World Clinics Obstetrics and Gynecology: Anemia Sabaratnam Arulkumaran, Mala Arora, Manju Puri
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Overview of Anemia

1,*Sadia Mansoor MS,
2Manju Puri MS
1Department of Obstetrics and Gynecology, King George Medical University Lucknow, Uttar Pradesh, India
2Department of Obstetrics and Gynecology, Lady Hardinge Medical College New Delhi, India

ABSTRACT

Anemia is the most common hematological disorder affecting the world. The etiologies are manifold; nutritional anemia being the commonest in developing countries. Anemia in pregnancy is considered to be one of the major causes of maternal mortality in the world. The importance of eliciting a thorough history and physical examination in building the diagnosis and assigning the etiology is indisputable. A complete blood count and peripheral blood smear analysis can help establish the diagnosis of anemia. Specific laboratory investigations are done to confirm the diagnosis and know the cause of anemia. This article aims at giving an overview of the disease burden, causes, diagnosis and management of anemia.
 
INTRODUCTION
Anemia is a global public health problem affecting both developing and developed countries with major consequences for human health as well as social and economic implications. It occurs at all stages of the life cycle, but is more prevalent in pregnant women and young children. Iron deficiency anemia (IDA) is considered to be the most important contributing factor to the global burden of disease.1
Regardless of its etiology, the World Health Organization (WHO) estimates that anemia affects over 1.62 billion people worldwide. The most affected group is preschool-age children with a prevalence of 47%, followed by pregnant women (41%), nonpregnant women (30%), school-age children (25%), and people older than 60 years of age (24%); men are the least affected (12%). However, globally, majority are nonpregnant women.2
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According to WHO, most affected regions are Southeast Asia and Africa.3 On an average, about 50% of the anemia is attributable to iron deficiency. Although, interventions are in place but the prevalence is still high indicating a need for revisiting this problem to identify the bottlenecks and redefine the strategies and ways to implement preventive measures effectively. Worldwide, the prevalence of anemia has a “social imbalance”, it is more prevalent in lower socioeconomic strata and population with low educational status.4
 
DEFINITION
“Anemia” is defined as a reduction in the oxygen carrying capacity of blood as a result of a decrease in the red cell mass to subnormal levels. It is the decrease in hemoglobin or hematocrit level below two standard deviations for that age and sex.
The decrease in hemoglobin concentration in the blood leads to a consequent decrease in the oxygen delivery at the tissue level with resultant compensatory physiological adaptations by the body. These adaptations are listed in table 1.
Anemia causes a decrease in oxygen delivery at the tissue level and hypoxia which leads to increased dissociation of oxygen from hemoglobin. Increase in blood flow, further increases the tissue oxygenation. Gradually, despite the compensatory adaptive mechanisms tissue hypoxia develops, causing increased secretion of erythropoietin from kidneys to increase the red cell mass the degree of impairment of tissue oxygenation is dependent on their level of oxygen requirement. The brunt is mainly borne by the tissues with high oxygen requirement like brain, heart and skeletal muscles during exercise. Therefore, the blood is redistributed from less important organs to vital organs like heart and brain to maintain their optimum functioning.
According to WHO,5 anemia is diagnosed when hemoglobin levels are lower than 12 g% in nonpregnant women and lower than 11 g% in pregnant women.
Iron deficiency anemia accounts for 50% of anemia with most of the surveys focused on women and children. Centers for disease control and prevention (CDC)6 cut off values for defining anemia in pregnant women are based on values corresponding to the fifth centile of hemoglobin levels appropriate for that gestational age.
Table 1   Compensatory Physiological Adaptations by the Body in Response to Anemia
  • Increase in dissociation of oxygen from hemoglobin
  • Increase in blood flow to the tissues
  • Increase in erythropoietin secretion
  • Redistribution of blood flow
  • Increase in cardiac output
3
Table 2   Trimester wise Hemoglobin Cut Off Defining Anemia in Pregnancy
Trimester
Hemoglobin level
Hematocrit
First trimester
Hb <11 g%
Hct <33%
Second trimester
Hb <10.5 g%
Hct <32%
Third trimester
Hb <11 g%
Hct <33%
Table 3   Indian Council of Medical Research Grading of Anemia
Mild
10.0–10.9 g%
Moderate
7.0–9.9 g%
Severe
4.0–6.9 g%
Very severe
<4.0 g%
The trimester wise hemoglobin values are shown in table 2.
Indian Council of Medical Research (ICMR)7 has defined the grades of severity of anemia based on the hemoglobin levels as given in table 3.
 
CLASSIFICATION OF ANEMIA
Anemia can result from multiple etiologies. These etiologies serve as the basis for classifying anemia. There can be an overlap of different causes in one patient. For instance, coexistence of defective hemoglobin production and increased red cell destruction is seen in thalassemia. Two of the widely accepted classifications are based on pathophysiology and morphology.8
 
Pathophysiological Classification
This classification depends upon the mechanism of development of anemia. This includes hemodilution, blood loss, increased destruction and impaired production.
Table 4 gives the various causes of anemia.
 
Morphological Classification
Anemia can also be classified on the basis of red cell morphology as visible on the peripheral blood smear under microscope. The morphology of cells can be predictive of specific etiology depending on their size, color and shape of cells. The smear is expressed quantitatively using certain parameters; mean cell volume (MCV), mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC) and red cell distribution width (RDW).4
Table 4   Various Causes of Anemia
Physiological
Pregnancy
Pathological
Blood loss
Acute
Trauma
Chronic
Gastrointestinal lesions
Increased destruction of cells
Intrinsic abnor-malities
Membrane defects
  • Hereditary Spherocytosis
  • Hereditary elliptocytosis
Enzyme deficiency
  • Glucose-6-phosphate dehydrogenase (G6PD)
  • Pyruvate kinase
  • Hexokinase
Hemoglobin defects
  • Sickle cell anemia
  • Thalassemia
Extrinsic abnor-malities
Antibody mediated
  • Transfusion reaction
  • Drug associated
  • SLE
Mechanical trauma to RBC
  • TTP
  • DIC
  • Defective cardiac valves
Infection
  • Malaria
Impaired RBC production
Disturbed proliferation
Aplastic anemia
Defective DNA synthesis
  • Megaloblastic anemia
  • Anemia of chronic disease
  • Anemia of endocrine disorder
Defective hemoglobin synthesis
  • Iron deficiency
  • Sideroblastic anemia
  • Thalassemia
Marrow replacement
  • Acute leukemia
  • Myelodysplasia
  • Metastatic neoplasm
  • Granulomatous disease
TTP, thrombotic thrombocytopenic purpura; DIC, disseminated intravascular coagulation; RBC, red blood cell; SLE, systemic lupus erythematosus; DNA, deoxyribonucleic acid.
5
  • Mean cell volume: The average volume per red cell, expressed in femtoliter (fL).
    MCV =
    Packed cell volume (PCV) in L
    Red blood cell (RBC) count/ L
  • Mean cell hemoglobin: The average mass of hemoglobin per red cell, expressed in picograms (pg).
    MCH =
    Hemoglobin /L
    RBC count /L
  • Mean cell hemoglobin concentration: The average concentration of hemoglobin in a given volume of packed red cells, expressed in grams per deciliter. This index is considered to be clinically important relative to other indices as it does not take into consideration the RBC size and count.
    MCHC =
    Hemoglobin /dL
    PCV in L/L
  • Red cell distribution width: It is the coefficient of variation in red cell volume.
These red cell indices are calculated in laboratories using automated machines. The reference range varies among laboratories and therefore, the laboratory reference range should be considered while interpreting the results. The standard range of various adult red cell parameters is given in table 5.8
Depending on the measurement of these red cell indices, the morphological classification is as follows (Table 6):
 
PHYSIOLOGICAL ANEMIA OF PREGNANCY
During pregnancy, the demand of iron, folic acid, other micro and macronutrients increases to support the growing fetus. To keep up with the increasing demand, blood volume increases. Hematological changes begin during the first trimester at around 6–8 weeks and reach their peak during the late second or early third trimester.
Table 5   Various Red Blood Cell Parameters with Their Range
Parameters
Range
Hemoglobin (g/dL)
12.0–15.0
Hematocrit (%)
33–43
Red cell count (* 106/mcL)
3.5–5.0
Reticulocyte count (%)
0.5–1.5
Mean cell volume (fL)
82–96
Mean cell hemoglobin (pg)
27–33
Mean cell hemoglobin concentration (g/dL)
33–37
Red cell distribution width
11.5–14.5
6
Table 6   Morphological Classification of Anemia
I. Microcytic, hypochromic
MCV, MCH, MCHC are reduced
  • Iron deficiency anemia
  • Thalassemia
  • Sideroblastic anemia
  • Anemia of chronic disease
II. Normocytic, normochromic
MCV, MCH, MCHC are normal
  • Hemolytic anemia
  • Bone marrow failure
III. Macrocytic, normochromic
MCV is raised
  • Vitamin B12 deficiency
  • Folate deficiency
  • Liver disorder
  • Hypothyroidism
>MCV, mean cell volume; MCH, mean cell hemoglobin; MCHC; mean cell hemoglobin concentration
There is an expansion of plasma volume by 40–50% and increase in the red cell mass by up to 30% of the prepregnancy status.9 This disproportionate increase in the blood constituents leads to a net decrease in the hemoglobin levels. This is known as the dilutional or physiological anemia of pregnancy. Plasma volume is maximum at around 28–32 weeks of gestation. Hence, hemoglobin levels reach a nadir during this period. In the later gestation, there is cessation of plasma expansion with continued production of erythroid cells. This leads to gradual increase in hemoglobin levels near term. The blood cells are normocytic unless the pregnancy is complicated by iron deficiency where the RBCs become microcytic and hypochromic. CDC gives hemoglobin and hematocrit criteria for defining anemia in pregnancy (Table 2).
 
WORKUP OF A PATIENT WITH ANEMIA
 
History
Anemia has a number of risk factors. For instance, vegetarian diet may predispose to vitamin B12 deficiency, likewise alcoholism and certain drugs may lead to folate deficiency. Similarly, cancers and chronic inflammatory disorders may cause bone marrow suppression leading to anemia. Familial inheritance may lead to transmission of hemoglobinopathies which is another important cause.
The symptoms of anemia are neither sensitive nor specific as they do not help to differentiate between the different types of anemia. They only reflect the degree of tissue adaptation to hypoxia in response to low hemoglobin levels. Symptoms of anemia are more pronounced in patients with decreased cardiopulmonary reserve or in those where the progression of anemia has been too quick.
Symptoms such as weakness, fatigue, lethargy, shortness of breath on exertion suggest anemia. Milder forms are generally asymptomatic. Anemia may present as 7vertigo, headache, pulsatile tinnitus, amenorrhea, and loss of libido. Heart failure or shock can develop in patients with severe tissue hypoxia or hypovolemia.
Certain symptoms may point towards the cause of anemia. For example, melena, epistaxis, hematochezia, hematemesis, or menorrhagia, suggest anemia due to chronic blood loss. Jaundice and dark urine, in the absence of liver disease, suggests hemolysis. Weight loss may suggest cancer. Diffuse severe bone or chest pain may suggest sickle cell disease, and stocking-glove paresthesias may suggest vitamin B12 deficiency.
Duration of anemia can be deciphered if the patient has old blood records or documents about prior illness. Similarly, history of rejection as a blood donor or previous prescriptions of oral hematinics suggest that the patient may have been suffering from anemia in the past. History of blood loss during pregnancy, abortion and menstruation should be carefully sought as this information is most notoriously inaccurate unless deeply probed into by the physician. Number of pads or tampons used per day should be quantified to estimate the amount of blood loss.
Dietary history is of utmost importance and should be taken in detail. It should include the type and quantity of food consumed or avoided by the patient. A meal to meal complete description of the diet should be obtained. Consumption of unpalatable substances such as clay, laundry starch, etc. should also be asked for.
A careful history of any increase or decrease in weight should also be asked as it may suggest anemia of wasting disease, infectious or neoplastic etiology.
Eliciting proper history from a woman suffering from anemia is of paramount importance and it is directed mainly to know the likely cause of anemia such as poor dietary intake, malabsorption, passage of worms in stool or chronic blood loss in conditions like menorrhagia, piles, etc. Important points to be elicited in the history have been mentioned in table 7.
 
Physical Examination
Complete physical examination is necessary. Signs of anemia are neither sensitive nor specific. Special attention should be given to the patient's habits, any features of malnutrition or chronic disease which may be an important clue to the underlying etiology. The vital signs; pulse rate, blood pressure, respiratory rate and temperature, are recorded. The skin and mucous membranes are inspected for pallor, abnormal pigmentation, icterus, purpura, petechiae or ulcers. Optic fundi are carefully examined for retinopathy of anemia.10 These include round or splinter hemorrhages along with cotton-wool spots or hard exudates in the retina. The fundal changes in anemia correlate with the severity of anemia and resolve with the correction of anemia. Conjunctiva and sclera may show signs of pallor, icterus, splinter hemorrhages, petechiae or telangiectasia suggestive of diabetes, hypertension, etc., that can help us plan further work up.8
Table 7   History Points to be elicited in Patients with Anemia
General symptoms
Fatigue, weakness, shortness of breath, vertigo, tinnitus, dizziness, loss of libido, syncope, fever, weight loss
Gastrointestinal symptoms
Gastritis, hiatal hernia, diverticula, passage of fresh blood in stools, dark colored stools, bulky stools, chronic diarrhea, recent gastrointestinal surgery, passage of worms
Urinary symptoms
Recurrent infection, abnormal color of urine, burning, increased frequency, suprapubic pain
Duration of symptoms
Previous blood examinations, previous blood records, history of rejection as a blood donor
Menstrual history
Cycle duration and interval, number of pads used, clots expelled
Obstetric history
Number of previous pregnancies, abortions, interpregnancy interval, history of antepartum hemorrhage or postpartum hemorrhage, need for blood transfusions
Contraceptive history
Insertion of intrauterine device and any menorrhagia following insertion
Past history
Frequent infections, recent major trauma, gastrointestinal surgery, transplant surgery, radiotherapy, bleeding disorder
Family history
Hemoglobinopathy, jaundice, cholelithiasis, bleeding disorders, splenectomy, recurrent blood transfusions
Personal history
Occupational exposure to paints, solvents, insecticide, etc. Smoking, intake of tranquilizers, aspirin, anticoagulants, steroids, alcohol. Recurrent blood transfusions
Dietary history
Foods avoided, quantity of food consumed, cooking habits, excessive consumption of tea, coffee, consumption of clay, laundry starch, ice, etc
Thyroid should be looked for any enlargement. Bilateral edema, if present, may point towards an underlying cardiac, renal or liver abnormality, whereas, unilateral edema may be due to lymphatic obstruction secondary to an underlying malignancy. A general examination for the enlargement of lymph nodes to rule out infectious or neoplastic pathology is done.
A careful systemic examination includes a search for splenomegaly or hepatomegaly as both are sites for extramedullary hematopoiesis with specific attention to their firmness, presence or absence of nodularity and tenderness. In chronic disease, the liver and spleen is enlarged, firm and nontender. Nodularity is mostly suggestive of malignancy while in an acute infection, the organs are tender on palpation. In cardiovascular system, hemic murmurs are often heard due to hyperdynamic circulation. Apex beat may be shifted more laterally in cases with 9moderate severe anemia. Heart size cannot be ignored as enlarged heart size is reflective of long-standing anemia.
The neurologic examination includes tests for sense of position and vibration. All the cranial nerves should be examined and deep tendon reflexes should be checked.11
A pelvic and rectal examination is indicated in women with anemia. A tumor or infection in these organs could be a cause for anemia. The external genitalia are to be examined for any evidence of blood loss. A per speculum and per vaginal examination is necessary in patients presenting with shock. In pregnant patients, a careful antenatal examination is done noting the fundal height and whether it corresponds to the period of gestation, uterine contour, tone, tenderness, palpation of fetal parts, amount of liquor and fetal heart sound. In cases of uterine rupture, bleeding per vaginum is accompanied with abnormal uterine contour, easily palpable fetal parts and loss of fetal heart sound while in a case of placenta previa, the presenting part is generally free floating. In abruptio placentae, fresh bleeding per vaginum is accompanied with increase in fundal height and uterine tone.
 
Laboratory Investigations
After a detailed history and physical examination the cause of anemia may be suspected. Laboratory investigations are done to confirm the diagnosis and to further aid in the management of the patient. The cost effectiveness of investigations should be assessed. If the etiology is not obvious on initial clinical assessment, the physician plans a scheme of investigations tailored for the patient. The most rational approach is to begin by evaluating the values and indices on the complete blood count report and examining the peripheral blood smear. This helps in making the diagnosis and knowing the type of anemia. Depending upon these basic investigations, further workup of the patient is planned to establish the etiology.
 
CONCLUSION
Anemia is not a standalone disease. It is the manifestation of an underlying disorder. A good history and a thorough physical examination not only aids in establishing the correct etiology but also prevents the need for unnecessary investigations thereby, reducing the financial burden on the patient. In cases where the etiology is not apparent, laboratory investigations aid in such cases and may even establish multiple causes leading to the development of anemia. Majority of the signs and symptoms improve with the correction of anemia. The management therefore, aims at identifying these underlying causes and successfully treating it to resolve the manifestations of anemia.10
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