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Fig. 1.3 Immunophenotypically defined progenitor populations along the B cell differentiation trajectory in the human fetus. The cell surface markers used to define these populations are shown below each cell type. Based on reference 9.

Red blood cell production and development in the fetus and neonate

Normal erythropoiesis, the production of red blood cells, is crucial to early embryonic and fetal development. Most of our knowledge about the cells and genes involved in this process derives either from mouse models or from inherited anaemias, particularly in children. Almost all the characteristic features of red blood cells are different in the fetus and the newborn compared with their adult counterparts. These differences are even greater in preterm neonates and are directly relevant to our understanding of neonatal anaemias. The differences in erythropoiesis during fetal development are summarised in Table 1.1 and those that are important for our understanding of neonatal anaemias are discussed below.

Table 1.1 Features of fetal and neonatal red cells compared with adult red cells

      2,3‐DPG, 2,3‐diphosphoglycerate; NADPH, nicotinamide adenine dinucleotide phosphate; PFK, phosphofructokinase.

      Erythropoietin production in the fetus and neonate

      The principal cytokine responsible for regulating erythropoiesis in the fetus and newborn, as in adults, is erythropoietin (EPO).³⁰ Since EPO does not cross the placenta, EPO‐mediated regulation of fetal erythropoiesis is predominantly under fetal control. The liver is the main site of EPO production in the fetus³¹ and the only stimulus to production under physiological conditions is hypoxia with or without anaemia (reviewed in reference 32). Little or no EPO is produced under normoxic conditions, but hypoxia very rapidly triggers expression by up to 200‐fold within 30 minutes, at least in hepatocyte cell lines.³³ This explains the high EPO levels in fetuses of mothers with diabetes mellitus or hypertension and in those with intrauterine growth restriction (IUGR) or cyanotic congenital heart disease;³⁴ EPO is also increased in fetal anaemia of any cause, including haemolytic disease of the fetus and newborn (HDFN). This, and the switch of EPO production from fetal liver to the neonatal kidney, may in part explain the physiological delay in triggering the production of new red blood cells, which is often not evident until the second month of life, even in healthy babies.

      Haemoglobin synthesis and red blood cell production in the fetus and newborn

      The rates of haemoglobin synthesis and red blood cell production fall dramatically immediately after birth and remain low for the first 2 weeks of life, probably in response to the sudden increase in tissue oxygenation at birth.³⁵ In healthy neonates the physiological rise in red cell production starts several weeks later, so that by 3 months of age a healthy infant, whatever the period of gestation at birth, should be able to produce up to 2 ml of packed red blood cells every day.³⁵ Studies in preterm neonates have estimated that over the first 2 months of life the maximal rate of red blood cell production may be closer to 1 ml/day. This is based on the observation that preterm babies receiving therapeutic EPO are unable to maintain their haemoglobin if more than 1 ml of blood per day is venesected for diagnostic purposes but can do so where sampling losses are less than this.³⁶

The gestation‐related changes in globin chain synthesis in the human embryo, fetus and neonate have been studied in detail and are summarised in Fig. 1.4.³⁷ The first haemoglobins, known as embryonic haemoglobins, are synthesised from approximately 2 or 3 weeks post‐conception, predominantly in the blood islands of the yolk sac, by the erythroblasts and red blood cells generated there. There are three embryonic haemoglobins (see Table 1.1). ζ or α globin, encoded by adjacent genes in the α globin locus on chromosome 16, combine with ε or γ globin, encoded by genes in the β globin locus on chromosome 11, to produce haemoglobin

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