The document provides an overview of approach to anemia in children. It begins with definitions of anemia and discusses clinical features and etiologies. Common causes of anemia include impaired red blood cell production, increased red blood cell destruction, and blood loss. The document reviews physiological neonatal anemia and pathological neonatal anemia. It outlines the clinical approach including history, physical exam, and initial lab workup. The approach depends on red blood cell indices and reticulocyte count to guide further testing and diagnosis of the underlying cause.

1. Approach to Anemia
Fatima Farid
Resident Year One

2. Contents
» Overview
» Neonatal Anemia
» Clinical Approach
» Case Review
» Conclusion

3. Definition
» “Anemia is defined as a reduction of the hemoglobin concentration or red blood cell
(RBC) volume below the range of values occurring in healthy persons”, Nelson
Textbook of Pediatrics, 20th Edition.
» Practically, the threshold for defining anemia is a hemoglobin or hematocrit value at
or below the 2.5th percentile for age, race and gender. UpToDate, 2017
» Anemia should not be considered a diagnosis, but rather a finding that warrants
further investigation.

4. Clinical Features
» Anemia may manifest clearly if developed acutely, or with minimal features if
chronically present.
» Common manifestations of anemia:
» Pallor
» Lethargy, easy fatiguability
» Poor feeding/ exercise intolerance
» Irritability
» Headache

5. Etiology
» Anemia is not a specific entity, but rather a manifestation of any number of underlying
pathological processes.
» Underlying conditions may be classified as:
» Inadequate production of red blood cells
» Increased destruction of red blood cells
» Blood loss
» Physiologically, anemia can even be present with normal hemoglobin concentrations,
such as in congenital cyanotic heart disease, pulmonary disease and conditions with
abnormally hemoglobin affinity for oxygen.

6. Source: Illustrated Textbook of Paediatrics, Fifth Edition

7. Impaired Red Cell Production
» Red Cell Aplasia:
» Parvovirus B19 Infection: It is the best documented viral cause of RBC aplasia in patients with
chronic hemolysis, immunocompromised states, or fetuses in- utero. Virus is toxic to marrow
erythroid progenitor cells.
» Diamond- Blackfan Anemia: Rare congenital bone marrow failure syndrome. Autosomal dominant
inheritance. More than 90% of cases are diagnosed in the first year of life. Present with profound
anemia at 2- 6 months of age. Approximately 50% of patients have congenital anomalies. Raised
erythrocyte adenosine deaminase (ADA) is characteristic.
» Transient Erythroblastopenia of Childhood (TEC): Most common acquired red cell aplasia.
Moderate to severe normocytic anemia with reticulocytopenia following viral infection in a
previously healthy child (aged 6 months to 3 years, usually older than 12 months). Recovery in 1- 2
months. Child must be followed closely to rule out Leukemia.

8. Impaired Red Cell Production
» Ineffective Erythropoiesis:
» Iron deficiency: Presents after 6- 9 months of age (after neonatal stores depleted). May be due in
inadequate intake (cow milk- iron deficient, milk protein allergic colitis), chronic bleeding (peptic
ulcer, Meckel diverticulum, polyp, hemangioma, IBD, parasitic infections, menstruation), or poor
absorption (Celiac disease, Giardiasis).
» Folic Acid deficiency: Inadequate intake (goat milk), increased requirements (chronic hemolysis,
premature babies), poor absorption (chronic diarrhea, diffuse bowel inflammatory disease), drugs
(Methotrexate, Pyrimethamine, Trimethoprim), inborn error of folic acid metabolism (severe
brain affliction).

9. Impaired Red Cell Production
» Ineffective Erythropoiesis:
» Chronic diseases with on- going immune activation:
» Shortened RBC life-span (high IL- 1 makes macrophages more active)
» Ineffective erythropoiesis due to effect of immune cells/ cytokines on BM
» Functional iron deficiency due to raised Hepcidin (diverts iron from circulation into RES
despite low circulatory concentration)
» Anemia of chronic kidney disease: Impaired erythropoietin production and chronic
blood loss (blood sampling, dialysis)

10. Source: Nelson Essentials of Pediatrics, Seventh Edition

11. Source: Illustrated Textbook of Paediatrics, Fifth Edition

12. Hemolysis
» Hereditary Spherocytosis: Mainly autosomal dominant inheritance. Affected patients
may be asymptomatic with minimal anemia/ hemolysis, or have severe disease
requiring regular blood transfusions and splenectomy. Significant cause of neonatal
anemia and jaundice requiring phototherapy or even exchange transfusion.
Splenomegaly is common after infancy, gall stones may develop. Diagnostic triad is
anemia, jaundice and splenomegaly, with spherocytes on blood film, reticulocytosis,
elevated MCHC, and suggestive family history.

13. Hemolysis
» G6PDD: X- linked inheritance. Asymptomatic till exposure to triggering agent, resulting
in rapid drop in hemoglobin, jaundice, dark urine. May present in neonates at birth in
case of maternal exposure, or if a certain genetic variant is present (G6PD A-, G6PD B-).
Diagnosed by enzyme activity ≤ 10%.
» Thalassemia: Spectrum of presentations depending on severity of condition. Diagnosed
by hemoglobin electrophoresis. Microcytic hypochromic anemia with normal/ high RDW.
» Autoimmune Hemolytic Anemia: Warm and cold types several underlying conditions.
May present acutely similar to HS, distinguished as AIHA is DAT positive.

14. Source: Illustrated Textbook of Paediatrics, Fifth Edition

15. Recap
Definition of Anemia
Clinical Features
Underlying Causes

16. * The production of androgens at the onset of puberty in boys causes males to maintain a normal hemoglobin
value about 1.5 to 2 g/dL higher than girls. Menstruation also plays a role in lower hemoglobin levels in post-
menarchal girls.
*
*
Source: Approach to the child with anemia, UpToDate

17. Neonatal Anemia

18. Physiological Anemia
» Healthy full- term infants have high hemoglobin concentrations, and larger RBC
volumes than to older children and adults.
» Within the first week of life, a progressive decline in hemoglobin concentration begins
and then persists for six to eight weeks.
» The hemoglobin concentration continues to decline until the tissue oxygen needs exceed
the oxygen delivery. This point usually occurs between 8 to 12 weeks, when a
physiological nadir of 11 g/dL is reached.

19. Physiological Anemia
» Represents the normal adaptation to extra- uterine life, and reflects the relative
excess of oxygen supply compared to tissue requirements.
» The is no hematologic problem, and no treatment is required unless anemia is
exacerbated by other ongoing processes.

20. Source: Approach to the child with anemia, UpToDate

21. Anemia of Prematurity
» The same physiological factors at play in term infants are exaggerated in prematurity.
» Hemoglobin decline is more severe and rapid, nadir is at 7- 8 g/dL at 3- 6 weeks of age,
and may be even lower in very small premature babies.
» Additionally, over- burdened erythropoiesis: shorter RBC life span with larger mass,
immature erythropoietin production.
» Not a benign condition, and may require blood transfusion.

22. Case: Neonatal Anemia
» A full- term infant is delivered with the use of forceps; the pregnancy and
delivery were otherwise uncomplicated.
The initial examination is normal, but on the second hospital day, he is pale
and fussy. The reticulocyte count and bilirubin level are normal, and the
hemoglobin is 9 g/dL. Repeat physical examination reveals an increased head
circumference.
Source: Evaluation of Anemia in Children, American Association of Family Physicians, Journal, Volume 81, Number 12, June 2010

23. Neonatal Anemia
» Pathological anemia in newborns and infants is distinguished from physiological anemia
by the presence of any one of the following:
1. Hemoglobin less than 13.5 g/dL in the first month of life
2. Anemia with lower hemoglobin levels than typically seen in physiological anemia (< 9 g/dL)
3. Signs of hemolysis or symptoms of anemia
» Common causes of pathological anemia in newborns include blood loss, immune
hemolytic disease, congenital infection, congenital hemolytic anemia, and twin- to- twin
transfusion syndrome.

24. Case: Neonatal Anemia
» Cranial hemorrhages are often associated with birth trauma, including vacuum and forceps
delivery. In particular, subgaleal bleeds (sub-aponeurotic hemorrhage) can be of sufficient
volume to cause shock. Physical examination findings may include mental status changes,
jaundice, tachycardia or tachypnea, and increased head circumference.
» In this patient, a computed tomography scan confirms a subgaleal hemorrhage, and the
infant is transferred to a neonatal intensive care unit for transfusion and monitoring.
Source: Evaluation of Anemia in Children, American Association of Family Physicians, Journal, Volume 81, Number 12, June 2010

25. Source: Evaluation of Anemia in Children, American Association of Family Physicians, Journal, Volume 81, Number 12, June 2010

26. Source: Nelson Essentials of Pediatrics, Seventh Edition

27. Source: Approach to the child with anemia, UpToDate

28. Recap
Definition
Clinical features
Etiology
Lab parameters
Neonatal Anemia

29. Clinical Approach

30. History
» Characterizing the symptoms helps elucidate the severity and chronicity of anemia,
and may identify patients with blood loss or hemolytic etiologies.
1. Onset and severity of symptoms: lethargy, pallor, poor oral intake, irritability
2. Symptoms of hemolysis: jaundice, darkening in urine
3. Bleeding symptoms: changes in stool colour (black, or with frank blood), bowel habits, severe/
chronic epistaxis, detailed menstrual history
4. Systemic review to detect underlying medical condition

31. History
» Past Medical History:
1. Previous diagnosis of anemia: features, cause, treatment nature and duration, resolution.
Review previous blood investigations if possible.
2. Recent infectious illness
3. Known medical disease
» Dietary History:
1. Type and amount of food/ formula/ milk
2. Age when breast feeding/ formula milk was discontinued
3. Dietary habits, including presence of pica

32. History
» Birth History:
1. Gestational age
2. Duration of birth hospitalization
3. Jaundice or pallor at birth
4. Reports of neonatal screening
» Developmental History: Age- appropriate milestones
» Drug History:
1. Current and past medications, including herbal/ homeopathic therapy, Phenytoin
2. Recent antibiotic use (immune- mediated hemolysis with Penicillin)
3. Specifically ask about drugs known to precipitate hemolytic episodes in G6PDD

33. History
» Family History:
1. Diagnosed hematological diseases
2. Jaundice/ dark urine after food/ medicine affecting only male members of family
3. History of cholecystectomy or splenectomy
4. Bleeding disorders (von Willebrand disease, Hemophilia, etc)
5. Inflammatory bowel disease, colorectal cancer, intestinal polyps
» Recent infectious exposure/ travel abroad
» Social History: primary care- giver, housing and living condition
Source: Nelson Essentials of Pediatrics, Seventh Edition

34. Physical Examination
» General examination with growth chart assessment.
» Head: cephalohematoma, sub-aponeurotic hemorrhage, frontal bossing with prominence of malar
and maxillary bones
» Skin: pallor, jaundice, petechia/ bruising
» Mouth: glossitis, angular stomatitis, cleft lip, telangiectasia
» Chest: shield- shaped chest, unilateral absence of pectoral muscle, murmur
» Abdomen: organomegaly, perineal exam for hemorrhoids
» Extremities: spoon nails, triphalangeal thumb, hypoplasia of thenar eminence, Beau’s lines
» CNS: irritability/ apathy, peripheral neuropathy, ataxia, stroke

36. Investigations
» Initial blood work- up should include:
1. Complete blood count: hemoglobin level, red cell indices (MCV, MCH, MCHC, RDW),
Hematocrit, WBC/ platelet counts.
2. Peripheral blood film
3. Reticulocyte count
1. Absolute Reticulocyte Count (ARC) : Value < 100 x 10^9 /L means an inadequate BM response.
2. Reticulocyte Production Index (RPI): Value < 2 means an inadequate BM response
» Further work-up depends on suspected underlying causes.

37. Source: Nelson Essentials of Pediatrics, Seventh Edition

38. Source: Approach to the child with anemia, UpToDate

39. Recap
Basics of anemia
Key points about neonatal anemia
Clinical approach anemia

40. Case Review
Source: 100 Cases in Pediatrics

47. Conclusion
» The threshold for defining anemia is hemoglobin or hematocrit concentration less than or equal
to the 2.5th percentile for age, gender and race. Physiological anemia of infancy involves a rapid
decline in hemoglobin to around 11 g/dL at 6- 9 weeks of age.
» Labs include a complete blood count, including RBC indices, reticulocyte count, and review of the
peripheral blood smear. Examination of the peripheral blood smear may reveal features that
suggest a specific cause of anemia, and helps to evaluate the possibility of a hematologic
malignancy.
» The MCV provides a preliminary categorization of the anemia, which guides additional testing.
Source: Approach to the child with anemia, UpToDate

48. Conclusion
» The reticulocyte count distinguishes disorders resulting from rapid destruction or loss
of RBCs (hemolysis or bleeding) from disorders resulting in an inability to adequately
produce RBCs (ie, bone marrow depression). Hemolysis and bleeding are usually
associated with a high reticulocyte count (>3 percent), whereas bone marrow
depression is associated with a low reticulocyte count.
» Once the diagnostic possibilities have been narrowed based upon RBC indices and
reticulocyte response, further confirmatory testing is performed.
Source: Approach to the child with anemia, UpToDate

49. References
» Nelson Textbook of Pediatrics, Twentieth Edition
» Nelson Essentials of Pediatrics, Seventh Edition
» Illustrated Textbook of Pediatrics, Fifth Edition
» “Approach to the child with anemia”, UpToDate
» Evaluation of Anemia in Children, American Association of Family Physicians,
Journal, Volume 81, Number 12, June 2010
» 100 Cases in Pediatrics, 2009 Edition

50. Thank You