a peripheral blood film is important, and it supplements the Full Blood Count. If the anaemia is due to ID, an increase of 10 g/L of Hb and or 3% increase in haematocrit will be seen after six weeks of oral iron supplements.

If the MCV is >100 fl, and the peripheral blood picture suggests the possibility of folate or Vitamin B ₁₂ deficiency, with the assistance of a Haematologist, appropriate investigations should be carried out to establish the diagnosis. Measurement of serum and red cell folate levels, bone marrow examination, and a therapeutic trial with high dose folate (5 mg daily) and Vitamin B ₁₂ (1000 μg IM) may be tried. The diagnosis will be confirmed by an increase of reticulocytes within seven days. The presence of plasma intrinsic factor antibodies will indicate pernicious anaemia. Although an undiagnosed pernicious anaemia with B ₁₂ deficiency is rare, the administrations of only folate in such a case may exacerbate the condition. Other causes for a MCV >100 fl include liver disease, hypothyroidism, myelodysplasia and alcohol consumption.

The cyanmethhaemoglobin method is used for assessment of Hb in a laboratory. The Haemocue, a portable battery operated photometer with disposable cuvettes for collection of blood is useful at point-of-care. The haematocrit complements and partially overcomes the limitations of a single measurement of Hb, but has no advantage over the Hb. Adequate puncture of tissue and spontaneous blood flow from the wound is required when obtaining capillary blood from a finger prick, in order to reduce potential errors in the Hb and haematocrit estimations. A new Colour Scale, similar to the original Talquist Scale, gives simple accurate assessments of Hb and is useful if there is no laboratory.

If even an Hb assessment is not possible, clinical screening is required to detect moderate to severe anaemia in individual pregnant women. Mucosal pallor especially on the under surface of the tongue and the conjunctivae, and palmar and nail bed pallor are important signs. However clinical examination per se has low sensitivity in moderate anaemia and is unlikely to detect mild anaemia.

Adverse effects

Employed women will need to continue to work and housewives will have to do their normal household chores during pregnancy. IDA leads to reduced work capacity, intellectual capacity and productivity, and increased susceptibility to infection. It also results in increased maternal mortality especially in non-industrialised countries with low resources, probably due to combination of anaemia with obstetric haemorrhage, infections and an impaired capacity to support vital functions. Anaemia was the direct cause of maternal deaths in 3.7% of cases in Africa and 12.8% of cases in Asia. Severe anaemia is associated with adverse perinatal outcomes such as preterm deliveries and small for gestational age babies. Furthermore, babies born to anaemic mothers are iron deficient and have a higher risk of developing anaemia during infancy, although they are not anaemic at birth. The adverse effects of ID at birth also have long term effects such as poor physical and mental growth and cognitive function leading to poor learning abilities continuing throughout childhood and adolescence, and even permanent neuro-physiological deficiencies.

Prevention

Women should be advised to stop smoking prior to pregnancy and to immediately quit smoking or chewing tobacco if they become pregnant.

The anthelmintics mebandazole and albendazole which have been found to be safe and effective during pregnancy, should be administered to pregnant women as well as non-pregnant women in communities with a high prevalence of helminthiasis especially hookworm infestation.

Teenage pregnancy and high parity should be avoided by counselling and the use of appropriate contraception. Temporary contraception to increase inter-pregnancy non-lactating intervals may also help.

Intermittent preventive treatment of malaria using sulphadoxin pyrimethamine is indicated for women residing in malaria endemic areas. All infections and chronic inflammatory conditions ( vide Table 2 ) should ideally be controlled prior to pregnancy.

Although dietary advice has a limited impact, energy rich balanced food supplementation through sustainable community based programmes can lead to an increase in pregnant women’s energy and protein intakes and thus improve fetal outcomes. However, high protein supplementation may be harmful to the fetus.

“Raising the social and economic status of women in the non industrialised countries with limited resources, would be the best long-term solution to the under-nourished, pregnant woman”.

Weekly iron folate supplementation for all menstruating women, including school girls

Globally, more than 460 million non-pregnant women (15–49 years) are estimated to be anaemic and two thirds of them will be from Asia ( Table 1 ). Weekly iron (60 mg of ferrous sulphate) and folic acid (3 mg) supplementation (WIFS) for WRA, including adolescent girls between 10–19 years could be an effective strategy to achieve good iron stores before a woman becomes pregnant. WIFS programmes for WRA have been effective in reducing the prevalence of anaemia in certain districts in Vietnam, the Philippines, and Cambodia. Selecting a fixed day in the week as ‘WIFS Day’ or ‘Iron Day’ could be effective in addressing the problem of forgetfulness and to improve compliance. The duration of supplementation should probably be for at least three months and it should be repeated preferably at six monthly intervals. Iron supplementation may lead to exacerbations of infections, and also malaria in communities with a high prevalence of malaria. In malaria endemic areas, screening for anaemia and iron supplementation for the prevention and treatment of anaemia is recommended. The implementation of a WIFS programme should be taken as an opportunity to establish or strengthen concurrent measures to prevent, control and treat malaria in malaria endemic areas.

Any possible adverse perinatal outcomes for the baby are most likely to occur if IDA and ID are present during conception and embryogenesis, and correcting them prior to conception could result in significantly improved perinatal outcomes, while improvements may not be evident with supplements which are usually commenced only in the second trimester. Therefore a WIFS program is important to ensure adequate iron stores in non-pregnant women including adolescents prior to them becoming pregnant.

Daily oral iron and folic acid supplementation for pregnant women

A daily supplement of 60 mg of elemental iron and 400 μg of folic acid should be started as soon as possible in all pregnant women including adolescents, given throughout pregnancy and continued for six months postpartum to ensure adequate iron stores in the woman, in communities where anaemia in pregnancy is considered to be a significant problem. This regimen increases maternal haemoglobin levels and the birth weight of the new borns, and reduces maternal anaemia and ID at term, and the delivery of low birth weight babies. However there is no significant reduction in preterm deliveries and neonatal deaths. Interactions between multiple micro nutrient deficiencies including iron and folate deficiencies, and underlying concurrent chronic inflammatory conditions will contribute to the adverse sequelae of anaemia in pregnancy. Therefore all the adverse effects of anaemia in pregnancy would not be expected to be reduced by iron and folate supplementation.

The iron requirements of the fetus as well as maternal iron absorption are very low in the first trimester. Furthermore ‘morning sickness’ and the possible gastrointestinal side-effects of iron supplements will usually reduce compliance.

In well-resourced settings, selective oral iron supplementation based on SF levels at the booking visit, is feasible ( Table 3 ).

If ID or latent ID manifests as clinical anaemia during pregnancy, correcting it and ensuring adequate Hb levels at partus is important especially in low resource settings to reduce the risk of maternal morbidity and mortality due to a combination of anaemia with obstetric haemorrhage and sepsis, as well as possible long term adverse effects in the newborn.

Oral iron supplements may interfere with absorption of other trace materials such as Zinc and affect fetal bone growth. Concurrent Zinc supplementation has been suggested to address this issue but the combined preparations could be less effective than individual supplements.

Vitamin A may be required for the mobilization and utilization of iron from haemoglobin synthesis, and thus contribute to haemopoesis. In Indonesia, antenatal iron and vitamin A supplements were shown to be better than iron alone. However studies in Malawi did not show a similar association.

Multiple micronutrient supplementation during pregnancy have no added benefit compared to supplementation with iron and folic acid alone.

The high prevalence of anaemia in non industrialised countries is in spite of antenatal daily oral iron and folic acid supplementation programmes. Globally, the reasons for failure of these programmes are poor compliance mainly due to side-effects, poor motivation and a lack of awareness of their value.

Gastrointestinal side-effects of oral iron supplements are dose related, and are increased if taken on an empty stomach. Therefore iron supplements are commonly taken after a meal in order to reduce these side-effects. However this reduction in side-effects is probably due to poor absorption due to phytates and polyphenolic compounds in a full stomach. This would decrease the effectiveness of the supplements.

Preparations containing 30 mg or less of iron have less side-effects and they could be used for preventing and treating anaemia in pregnancy but they carry a higher risk of ID.

Most oral iron supplements contain ferrous sulphate. To reduce the unpleasant gastrointestinal side-effects and improve compliance, supplements containing ferrous fumarate, gluconate and glycine and various gastric delivery systems have been tried out, without much success. The non ionic ferric polymaltose complex, given with meals for better absorption, has been shown to be in-effective in treating IDA. Calcium and iron supplements should not be taken together because calcium inhibits iron absorption.

Antenatal oral supplementation with iron 65 mg and folic acid 1 mg, daily throughout pregnancy, has been found to be safe in multigravidae in a high malarial transmission area.

Weekly oral iron and folic acid supplementation for pregnant women

It has been suggested that daily oral iron supplementation results in high iron levels in the intestinal mucosal cells and lumen, leading to an increased severity and frequency of undesirable gastrointestinal side-effects, and progressively reduces further iron absorption. Weekly supplements, based on a mucosal cell turnover of five to six days, which may improve iron absorption and patient compliance, has been suggested as a better option which is equally effective as daily supplements. However a radio-isotopic iron absorption study found no evidence of any progressive mucosal block following daily oral iron. Iron supplements given twice weekly with food were found to provide <10% of the iron requirements during the third trimester of pregnancy.

The association of Hb levels to perinatal outcome has been shown to be U shaped with both high and low Hb levels being associated with adverse perinatal outcome such as low birth weight, increased still births and increased perinatal mortality rates. High Hb levels especially >130 g/L at term have been found after daily oral iron supplementation and therefore it has been suggested that intermittent weekly iron supplementation should be considered as a better alternative. While weekly iron supplements should have some effect, the marked reduction in the total dose is unlikely to be as effective as a seven day dose. Weekly or even twice weekly iron supplements could be grossly inadequate to meet the iron requirements of pregnancy especially in communities where ID is high and the normal diet of pregnant women not only lack iron rich food sources but also contain substances which reduce iron absorption.

Intrapartum management

Prior to admission to the labour ward, maternal Hb should be >10 g/dl. If the Hb is <7 g/dl, there is a high risk of maternal death due postpartum haemorrhage (PPH), cardiac failure or sepsis. During labour women should be propped-up and in a semi-recumbent position, have peri partum intravenous antibiotics, adequate analgesia and intermittent oxygen inhalation if necessary. Undue straining and a prolonged second stage of labour should be avoided. Active management of third stage of labour is indicated to reduce the risk of even a mild PPH. Delaying the clamping of the umbilical cord for 1–2 minutes improves the iron stores of the neonate. This simple intervention can reduce the risk of the adverse sequelae of ID during infancy and childhood, in communities where women have ID.

Postpartum management

If the postpartum Hb is <8 g/dl after delivery, a blood transfusion should be considered. Appropriate contraceptive counselling and services are required to either prevent future childbearing or delay the next pregnancy for at least one year, depending on the woman’s needs.

Treatment

The treatment of anaemia in pregnancy needs identification of the underlying cause ( vide Table 2 ) and its appropriate treatment. Expert advice should be sort where relevant.

It has been suggested that all pregnant women with severe anaemia in a malaria endemic area should be treated with antimalarials because malaria contributing for their anaemia cannot be excluded as more than half of them will not have positive peripheral blood films or fever.

The threshold for a blood transfusion is often considered to be <6 g/dl in general clinical practice, and <7 g/dl in pregnancy. Considering the very high risk of maternal mortality due to PPH and sepsis especially in low resource settings, it would be prudent to use packed cell transfusions if the Hb is <9 g/dl at term.

Dietary advice

Pregnant women should be advised to have a realistic, easily digestible and affordable, balanced diet rich in iron and protein. Although red meat and liver are excellent sources of haem iron which promotes erythropoiesis, many women especially in Asia, are vegetarians. Vegetarians should be advised to increase the intake of iron rich food sources such as lentils, green peas, green vegetables, figs etc. and also to include an iron absorption enhancer such as a vitamin C rich food source e.g. orange juice. They should also be advised to avoid coffee and especially tea (which inhibits iron absorption) soon after a meal.

Iron therapy

Current available evidence does not clarify the best method of treating IDA of pregnancy. However oral iron therapy is the most feasible. Sensitivity reactions and increased risk of venous thrombosis, and pain and skin discoloration at site of injection, have been associated with intravenous and intramuscular iron therapy respectively. In comparison to iron dextran and iron sorbitol which have been used frequently in the past, intravenous iron sucrose complex and iron polymaltose complex have been found to be effective in special situations such as unresponsiveness, intolerance or non-compliance with oral iron supplements or in the presence of severe anaemia which requires urgent correction while avoiding the risks of blood transfusion and it could be combined with recombinant human erythropoietin in well resourced settings ( Table 4 ).

IDA summary

IDA in pregnancy is a major public health problem, especially in Asia, and is associated with increased maternal and perinatal morbidity and mortality, and adverse effect in the newborn which could persist throughout infancy, childhood and adolescence. Because of physiological haemodilution, underlying inflammatory conditions and several other factors which have an effect on Hb and the other haematological indices during pregnancy, the diagnosis of anaemia in pregnancy and the adoption of preventive and therapeutic strategies to manage it are difficult.

Ideally a woman should have adequate iron stores when she conceives, in order to meet the additional requirements of pregnancy. Weekly supplementation of all menstruating women including adolescents periodically with iron and folic acid, may achieve this. However, most pregnant women will need additional iron supplements, which are best given daily to meet this additional need ( Table 4 ). Delayed cord clamping can increase the iron stores of the newborn.

The optimum dose, frequency and formulation of oral iron supplements, methods of improving compliance in women, the feasibility and cost effectiveness of universal iron supplementation or targeted iron supplementation of pregnant women, and their safety in malaria endemic areas, women who are iron replete and women who could have excess iron stores, needs to be established. The possible improved clinical outcomes of iron supplementation in pregnant women with latent ID, ID or IDA, also needs to be established.

Vitamin B12 deficiency in pregnancy

Folate deficiency in pregnancy