Anaemia in children

Anaemia is a quantitative deficiency of haemoglobin (Hb). Haemoglobin is the oxygen-carrying component of RBCs.

The WHO defines anaemia as:

• Hb <130g/L in men aged >15 years.
• Hb <120g/L in women aged >15 years.
• Hb <110g/L in pregnant women.

Let’s look at the normal ranges for children throughout different ages

🏃🏻‍♀️ Physiology

First, let’s recap what haemoglobin does and how it works:

Haemoglobin is made of four subunits, 2 alpha subunits and 2 beta subunits. Each of these subunits contains a haem group with iron. This allows it to bind to oxygen (4 molecules of oxygen per haemoglobin).

Hb is able to change shape (i.e. affinity) depending on the number of oxygen molecules bound to it. As more molecules bind to Hb, its affinity increases. This is known as cooperativity. If no oxygen is bound, Hb is in a tense state (T-state) and when the first oxygen binds, it changes to a relaxed state (R-state) with more affinity.

Oxyhaemoglobin reaching tissues with low pO2 causes a dissociation of oxygen → increasing local pO2.

When there is a higher pO2 concentration (as in the pulmonary circuit), Hb will bind to oxygen and will dissociate from CO2 (carbaminohaemoglobin).

2,3-DPG, temperature, pH, pCO2 all affect oxygen affinity.

Let’s recap erythropoiesis quickly:

Our body produces approximately 2.5 billion erythrocytes per kg per day.

Erythropoiesis occurs in the yolk sac within the early foetus, before changing to the liver and spleen between 2-5 months. At 5 months it finally moves to bone marrow. In children, most bones’ bone marrow can produce RBCs, however, in adults it is mostly in the vertebrae, ribs, sternum, sacrum, pelvis and proximal femur.

Extramedullary haemotopoiesis may be triggered when there is insufficient bone marrow production (it is triggered by erythropoietin which is produced by the kidneys in response to hypoxia) which can be seen in thalassemias, myelofibrosis and other haemoglobinopathies.

A multipotent haematopoietic stem cell (MHSC) known as a haemocytoblast is the origin of all blood cells. They differentiate into a common myeloid progenitor which will go on to produce RBCs, mast cells, megakaryocytes (which then form thrombocytes) and myeloblasts (which then form myeloid WBCs).

Let’s look at the steps between our common myeloid progenitor and our mature erythrocyte:

We progress from a CMP to a megakaryocyte erythroid progenitor (which makes erythrocytes and megakaryocytes). It then forms into a proethryoblast which is the earliest identifiable morphological precursor of an RBC. As our erythroid cells mature, they shrink and lose their nuclei. The reticulocyte is the first erythroid cell to be anucleate. It retains some RNA to produce haemoglobin in the bone marrow and then enters peripheral blood where its RNA is lost → mature RBC.

RBCs are cleared via the spleen when they are senescent (age-related), rigid or abnormally shaped. This is because they are unable to squeeze through the splenic slits and are retained in the spleen before being cleared. A normal RBC lifespan lasts from 110-120 days.

Causes of anaemia in neonates, infants and older children

In children there are numerous causes of anaemia, but we can break it down into 5 groups of causes:

1. Blood loss
2. Decreased RBC production
3. Increased RBC destruction
4. Physiologic process
5. Anaemia of prematurty

1. Blood loss

As the blood volume of neonates is very little, a loss of 15-20mL of blood is relatively a lot and can lead to anaemia. Full term babies have a range of 78-86ml/kg (and preterm babies have a blood volume of 90-105ml/kg).

Let’s look at some causes of blood loss prenatally, perinatally, and postnatally:

2. Decreased RBC production

3. Increased RBC destruction (haemolysis)

• Infections - malaria, rubella, CMV, parvovirus B19.
• Immune-mediated disorders
• Haemoglobinopathies - such as sickle cell anaemia, thalassaemia.
• RBC membrane disorders - spherocytosis, elliptocytosis.
• RBC enzyme deficiences - such as G6PD, glutathione synthetase, pyruvate kinase, hexokinase.

PRENATAL HAEMORRHAGE

1. Foetal-to-maternal haemorhage - this is the entry of foetal blood into the maternal circulation before or during delivery. It most often occurs spontaneously or may be the result of maternal trauma, amniocentesis, external cephalic version, placental tumour. It affects approximately 50% of pregnancies in some small way, but the volume of blood loss is usually very small (2mL).
2. Twin-to-twin transfusion syndrome - this is when there is unequal sharing of blood supply between twins. In monozygotic, monochorionic twin pregnancies (identical twins sharing the same placenta) it affects up to 33% of pregnancies. The twin receiving more blood is the recipient twin while the twin with inadequate blood is the donor twin. The donor twin becomes very anaemic and develops heart failure. The recipient twin becomes polycythaemic and can develop hyperviscosity syndrome.
3. Cord malformations - this includes velamentous insertion, vasa praevia, abdominal or placental insertion. Usually these result is cord shearing or rupture leading to massive, rapid, life-threatening haemorrhage.
4. Placental abnormalities - most importantly placental abruption and placenta praevia.
5. Diagnostic procedures - these include amniocentesis, chorionic villus sampling, and umbilical cord blood sampling.

OBSTETRIC ACCIDENTS

• Cephalohaematoma - these are subperiosteal haematomas that are the result of procedures such as ventouse delivery or forceps delivery. They are usually harmless and do not cross suture lines.
• Subgaleal bleeds - these are caused by rupture of the emissary veins, which are connections between the dural sinuses and the scalp veins. These are concerning as they may cross the suture lines and may lead to sequestration of blood that is not as apparent. It can lead to anaemia, hypotension, shock and death. It can be felt as a “boggy”, fluctuant scalp.
• Caput succedaneum - caput succedaneum is a benign oedema of the scalp that can also cross the suture lines. It is not of major concern and resolves within hours to days.

VITAMIN K DEFICIENCY BLEEDING OF THE NEWBORN (VKDB)

Previously termed haemorrhagic disease of the newborn, it is when there is haemorrhage within a few days of normal delivery. It is causes by a transient physiologic deficiency in factors that are dependent on vitamin K (II, VII, IX, X [1972 if you wish to remember it easily]).

The reason for this is that placental transfer of these factors is poor. Coupled with the fact that the intestine of the newborn is initially sterile this means vitamin K levels themself are quite low (vitamin K is produced by intestinal bacteria).

There are 3 forms of VKDB:

• Early - occurring in the first 24 hours of life. Most often caused by maternal use of vitamin K inhibiting drugs (such as certain antiepileptic drugs, isoniazid, rifampicin, warfarin and also broad-spectrum antibiotics which suppress colonisation of the intestine by bacteria).
• Classic - occurring in the first week of life. This occurs in neonates who do not receive vitamin K supplementation after birth. A vitamin K injection is usually given straight after birth. Administration of 0.5-1mg of vitamin K (IM) rapidly activates the clotting factors and prevents VKDB.
• Late - occurring in 2-12 weeks of life. The late form occurs in babies who are exclusively breastfed who do not receive vitamin K supplementation after birth.

CONGENITAL CAUSES OF DECREASED RBC PRODUCTION

• Fanconi’s anaemia - a congenital form of aplastic anaemia. It is usually autosomal recessive but X-linked mutations have been identified. It results in decreased haematopoiesis and bone marrow failure. Usually diagnosed after the neonatal period.

Some features of Fanconi anaemia include:

1. Solid tumours
2. Hearing loss
3. Pancytopenia
4. Absent or hypoplastic thumb
5. Renal and genital abnormalities
6. Pigmentation abnormalities
7. Short stature

• Dyskeratosis congenita - an X-linked autosomal recessive/dominant disorder arising from genetic issues relating to telomere integrity. This leads to the loss of self-renewal and regeneration. It is a form of pancytopenia.

It has a classic triad of:
1. Abnormal nails
2. Reticulated skin rash
3. Leukoplakia

• Diamond-Blackfan anaemia - an anaemia characterised by a lack of RBC precursors in the bone marrow (red cell aplasia), microcytic RBCs, low reticulocyte count. Unlike the other 2 congenital diseases mentioned above, it usually does not involve other blood cell lineages.

It often comes as a part of a syndrome of congenital anomalies, including microcephaly, cleft palate, eye anomalies, thumb deformities, webbed neck. Up to 25% of infants are anaemia at birth with 10% having a low birthweight.

NUTRITIONAL DEFICIENCIES

Nutritional deficiencies are a cause of anaemia at any stage in life. They are usually not the cause of anaemia at birth, but rather the early months of life.

Let’s take a look at some of these:

• Iron - iron deficiency anaemia is the most common nutritional deficiency. It is more prevalent in less developed countries where dietary insufficiencies are more prevalent.

Exclusive, prolonged breastfeeding may predispose to iron deficiency anaemia. It is also common among neonates whose mother’s have iron deficiencies. Preterm infants who have not been transfused deplete their iron stores by 10-14 weeks if not supplemented. We can use fortified milk supplementation to ensure that children receive iron supplementation.

• Copper - copper is important for intestinal absorption of iron.
• Folate and vitamin B12
• Vitamin E - vitamin E is fat soluble and can be acquired through plant oils (such as rapeseed sunflower and olive oils), nuts and seeds. The recommended daily intake is only 3-4mg and thus the deficiency is rarely due to diet but rather due to mutation is in dietary fat absorption.

Symptoms of vitamin E deficiency are a mild haemolytic anaemia (due to fragility of RBCs) and nonspecific neurological deficits (due to the degeneration of neurons, especially in the dorsal column and peripheral axons.

HAEMOLYTIC DISEASE OF THE NEWBORN (HDN)

We will discuss this in more depth when discussing rhesus haemolytic disease as it often occurs as a result of rhesus incompatibilities.

ABO incompatibility can occur when the mother has the O blood type and the foetus has the A/B blood type. In this instance if maternal blood gets exposed to the foetus, maternal anti-A/anti-B antibodies will cause haemolysis. However, this is usually very mild and does not require treatment.

PHYSIOLOGIC ANAEMIA OF INFANCY

Physiologic anaemia is the most common cause of anaemia in the neonatal period (first 4 week’s of life). Normal physiologic processes result in a normocytic-normochromic anaemia. This occurs at an expected time after birth in both term and preterm infants. It does not require extensive evaluation or treatment.

At around 6-9 weeks after a healthy baby is born, the increase in oxygenation (due to normal breathing, along with increased levels of Hb available at birth) leads to an abrupt rise in the oxygen level. This results in a negative feedback process which results in suppression of EPO production from the kidney → reducing erythropoietin’s in the bone marrow.

The reduction in erythropoietin, coupled with the shorter life span of infant RBCs (90 days as opposed to 120 days seen in adults) leads to a reduction in the concentration of haemoglobin over the first 2-3 months of life. This is called the “physiologic nadir”. The haemoglobin then remains stable over the next few weeks before slowly rising in the 4th-6th month due to stimulation of EPO once again.

ANAEMIA OF PREMATURITY

This is when there is a physiologic anaemia in premature infants. It is a more pronounced anaemia that happens earlier and has a more pronounced nadir.

What are the mechanisms behind this physiologic anaemia:

• Reduced EPO production
• Shorter RBC lifespan of 35-50 days
• Rapid growth
• More frequent phlebotomy
• Less time in utero receiving maternal iron

All of these features result in a nadir of 8-10g/dL in preterm infants.

It most commonly occurs in infants that are very preterm (<32 weeks).

Almost all acutely ill and extremely preterm infants (<28 weeks) will develop an anaemia that is severe enough to require transfusion during their initial hospitalisation.