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9. Anaemia in Pregnancy
Keywords
Maternal anaemiaIron supplementationParenteral iron formulationsBlood transfusionAnaemia in pregnancy is one of the most common medical conditions worldwide. The WHO has defined anaemia in pregnancy if haemoglobin (Hb) is <11 g/dL at any stage of antenatal period [1]. According to NICE guideline and CDC recommendation, the haemoglobin cut-off to define anaemia in pregnancy is <10.5 g/dL in the second and third trimesters and <10 g/dL in the postpartum period [2, 3].
9.1 Incidence and Prevalence of Anaemia in Pregnancy
Anaemia in pregnancy is one of the commonest health problems worldwide especially in developing countries. Despite all efforts of national health programmes to provide optimum antenatal care to all pregnant women, and recommendation of screening for anaemia on their first antenatal visit, more than half of the pregnant women in the world are suffering from this condition [4]. In developed countries, incidence of anaemia in pregnant women is only 15%, whereas relatively higher prevalence (33–75%) has been reported in developing countries [5, 6]. Anaemia in pregnancy has a major impact on nation’s health and its economy. It is a major contributing factor in maternal mortality and morbidity and also affects foetal outcome by causing preterm delivery, low birth weight and lower infant Apgar score, thereby adding to the economic burden of healthcare as well [7, 8].
9.2 Grading of Severity of Anaemia in Pregnancy by the WHO
Mild | 10.0–10.9 g/dL |
Moderate | 7.0– 9.9 g/dL |
Severe | <7.0 g/dL |
9.3 Classification of Anaemia and Their Causes Based on Absolute Reticulocyte Count, RBC Indices and Morphology
9.3.1 Low or Normal Reticulocyte Count (<75,000/cmm), i.e. Hypoproliferative Anaemia
9.3.1.1 Microcytic, Hypochromic (MCV < 80 fL)
Iron deficiency anaemia
Thalassemia syndromes
Sideroblastic anaemia
Transferrin deficiency
9.3.1.2 Macrocytic (MCV > 100 fL)
Megaloblastic anaemias
(Folic acid/vitamin B12 deficiency)
Liver disease
Reticulocytosis
Bone marrow failure syndromes
Drugs (zidovudine, trimethoprim sulphate)
9.3.1.3 Normocytic (MCV 80–100 fL) with Normal Morphology
Anaemia of renal disease
Aplastic anaemia
Infections (malaria, tuberculosis)
Chronic disease
9.3.2 Increased Reticulocyte count (>100,000/cmm), i.e. Hyperproliferative Anaemia Because of Excessive Haemolysis
9.3.2.1 Normocytic (MCV 80–100 fL), Abnormal Morphology
Hemoglobinopathies (SS, SC, CC)
Hereditary spherocytosis
Autoimmune haemolytic anaemia
Some enzymatic deficiencies
9.3.2.2 Acute Haemorrhage
Effect of pregnancy on anaemia: The maternal haematological system undergoes dramatic changes during pregnancy. There is an expansion of maternal plasma volume by approximately 40–50%, with increase in red blood cell (RBC) mass also but by 30% only, leading to hemodilution [9]. This may lead to fall in maternal haemoglobin and haematocrit value. Henceforth women who are already anaemic in pre-pregnant state, their Hb falls, and anaemia worsens progressively as the period of gestation advances, if not started on iron therapy. Conversely non-anaemic women in pre-pregnant state achieve normal Hb till the end of 6 weeks of puerperium, if no history of significant obstetric haemorrhage is there.
Approach towards anaemia in pregnancy: Proper history taking includes inquiry about supplementation of iron and folic acid during pregnancy, history of menorrhagia prior to conception, any episode of obstetric haemorrhage, history of pica, worm infestation, hematemesis, melena, hematuria, chronic illness, easy bruising, or family history suggestive of haemoglobinopathies etc. On physical examination, one should look for pallor, icterus, oedema, koilonychia, increased jugular venous pressure, hepatomegaly and splenomegaly. In severe anaemia, there may be presence of soft systolic murmur in the heart (may be physiological) and sometimes basal crepitations denoting lung congestion. Severe anaemia may present with features of congestive cardiac failure.
9.4 Laboratory Investigation
9.4.1 Haemoglobin Concentration
Reduction in Hb value less than 11 g/dL in first trimester and <10.5 g/dL in second and third trimester is the simplest method of diagnosing anaemia. Though decrease in Hb is preceded by depletion of iron store first in cases of iron deficiency anaemia followed by defective erythropoiesis and finally anaemia becomes evident.
9.4.2 Peripheral Blood Picture (PBF)
In iron deficiency anaemia, there is microcytic, hypochromic picture in peripheral blood film along with anisocytosis and poikilocytosis. In mild anaemia or concomitant vitamin B12 or folate deficiency, normocytic picture may be present in lieu of microcytic picture. Macrocytic picture is a characteristic feature of vitamin B12 or folate deficiency. PBF is also looked for WBC differential count, platelet count and their morphology, evidence of haemolysis and malarial parasite.
9.4.3 Red Blood Cell Indices
Impaired haemoglobin synthesis may affect all or any value of MCV, MCH or MCHC. RBC indices help in typing of anaemia. Normal range of MCV is 80–100 fL, of MCH is 27–31 pg/cell and of MCHC is 32–36 g/dL. Red blood cell distribution width (RDW) along with MCV may help in determination of possible cause of anaemia.
9.4.4 Reticulocyte Count
Increased or decreased reticulocyte count seen in peripheral blood film indicates hypercellular or hypocellular bone marrow, respectively, and cause of anaemia can be predicted with support of other investigations.
9.4.5 Electrophoresis
Electrophoresis is an important test to detect the qualitative or quantitative abnormality of haemoglobin and help in diagnosis of haemoglobinopathies like thalassaemia and sickle cell anaemia.
9.4.6 ESR
Although ESR is raised in anaemia, this is a nonspecific indicator.
Other investigations that may help to establish the cause of anaemia are serum bilirubin; serum LDH; renal function test; urinalysis (routine examination including urinary protein, bilirubin and urobilinogen and microscopy); stool test for occult blood, ova and cyst; X-ray chest PA view; and USG whole abdomen.
Iron deficiency anaemia: Iron deficiency anaemia is the most common cause of anaemia in pregnancy and responsible for about 70–95% of cases [10].
9.5 Physiology and Iron Metabolism
The total iron requirement over the course of pregnancy is approximately 900 mg (range 700–1400 mg), 450 mg of which is consumed in red blood cell expansion [11]. Around 350 mg of iron is used in foetus and placenta. The blood loss in delivery causes loss of 190 mg of iron, and the same amount of iron is consumed in lactational period (1 mg/day). At the same time, amenorrhoea during pregnancy saves approximately 256 mg of iron. Henceforth, at the end of pregnancy followed by postpartum, the woman is left with total iron deficit of approximately 580 mg. Therefore even in iron-replete woman, there is increased iron demand as 4–6 mg/day and 6–8 mg in second and third trimester, respectively [12].
The increased requirement of iron during pregnancy cannot be met by diet alone but is derived partly from maternal reserve. In a well-nourished woman, about half of the total iron requirement get fulfilled from iron store. When the iron reserve already is low due to malnutrition and/or frequent pregnancy, iron deficiency anaemia results.
Foetal iron metabolism: During pregnancy, following absorption of iron from maternal gastrointestinal tract, its transportation occurs to foetal circulation from maternal circulation against the gradient, in contrast to non-pregnant state where it goes to the bone marrow. The transferrin-bound iron from maternal circulation reaches to placenta where several transferrin receptor 1 (TfR1) are present on apical membrane of syncytiotrophoblast. The bivalent iron transferrin complex is internalized after binding with the TfR1 by process of endocytosis, and change in pH leads to release of iron in cytoplasm [13, 14]. Foetal heptacidin has important role in foetal iron metabolism. The overall mechanism is aimed to supply maximum iron to the foetus despite maternal anaemia.
Clinical signs and symptoms: Iron deficiency anaemia in pregnancy can be asymptomatic, and its detection occurs first time during routine antenatal screening. The signs and symptoms are often nonspecific with fatigueness being the commonest complaint. She may complain of weakness, exhaustion, giddiness, palpitations, dyspnoea, hair loss and reduced work performance and swelling of the lower limb or anasarca. Pregnancy with severe anaemia is at risk to have recurrent infection and also associated with increased risk of pre-eclampsia [15, 16]. Few patients with severe anaemia may present with heart failure during pregnancy (mostly at 32 weeks) or following delivery because of cardiac overload. Anaemic mothers are also at risk to have PPH following delivery. Literature reports high maternal mortality rate in developing countries (varying from 27 to 194 per 100,000 live birth) due to severe anaemia [17]. They may develop lactation failure and postpartum depression in puerperium.
Maternal anaemia causes placentomegaly and affects foetus leading to preterm delivery, low birth weight and its consequences and henceforth increases foetal and neonatal morbidities [18–20]. Literature suggests increased risk of preterm premature rupture of membranes if anaemia develops early in pregnancy, while anaemia later in pregnancy is associated with preterm labor [21]. Maternal anaemia is also associated with risk of birth asphyxia and poor infant Apgar score. Positive correlation has been found between maternal iron supplementation and improvement of Apgar score [22]. Subsequent to preterm labour and low birth weight, associated short-term and long-term outcomes are cerebral palsy, blindness, deafness and hypertension. Mild to moderate anaemia during pregnancy is also a risk factor for iron deficiency anaemia in infant, especially between 6 and 12 months of age [23].
Laboratory diagnosis of iron deficiency: Besides routine test for anaemia, few specific tests are recommended to establish the definite diagnosis of iron deficiency anaemia.
Red blood cell indices: MCV < 75 fl, MCH <25 pg and MCHC<30 g/dL are typical of iron deficiency anaemia. Any or all values of MCV, MCH and MCHC are reduced in iron deficiency anaemia.
Reticulocyte count: Reticulocyte count is decreased in iron deficiency anaemia because of impaired erythropoiesis. On commencing iron therapy, the first sign of improvement seen is increase in reticulocyte count appearing after 7–10 days.
Peripheral blood picture: In iron deficiency anaemia, there is microcytic, hypochromic picture characterized by plenty of pale staining cells different in sizes (anisocytosis) and shape (poikilocytosis) present in peripheral blood film. In mild anaemia or concomitant vitamin B12 or folate deficiency, normocytic picture may be present in lieu of microcytic picture.
Serum ferritin: Serum ferritin is a stable, high molecular weight glycoprotein, and its normal level in serum varies from 50 to 150 ng/mL. This provides an accurate estimation of iron stores. Its serum level can be assayed by ELISA, and the value is not affected by recent ingestion of iron except inflammatory states. Decreased serum ferritin (<30 ng/mL) is the first abnormal sign of iron deficiency anaemia before decline in Hb concentration.
Serum transferrin receptor: This is a newer and reliable method for assessing tissue iron status, and its value increases > threefold in response of iron deficiency anaemia (normal 4–9 mg/L). It provides an early and accurate estimation of the iron deficit between the point of iron store depletion and appearance of iron deficiency anaemia before the MCV gets affected.
Serum iron studies: This includes estimation of serum iron and total iron binding capacity (TIBC); both can help in estimating serum transferrin saturation. Serum iron, transferrin saturation and soluble transferrin receptor are decreased, and TIBC is raised in iron deficiency anaemia, while in chronic disease, serum iron and TIBC both are decreased with normal value of soluble transferrin receptor.
Erythrocyte Zn protoporphyrin concentration: This is a nonspecific indicator because of ineffective erythropoiesis in iron deficiency anaemia. The value is raised >40 mumol/mol haem.
Bone marrow examination: The absence of stainable iron (hemosiderin) in normoblast present in bone marrow is diagnostic of iron deficiency anaemia. This is an invasive test and reserved for cases of severe anaemia where the cause is not established or they are not responding to hematinic.
Prevention and management of iron deficiency anaemia: The WHO recommends 60 mg/day of oral iron supplementation to all antenatal mothers throughout the pregnancy and continued till 3 months of postpartum [24, 25]. Apart from supplementary iron therapy, easily accessible protein- and iron-rich diet should be advised. Common causative agents responsible for anaemia like malaria, hookworm or urinary tract infections are also get treated simultaneously. After delivery, women should be advised contraception to avoid early and frequent pregnancy because even non-anaemic woman takes a minimum of 2 years to replenish her iron store which is exhausted in pregnancy and delivery.
Management of iron deficiency anaemia includes correction of the cause of anaemia along with iron therapy. Iron can be administered by oral or parenteral route; decision depends upon the period of gestation at which anaemia is diagnosed and the remaining time available for anticipated delivery.
Oral iron therapy: Oral iron therapy is of choice and recommended ideally when anaemia is not severe and gestation-delivery interval is at least 10 weeks. Oral iron formulations are safe, cheap and effective measures to correct the haemoglobin and replenish the iron store. The current guidelines for iron deficiency anaemia recommend a dose of 100–200 mg of elemental iron per day for a minimum duration of 3 months [27]. Iron preparations are ideally taken on an empty stomach or 1 h before food, as dietary factors may interfere with its absorption or may cause iron chelation making it less bioavailable. Tea and antacids interfere with its absorption, while vitamin C and vitamin A facilitate its absorption. Oral iron preparations are notorious to cause gastric irritation. Henceforth low elemental dose of iron to start with or taking it even in conjunction with meals is advisable for patient having iron intolerance to improve its compliance. Later on, dose is titrated gradually till the recommended dose with growing compliance of the patient. Shifting to different iron formulations or iron syrups may be of help in such group of patients. As iron syrups may cause staining of teeth, taking such preparations with straw is advisable.
Oral iron preparations available over the counter
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