Anaemia in pregnancy

Definition

Anaemia is defined by a low haemoglobin level of less than 110 g/L which is two standard deviations below the mean for a matched healthy population (125). Due to the physiological haemodilution of pregnancy, haemoglobin levels vary each tri­mester, with levels of less than 105 g/L in the second and third trimesters and less than 100g/L postpartum used to diagnose anaemia (1, 126).

Haemoglobin measurement identifies the presence of anaemia but not the cause of anaemia. There are many causes, with iron deficiency being the commonest cause, leading to approximately 50% of cases of anaemia (3, 127). This percentage varies among dif­ferent populations in different geographical areas (1). Other causes of anaemia include deficiency of macronutrients such as folate and vitamin B12; acute and chronic infections such as malaria, tuber­culosis, and HIV; malignancies; and inherited or acquired haemo­globin synthesis disorders, and red blood cell production or function such as haemoglobinopathies (1, 3).

Background

Anaemia in pregnancy is a global problem, in 2011 the World Health Organisation estimated the prevalence of anaemia in pregnant women to be 38%, and 29% in all women of reproductive age. This translates to 32 million pregnant women and 496 million women of reproductive age affected globally. This prevalence varies depending on geographical area, the highest being in Africa, where 55% of pregnant women are affected compared to North America which has the lowest prevalence of 6.1% (128).

Causes

Iron deficiency is the commonest cause of anaemia in pregnancy. The second commonest cause is folate deficiency; anaemia related to folate deficiency varies considerably with nutritional variation and socioeconomic status (129). The common causes of anaemia are summarized in Table 15.6.

Effect of pregnancy on anaemia

Many women enter pregnancy with depleted iron stores, the in­creased demands and increased mobilisation of iron from cir­culating red blood cells leads to further depletion and has a direct effect on maternal and perinatal mortality and morbidity.

Source data from Goonewardene M, Shehata M, Hamad A.

blood loss all contribute to increase incidence and worsening of pre-existing anaemia.

Effect of anaemia on pregnancy

Adequate iron and folate are needed for normal tissue enzyme function. Initially the fetus compensates by upregulating placental iron transport proteins (130), but further depleted stores increase the risk of developing anaemia in the first 3 months of life. Some of the reported obstetric outcomes in relation to anaemia are as follows:

Maternal

• Lower immunity and increased susceptibility to infections

• Tiredness

• Lethargy

• Poor concentration and work performance

• Postpartum depression

• Spinal and peripheral nerve involvement with vitamin B12 deficiency.

Fetal

• Impaired psychomotor and/or mental development

• Low birth weight

• Preterm birth

• Placental abruption

• Postpartum haemorrhage

• Neural tube defects with vitamin B12 and folate deficiency.

Diagnosis

Clinical symptoms and signs of anaemia in pregnancy are non­specific and can sometimes be difficult to differentiate from normal symptoms of pregnancy, unless the anaemia is severe. Fatigue is the most common presenting symptom. Women may also complain of weakness, palpitations, dyspnoea, dizziness, and irritability.

Laboratory tests include the following:

• Full blood count, blood film, and red cell indices: in iron defi­ciency anaemia, this will show low Hb less than 11 g/dL, mean cell volume less than 80 fL, mean cell haemoglobin less than 30 mg/dL, and mean cell haemoglobin concentration less than 30%; a blood film may show microcytic hypochromic red cells and char­acteristic ‘pencil cells' (131).

■ A raised mean cell volume greater than 100 fL is indicative of folate deficiency, but can also be raised with liver disease and alcohol consumption.

• Serum ferritin: ferritin is a glycoprotein which reflects iron stores. It is the first laboratory test to become abnormal as iron stores decrease and it is not affected by recent iron ingestion. It is an acute phase reactant, so levels may rise in the presence of infection or inflammation.

• Serum iron and total iron binding capacity (TIBC): serum iron and TIBC are unreliable in predicting availability of iron to tissues due to fluctuation of levels with infection, diurnal variation, and ingestion of iron. Levels decline in normal pregnancy but serum iron of less than 12 pg/L and TIBC of less than 15% indicate iron deficiency.

• Soluble transferrin receptor: the transferrin receptor is a trans­membrane protein that transports iron into the cell (133). It is a sensitive measure of tissue iron supply and is not an acute phase reactant. Initially there is little change in concentration, but in es­tablished iron deficiency the soluble transferrin receptor concen­tration will increase in direct proportion to the total transferrin receptor concentration. However, this is an expensive test which limits its use in pregnancy.

• Reticulocyte haemoglobin content and reticulocytes: reticulocyte haemoglobin concentration and reticulocyte count is reduced in iron deficiency anaemia. Erythropoietic activity in anaemia can be assessed early by measuring reticulocyte cellular characteristics. This is not widely available and there are limited data in pregnancy.

• Serum and red cell folate: folate deficiency results in macrocytosis (mean cell volume >100 fL) and the development of megaloblastic change in the bone marrow. A serum folate of less than 2.0 pg/L, and red cell folate concentration of less than 160 pg/L is diagnostic of folate deficiency.

• Vitamin B₁₂ (cobalamin) level: vitamin B12 deficiency also leads to macrocytosis and megloblastic change in the bone marrow. Cobalamin level vary in pregnancy with the lowest being in the third trimester, a level of less than 100 pg/mL is diagnostic of vitamin B12 deficiency.

■ An adjunct to diagnosis of B12 deficiency is a reduction in holotranscobalamin level, and an increase in methylmalonic level and lactate dehydrogenase level. The latter is due to de­struction of red blood cells in the bone marrow.

• Bone marrow biopsy: a bone marrow sample is considered the gold standard for assessment of iron stores; however, this test is very invasive and should only be used in complicated cases where the underlying cause cannot be identified by simpler methods.

• Haemoglobin electrophoresis: can be used to measure amounts of normal HbA and HbA2, and measure abnormal haemoglobin levels such as HbS, HbF, and HbC which can be elevated in condi­tions such as sickle cell disease (SCD).

Prevention

The type of nutritional deficiency anaemia varies with geographic location.

Dietary advice is important in all types of nutritional anaemias especially in vegan and vegetarian women—a balanced diet, rich in iron, protein, and folic acid-fortified breads and cereals is advised. In countries with a high prevalence of anaemia, a daily supplement of 60 mg of elemental iron and 400 mg of folic acid should be given to all pregnant women throughout pregnancy and continued for 3­6 months postpartum to ensure adequate iron stores (134, 135). This can be associated with considerable gastrointestinal side effects and lead to poor compliance, so a weekly dose may be appropriate in areas with less prevalence of anaemia.

Treatment

All pregnant women should be screened for anaemia at booking and again at 28 weeks' gestation (136).

Iron deficiency anaemia

Oral iron

A trial of iron therapy can be used as a diagnostic and therapeutic measure. Oral iron should demonstrate a rise in haemoglobin within 2 to 3 weeks. A rise confirms the diagnosis, if there is no rise in haemoglobin—further tests must be carried out.

Oral iron is a cheap and effective way to restore iron stores. There are only marginal differences between the different ferrous salts.

The recommended dose of elemental iron for treatment of iron deficiency is 100-200 mg daily.

Haemoglobin concentration should rise by 20 g/L in 3-4 weeks, although compliance and intolerance to oral iron may limit efficacy. Repeat testing should be performed 2-3 weeks following initiation of treatment to assess response. Once haemoglobin levels normalize, treatment should be continued for 3 months and carried on for 6 weeks postnatally to replace stores.

Parenteral iron

Parenteral iron should be reserved for women with poor compli­ance, malabsorption, or non-tolerance to oral iron (137).

Several authors have reported faster increase in haemoglobin levels, quicker replenishment of iron stores, and less need for blood transfusions with parenteral iron therapy (138-140).

Different preparations are available, iron III carboxymaltose (Ferrinject) and iron III isomaltoside (Monofer) are examples of fast-acting intravenous iron preparations.

Intramuscular preparations

The only intramuscular preparation available in the United Kingdom is low-molecular-weight iron dextran. Significant pain at the injec­tion site and the risk of permanent skin discolouration limit its use in clinical practice (141).

Blood transfusion

Blood transfusion should be given in obstetric haemorrhage as in­dicated, in line with local guidelines. Efforts should be made to re­duce unnecessary blood transfusions by appropriate assessment of women in the postpartum period and balancing the risks of transfu­sion against potential benefit (142).

Folic acid

A prophylactic dose of 400 mcg daily is recommended for all women at least 3 months preconceptually. A therapeutic dose of 5 mg is re­commended in women with haemolytic anaemias such as SCD, or on medications affecting folate metabolism such as antiepileptic drugs (143).

Vitamin B12

Vitamin B12 levels must be measured prior to giving folate supple­ments as this may mask B12 deficiency.

Women with a balanced diet rarely need vitamin B12 supplemen­tation, but vegans or patients with pernicious anaemia benefit from treatment. Treatment is usually in the form of hydroxocobalamin intramuscular injections.