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SamppaRyhänen

Anaemia in Children

Essentials

  • Identify readily leukaemias, haemolytic crises and bleedings as these conditions require immediate further investigations and treatment.
  • Reveal the underlying cause of iron deficiency and ensure adequate response to iron medication.
  • Note the age-dependent variation of blood haemoglobin concentration:
    • at birth > 150 g/l
    • 1-4 months > 100 g/l
    • 5 months-5 years > 105 g/l
    • 6-15 years > 115 g/l

Examinations in primary health care

  • Register the general condition, colour (skin, conjunctivase, paleness and jaundice), signs of infection, pains, lymph nodes, size of liver, spleen and testes, cardiovascular functions, signs of bleeding, oedema.
  • In case of a child with anaemia, examine always complete blood count and reticulocyte count and, as necessary, other targeted investigations.
  • Exceptionally high red blood cell distribution width (RDW) is a sign of e.g. mild iron deficiency in which the haemoglobin concentration and the mean corpuscular volume (MCV) may still or already be normal.
    • Small MCV usually is a sign of iron deficiency, but it may also be caused by thalassemias Thalassaemias, haemoglobinopathies (HbS, HbE etc.), recurrent infections, inflammation, or a tumour (so-called anaemia of chronic disease).
    • If the MCV is not small (normocytic or macrocytic anaemia), consult a paediatric haematologist or paediatrician (usually a direct Coombs test, liver and kidney function tests, folate and vitamin B12, and faecal and urinary blood search are recommended).
    • The patient may have iron deficiency even if haemoglobin concentration and MCV were normal. In unclear cases, determine soluble transferrin receptor (sTfR: increased concentration seen in iron deficiency and in accelerated production of red blood cells, decreased in suppression of red blood cell production) and ferritin (decreased in iron deficiency, may be increased - independent of iron stores - by infections or inflammations and in hepatic and malignant neoplastic diseases).
    • Serum hepcidin concentration is reduced in iron deficiency and increased in inflammatory reaction. Measuring hepcidin is useful in identifying anaemia caused by a chronic inflammatory disease because then hepcidin is pathologically increased even though there is not a lot of iron in the body.
  • If a child has a pure anaemia with normal other blood cells, the direct Coombs test is negative and he/she is not bleeding, prompt action is unnecessary. If a child with anaemia has positive result in direct Coombs test, he/she has autoimmune haemolytic anaemia (AIHA Haemolytic Anaemia) and is immediately referred as an emergency case to a paediatric hospital to receive glucocorticoid therapy.
  • If other cell lines are also deviant and the patient does not have an infection that would explain the abnormality, suspect leukaemia and refer the child on the same day to a hospital with preparedness for bone marrow examination and treatment of leukaemia.

Treatment of iron deficiency anaemia Iron Therapy for Improving Psychomotor Development and Cognitive Function in Children Under the Age of Three

  • If the haemoglobin and MCV values are low, but in line with each other, the child usually has iron deficiency anaemia. Start oral iron replacement (Fe++ ) at a dose of 4-6 mg/kg/day in 1-3 doses daily, taken into an empty stomach. Taking the iron replacement preparation with juice that contains vitamin C (e.g. orange juice) improves the absorption of iron. The treatment response seems to be at least as good when the daily dose 4-6 mg/kg is taken as a single dose every second day only. It is simpler for the family and can lead to better compliance.
    • The number of iron preparations suitable for children has been declining over the recent years. Liquid products are available as Fe++ ferrous salts (Enfamil Fer-in-Sol® and Niferex® ) and as Fe+++ hydroxide polymaltose complex (Maltofer® ).
    • Iron in liquid form stains teeth, and hence other preparations should be preferred in older children. If the iron is administered every second day, the treatment can be carried out even in quite small children with 100 mg iron capsules by opening them and mixing the iron powder (the full amount of a capsule or approximately half of it) with a small amount of fruit purée.
    • Sucrosomial iron is a new option for oral iron administration, also in children. In this form, iron is better protected from stomach acids and the absorption pathway is independent of hepcidin, so bioavailability is likely to be better. No good-quality studies have been done in children on sucrosomial iron, and hence it cannot be recommended as a first-line option, but trying it may be considered in patients who get significant adverse effects from conventional iron preparations or whose treatment has failed with conventional preparations.
  • Iron therapy should be carefully implemented because iron deficiency may cause impairment of cognitive capacity at least in infants. On the other hand, iron therapy should not be unnecessarily started or continued because iron excess is harmful Haemochromatosis.
  • Follow up haemoglobin after two weeks, and if possible, reticulocyte count. The diagnosis was correct if a treatment response is observed. Reticulocytosis and an increase in RDW are clearly more rapid measures of successful iron therapy than the raised haemoglobin value.
  • Continue iron medication for at least three months after haemoglobin has normalized.
  • Iron therapy may be discontinued when the ferritin concentration is normalised (provided that there is no acute phase reaction ongoing). The haemoglobin or MCV do not usually increase once ferritin reaches level 20-25 µg/l.
  • When the diet has provided too little iron, correcting the child's nutrition is an important part of therapy. Consumption of milk should be limited to a maximum of 500 ml per day.

Investigating the cause of iron deficiency

  • Iron deficiency is merely a symptom, not a disease. Find its cause. In cases of poor response to iron medication, think again! Look for dietary causes for insufficient intake of iron (especially in small children), for malabsorption and for blood loss due to bleeding (in older children in particular).
    • Diet history (too much milk?) and, if necessary, a diary of one week's meals
    • Colour of stools (black?)
    • Growth curves; relevant antibodies in the serum for the detection of coeliac disease Coeliac Disease, if indicated.
    • Tests for blood in urine and stool (blood is examined from three stool samples)
    • Refer to a paediatric hospital if blood is detected in the stools (sedimentation rate, endoscopies, Meckel scan). Possible diagnoses include Meckel's diverticulum or terminal colitis, in older children ulcerative colitis or Crohn's disease Inflammatory Bowel Diseases in Children.
    • Sometimes anaemia of a pre-school-aged child results from occult gastrointestinal bleeding associated with excessive intake of cow's milk. The child may also have hypoproteinaemia that responds to iron medication. Usually the child drinks large amounts of milk, and reduction of milk consumption can be recommended on the basis of history alone. Total abstinence is not necessary.
    • In teenagers, rapid growth and the onset of menses in girls cause iron deficiency. Extensive exercise increases the risk of developing iron deficiency. In addition, a low-iron diet can contribute to the development of iron deficiency.

Investigations and treatment of anaemia at the hospital

  • If a direct Coombs test is positive: the child has autoimmune haemolytic anaemia (AIHA). Start prednisolone immediately with 2-4 mg/kg/day in three doses. RBC transfusion is given only in emergency, and finding a suitable red blood cell unit is often difficult.
  • If the child has Coombs-negative haemolytic anaemia and spherocytes are seen on a blood film during the neonatal period, the newborn's and mother's blood groups (ABO; Rh) should be examined. From older children take family history (red blood cell anomalies, e.g. spherocytosis) and examine the lack of band-3 protein by flow cytometry. Patients with congenital spherocytosis (CS) may need RBC transfusions if the haemoglobin concentration falls clearly below 80 g/l. Plasma bilirubin and haptoglobin might give additional information on the degree of haemolysis. High plasma haemoglobin level, disappearance of haptoglobin binding capacity, and the presence of RBC fragments in the blood smear indicate intravascular haemolysis.
  • If there is also thrombocytopaenia, ask about intestinal symptoms and check the urine and plasma creatinine concentrations for possible haemolytic uraemic syndrome.
  • If the reticulocyte count is low despite anaemia and the MCV is not low, the patient has red blood cell production disorder. Check for other blood cell lines and ensure that the child does not have congenital spherocytosis http://www.orpha.net/en/disease/detail/822 (aplastic crisis usually after erythema infectiosum). Transient erythroblastopenia of childhood (TEC) is the most probable aetiology. Diamond-Blackfan anaemia http://www.orpha.net/en/disease/detail/124 (infants) and Fanconi's anaemia http://www.orpha.net/en/disease/detail/84 or acquired aplastic anaemia (toddlers and preschoolers) should also be kept in mind (anomalies, high foetal haemoglobin, rather high MCV). Bone marrow examination is performed, if necessary, electively, after consultation with a haematologist.
  • Thalassaemia Thalassaemias and haemoglobinopathies are examples of microcytic anaemias that do not respond to iron medication (haemoglobin concentration disproportionally high in relation to low MCV; TfR and ferritin normal or increased). Take family history, find out the child's earlier blood cell counts, examine parents' haemoglobin and MCV, and consider examination of the child's red blood cells (haemoglobin) with haemoglobinelectrophoresis and haemoglobin isoelectric focusing (haemoglobin fractions).

Alternative diagnoses and investigations

  • See figure 1.

    References

    • Parkin PC, Borkhoff CM, Macarthur C, et al. Randomized Trial of Oral Iron and Diet Advice versus Diet Advice Alone in Young Children with Nonanemic Iron Deficiency. J Pediatr 2021;233():233-240.e1. [PubMed]
    • Parkin PC, Koroshegyi C, Mamak E, et al. Association between Serum Ferritin and Cognitive Function in Early Childhood. J Pediatr 2020;217():189-191.e2. [PubMed]
    • Camaschella C. Iron deficiency. Blood 2019;133(1):30-39. [PubMed]