(20% of adult values) in preterm neonates.95 This means that reserves of mature neutrophils in the bone marrow (sometimes referred to as the neutrophil storage pool) are rapidly depleted in neonates. This explains the frequent occurrence of severe neutropenia in preterm neonates as an immediate response to acute bacterial infection or necrotising enterocolitis (NEC) (Fig. 1.16) (see Chapter 3).98–100 In contrast, adults have large reserves of neutrophils and neutrophil progenitors in the bone marrow, which can be rapidly recruited to boost neutrophil numbers in response to sepsis.
Fig. 1.15 Blood film of a well preterm neonate showing a myelocyte and three normal neutrophils. MGG, ×100.
Fig. 1.16 Blood film of a preterm neonate with early clinical signs of necrotising enterocolitis showing severe neutropenia and moderate thrombocytopenia. Note the cytoplasmic vacuolation in the single neutrophil and the presence of large platelets and some schistocytes suggestive of disseminated intravascular coagulation (DIC). MGG, ×40.
Normal ranges for neutrophil counts in neonates were updated by Schmutz et al. in 2008.64 These vary by gestational age at birth (see Table 1.2) and also by postnatal age, particularly over the first 24 hours. In healthy term babies the neutrophil count peaks at around 15.0 × 109/l (range 7.5–28.5 × 109/l) 6–12 hours after birth, with a very similar pattern also seen in healthy preterm babies over 28 weeks’ gestation.64 Normal ranges for very low birthweight neonates less than 28 weeks’ gestation are difficult to establish because of the high frequency of medical problems, including infection, in these babies. In practice, the main clinical value of neutrophil normal ranges is to identify neonates with clinically significant neutropenia, especially those with severe congenital neutropenia (SCN), where prompt diagnosis is essential to prevent life‐threatening complications. In SCN, the neutrophil count will nearly always be persistently low, although transient and moderate rises sometimes occur in the setting of infection. As a result, serial neutrophil measurements, as well as assessment of a blood film, are essential to rule out acquired disorders associated with neutropenia persisting for more than a week, for example cytomegalovirus (CMV) infection.
Monocytes
There are few monocytes in early second‐trimester fetal blood (<0.06 × 109/l) but the numbers slowly increase to reach 0.1 × 109/l towards the end of the second trimester.101 Normal ranges for monocyte counts at birth in term and preterm babies are shown in Table 1.2. These show a gradual rise from a mean of 0.75 × 109/l in preterm neonates less than 28 weeks’ gestation at birth to 1.5 × 109/l in term babies.65 Monocytes play a key role in the innate immune response of neonates to pathogens. Investigations have shown that although the ability of neonatal monocytes to phagocytose microorganisms is not impaired, other aspects of monocyte function in neonates are impaired compared with adult monocytes.102,103 For example, neonatal monocytes have reduced expression of a number of functionally important cell surface molecules compared with adult monocytes, including HLA‐DR, CD80 and L‐selectin, which leads to a reduced ability to present antigens efficiently and to migrate to sites of inflammation.104 In addition, many studies have reported differences in the pattern of pro‐ and anti‐inflammatory cytokine production in neonatal monocytes, which may impair the antimicrobial activity not only of the monocytes themselves, but also of neutrophils,105–108 although their ability to respond appropriately to bacille Calmette–Guérin (BCG) vaccine appears to be preserved.109
Eosinophils
Eosinophils are barely detectable in fetal blood until the middle of the second trimester.101 Recent data indicate that there is no eosinophil production in fetal liver9 and that circulating eosinophils are likely to be derived entirely from the bone marrow. The numbers of eosinophils in neonates gradually increase with gestational age from a mean of 0.02 × 109/l in preterm infants less than 28 weeks’ gestation to 0.06 × 109/l in term neonates.65 Normal ranges for neonatal eosinophil counts are shown in Table 1.2.
Lymphocytes
There are few studies of lymphopoiesis in the human fetus. Although B lymphocytes are found in low numbers in fetal liver and fetal blood by 8 weeks’ gestation110 and gradually increase in number during the second trimester,111 the bone marrow is the main site of B lymphopoiesis in fetal life.8 By the second trimester, both fetal liver and fetal bone marrow B cells are polyclonal with equally diversified IgH chain repertoires, although at this stage the main source of IgM natural immunity seems to reside in the fetal liver as the majority of bone marrow B cells are still immature.112 Two types of fetal B cell have been described in mice (B1 and B2 cells), with B1 cells being specific to fetal life and hypothesised to mainly play a role in innate immunity as they have limited Ig production capacity.113 Putative B1 B cells have also been described in human fetal liver and bone marrow and in cord blood,114 but their developmental origin and function are still to be defined.
T cell progenitors are first detected in the thymus at 9 weeks post‐conception and mature T cells by 12–13 weeks post‐conception followed by T cells appearing in the spleen and lymph nodes by 24 weeks.115 Regulatory T cells, which are critical for promoting self‐tolerance in fetal life, are detected in the thymus at 12 weeks post‐conception.116,117 T lymphocytes are detectable in fetal blood, marrow and thymus during the second trimester118 and T cell development is largely complete by birth.119 By term, T lymphocytes form 40–45% of circulating mononuclear cells, with a CD4:CD8 ratio of around 5:1, slightly higher than that in adult blood (3.1:1). The normal ranges for the total lymphocyte count in neonatal blood are the same in term and preterm neonates (see Table 1.2) and remain stable over the first month of life in healthy neonates.67
Blast cells
Blast cells, usually resembling myeloblasts, are a normal feature on neonatal blood films (see Fig. 1.14). Their numbers are increased in preterm compared with term babies and in babies with severe infection. A study that evaluated blood films in 123 healthy neonates found an upper limit of 4% for the frequency of circulating blasts in neonatal blood, whereas for sick babies up to 8% blasts were occasionally seen.68 The causes of increased blast cells in neonates are discussed in Chapter 3 (see Table 3.6).
Leucocyte function in the fetus and neonate
The clinical importance of the immaturity of the innate immune system in neonates is best demonstrated by the fact that the pattern of infections in neonates closely mimics that seen in children with SCN. While neutrophil numbers at birth are similar to those in older children and adults, the lack of neutrophil reserves discussed above