Overview
Anaemia is a common condition affecting more than half (57%) of pregnant women in Sub-saharan Africa. It is defined as a reduction in the hemoglobin concentration of the blood or red blood cell mass below the normal range for age and sex. According to WHO, during pregnancy, it is defined as hemoglobin levels lower than 11.0g/dL and a hematocrit level lower than 0.33/L (33%)
- Classification according to severity
- Mild = 9 – 10.9g/dL
- Moderate = 7 – 8.9g/dL
- Severe = any reading below 7g/dL
- Classification according to trimesterCut-offs for diagnosis of anaemia
- First trimester = <11.0g/dL
- Second trimester = <10.5g/dL
- Third trimester = <11.0g/dL
- Classification according to etiology
| Classification | Types |
| Physiological anaemia | |
| Pathological anaemia | Iron, folic acid and Vitamin B12 deficiency |
| Hemolytic anaemia | Inherited – Sickle cell anaemia Acquired – Malaria |
| Bone marrow insufficiency | Aplasia due to drugs, radiation or infection |
| Hemoglobinopathies | Thalassemia syndromes |
- Risk factors associated with anaemia
- Closely spaced pregnancies
- Multiple pregnancy
- Poor and unbalanced diet
- History of anaemia before pregnancy and in previous pregnancies
- Lack of access to antenatal services
- History of complications such as postpartum hemorrhage, preeclampsia
Physiological anaemia is a normal change during pregnancy. It occurs due to an increase in blood volume by approximately 50% resulting in hemodilution. Though red blood cell mass also increases during pregnancy by approximately 33%, plasma volume increases to a greater degree resulting into a lower hematocrit and hemoglobin which does not truly represent anaemia. Mean corpuscular volume and mean corpuscular hemoglobin concentration should remain normal.
Iron Deficiency Anaemia
- This is the most common form of anaemia worldwide affecting 75%-95% of pregnant women.
- This is due to a two to three fold increase in iron requirements and insufficient stores to meet these requirements.
- Often asymptomatic and picked during routine tests done in an antenatal clinic.
- In the first half of the pregnancy iron absorbed from the diet and sufficient iron stores are enough to meet the requirements (which haven’t increased that much)
- The second half of the pregnancy is characterised by a rapidly growing fetus and an increasing red blood cell mass. This increases the amount of iron required by the body hence the mother needs supplements otherwise iron deficiency will occur.
- Iron math
- About 10-15 mg of iron can be found in a well balanced diet.
- 1-2mg is absorbed and is sufficient to meet an unpregnant body’s requirements.
- However, as mentioned above the second half of pregnancy needs more iron.
- The body’s iron stores are about 200-300mg in a female spread among hemoglobin (67%), reticulo-endothelial system (25%) and the rest can be found in myoglobin and in enzyme systems.
- A rapidly growing fetus requires about 350mg with 250mg of iron being lost in the process of delivery. The expanded RBC mass requires about 450mg. In total a pregnant woman requires an extra 1000mg.
- The body’s iron stores cannot meet this figure and gets depleted predisposing pregnant women to iron deficiency.
- Clinical presentation
History
- Fatigue and inability to participate in physically taxing activities that they could perform with ease before
- Headaches that occur daily
- Cold intolerance
- Palpitations
- Dyspnea
- Leg cramps on activity
- Restless leg syndrome – low levels of iron=low dopamine levels
- Increased number of infections
- Pica – in extreme cases
Physical examination
- Pallor of the mucous membranes
- Tachycardia
- Koilonychia
- Glossitis with atrophy of lingual papillae
- Angular stomatitis
- Investigations
- Complete blood count
- Reduced hemoglobin – below 11.0g/dL
- Reduced mean corpuscular volume
- Reduced mean corpuscular hemoglobin concentration
- Reduced hematocrit – below 33%
- Increased platelet count – iron deficiency increases megakaryopoietic differentiation and alters platelet phenotype without changes in megakaryocyte growth factors, specifically thrombopoeitin. It is thought to have evolved to improve coagulation ability especially in IDA caused by chronic bleeding.
- Normal or elevated white blood cell count
- Peripheral blood film
- Microcytic and hypochromic red blood cells
- Note the fewer number of target cells (rules out thalassemia)
- Anisocytosis and poikilocytosis are not marked
- Complete blood count
- Iron studies
- Low serum iron
- Low serum ferritin
- Raised total iron binding capacity
- Hb Electrophoresis
- Done to rule out beta-thalassemia
- Bone marrow studies
- Not routinely done for uncomplicated cases
- Lack of stainable iron in bone marrow is diagnostice
- Lack of sideroblasts rules out sideroblastic anaemia
- Treatment
- Iron therapy
- Oral iron
- Ferrous sulphate is commonly used. 325mg is given orally, three times a day. If it is not tolerated well then give ferrous fumarate or gluconate.
- Therapy should continue 3 months after hemoglobin levels stabilize to build sufficient iron stores.
- Supplemental ascorbic acid or citrus juice can be given to increase iron absorption.
- Given in cases where there is intolerance to oral iron or worsening condition despite adequate oral supplements.
- Examples of agents used: Ferric carboxymaltose and ferric derisomaltose.
- Blood transfusion
- This is reserved for severe anaemia diagnosed near term and women with evidence of active bleeding.
- Erythropoetin
- Usually administered in conjunction with IV iron.
- Not normally done but it is indicated in cases where you need to increase hemoglobin fast such as in the third trimester
- Complications
- Maternal complications
- Postpartum depression
- Angina pectoris or congestive heart failure
- Worsening underlying medical conditions
- Constipation from iron supplements
- Preterm delivery
- Restricted intrauterine fetal growth
- Low birth weight
- High risk of intrauterine demise
- Increased risk of sepsis and/or contracting infections
- Perinatal mortality
- Higher risk of developing autism, ADHD and intellectual disability
- Differential diagnoses
- Anaemia of chronic disease
- Anaemia due to thalassemia trait – will have normal iron studies
- Sideroblastic anaemia – absence of ring sideroblasts in bone marrow
- Anaemia due to lead poisoning
- Prevention
- The best prevention is for pregnant women to attend their antenatal clinics when due where they will:
- Have screening tests conducted that will pick up anaemia
- Receive iron supplements
- Receive malaria prophylaxis and insecticide treated nets (malaria can cause serious anaemia)
- In multiple pregnancies and women with a history of iron deficiency, iron supplements should be given even if there is no evidence of anaemia
Folate and B12 Deficiency Anaemia
- Folate and B12 deficiency causes megaloblastic anaemia which is characterised by large precursor red blood cells in the bone marrow.
- It is less common than iron deficiency anaemia.
- Folic acid is important in DNA and RNA synthesis as well as in forming amino acids used in cell division.
- B12 is used as a cofactor in DNA synthesis and in fatty acid and amino acid metabolism.
- Due to the roles they play, folate and B12 are very important in cell division, particularly in pregnant women who are carrying a growing baby with rapidly dividing cells.
- Etiology
- Folic acid can be found in green vegetables, meat and fruits. The recommended daily intake for pregnant women is 600 mcg.
- Folate is stored in the liver (about 5mg which is sufficient for 3-4 months) however due to increased demand for folate in pregnancy, folate stores are quickly decimated without supplements.
- Anticonvulsants and chemotherapeutic drugs affect folate metabolism as well.
- B12 deficiency is rare and is usually established before pregnancy (uncommon to make a new diagnosis in pregnancy). Occurs in pernicious anaemia, terminal ileum, strict vegetarians, atrophic gastritis, ileal resection, gastrectomy, blind loop syndrome etc.
- B12 can be found in meat, fish, eggs and dairy products.
- Risk factors
- Poor diet
- Hematological abnormalities with high cell turnover such as hemolytic anaemias
- Drugs that interfere with folate metabolism such as antiepileptics
- Drugs that cause megaloblastic changes in the bone marrow
- Allopurinol
- Azathioprine
- Capecitabine
- Cladribine
- Fludarabine
- Fluorouracil
- Gadolinium
- Gemcitabine
- Hydroxyurea
- Lamivudine
- Leflunomide
- Mercaptopurine
- Methotrexate
- Mycophenolate mofetil
- Trimethoprim
- Zidovudine
- Drugs that affect metabolism and/or intestinal absorption of B12 and folate
- Aminosalicylic acid
- Antacids and proton pump inhibitors
- Penicillin antibiotics
- Chloramphenicol
- Erythromycin
- Oral contraceptives
- Metformin
- Phenytoin
- Tetracyclines
- Valproic acid
- Pathophysiology
- This condition is characterised by ineffective erythropoesis due to abnormalities in DNA synthesis due to folate and B12 deficiencies.
- Folate and B12 are important in DNA synthesis as shown below:
- A deficiency of either disrupts DNA synthesis slowing nuclear maturation. In contrast, cytoplasmic maturation continues normally.
- Arrested nuclear maturation leads to formation of megaloblasts with abnormal nuclei such as those seen in hypersegmented neutrophils.
- Impaired DNA synthesis leads to apoptosis of the affected cells (intramedullary hemolysis) causing jaundice and anaemia.
- The neurological manifestations seen in B12 deficiency are thought to occur due to demyelination of neurons.
- Clinical presentation
- History
- Fatigue
- Dyspnea
- Palpitations
- Headaches
- Mouth ulcers
- Sore tongue
- Nausea and vomiting
- Diarrhoea
- Strict vegetarian
- Poor nutrition
- Chronic alcohol consumption
- Psychosis
- Peripheral neuropathy – hands and feet are painful, tingling and may even lack sensation
- Unsteady gait*
- Pallor of mucous membranes
- Jaundice – intramedullary hemolysis
- Tachycardia
- Glossitis
- Splenomegaly
- Hyperpigmentation of skin
- Mental changes ranging from irritability to psychosis
- Peripheral neuropathy
- Abnormal gait*
- Loss of balance* – positive Romberg test
- Loss of vibratory and proprioceptive senses*
- Blindess due to optic nerve atrophy*
- Hyporeflexia, clonus and Babinsky sign can occur but not frequently *
- History
- Investigations
- Complete blood count
- Reduced hemoglobin – <4-6 g/dL
- Raised MCV – >100fL
- Reduced red blood cell count – <2 million per microliter in severe cases
- Peripheral blood smear
- Macroovalocytes
- Hypersegmented neutrophils – at least 5% have 5 or more lobes
- Nucleated red blood cells
- Howell Jolly bodies, cabot rings and remnants of nuclear material may be seen in red blood cells
- Complete blood count
- Lactate dehydrogenase levels
- Increased in severe cases.
- Marker of hemolysis
- Reticulocyte count
- Markedly reduced indicating ineffective erythropoesis and hemolysis.
- Serum folate levels
- Normal levels range from 2 to 20 ng/mL
- Folate deficiency starts at <2.5 ng/mL
- Serum B12 levels
- Reference range is 200-900 pg/mL (picograms per milliliter)
- Results below 150 pg/mL is diagnostic of B12 deficiency
- Bone marrow aspiration
- Not necessary to make a diagnosis but can be used to assess iron stores and rule out malignancy.
- The bone marrow is hypercellular with megaloblasts (large red blood cell precursors) and large, lobulated megakaryocytes
- Other tests
- Homocysteine and methylmalonic acid levels can be used to differentiate B12 deficiency from folate deficiency. Both are elevated in B12 deficiency but only homocysteine is raised in folate deficiency.
- Schilling test – valuable test but is contraindicated in pregnancy due to the use of radioactive substances.
- Iron studies – iron deficiency may mask megaloblastic anaemia hence the need to assess iron stores. Plus folate and B12 therapy may consume iron stores.
- Treatment
- Folate treatment
- Dosage range is from 1-5 mg a day, oral. Usually 1mg once a day is sufficient.
- After 5 to 6 days of therapy hematocrit levels will increase by 1% daily.
- After 3- 4 days, reticulocyte count will increase as well.
- B12 treatment
- 1000 micrograms of B12 should be administered intramuscularly or subcutaneously on a monthly basis.
- Folate treatment
- Complications
- Fetal/ Infant complications
- Low birth weight babies
- Neural tube defects in infants
- Subacute combined degeneration – permanent neurological damage with gait ataxia, memory loss, peripheral neuropathy and psychiatric disturbances.
- Increased risk of developing malignancy especially in folate deficiency
- Fetal/ Infant complications
- Differential diagnoses
- Celiac disease
- Alcoholic hepatitis
- Gastric cancer
- Atrophic gastritis
- Tropical sprue
- Myelodysplastic syndrome
- Prevention
- Proper nutritional counselling to ensure a balanced diet. Vegetarians should add eggs and dairy products to prevent B12 deficiency. Eat foods rich in folate such as broccoli, spinach, lettuce and many more as well as avoid excessive cooking to prevent loss of folate.
- Folic acid supplements should be given preconception and in early pregnancy (about 0.4mg a day for non high risk patients). Should be continued through lactation and the perinatal period
- Counsel patients who are on the drugs mentioned above that may cause B12 and folate deficiency on the importance of adequate supplementation.