Williams Hematology



Fetal Hematopoiesis

Production of Embryonic and Fetal Hematopoietic Cells

Ontogeny of Hematopoietic Stem Cells

Synthesis of Fetal Hemoglobins

Fetal Blood
Neonatal Hematopoiesis

Red Cells

White Cells


Neonatal Lymphopoiesis

Coagulation in the Neonate

Hematologic Effects of Maternal Drugs on the Fetus and Newborn
Chapter References

A newborn represents the culmination of developmental events from conception and implantation through organogenesis. The embryo requires red cells for the transport of maternal oxygen to permit this growth and development. Birth brings dramatic changes in circulation and oxygenation, which affect hematopoiesis, as the newborn makes the transition to a separate biological existence. This chapter discusses the ontogeny of hematopoiesis and focuses on hematopoiesis of the normal newborn.

Acronyms and abbreviations that appear in this chapter include: AGM, aorta-gonad-mesonephros; BFU-E, burst forming unit–erythroid; BMP, bone morphogenetic protein; BPG, bisphosphoglycerate; CFU-E, colony forming unit–erythroid; CFU-GEMM, colony forming unit–granulocyte-erythroid-monocyte-macrophage; CFU-GM, colony forming unit–granulocyte-monocyte; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-monocyte colony stimulating factor; IL, interleukin; MCV, mean cell volume; NBT, nitroblue tetrazolium; SIDS, sudden infant death syndrome; TNF, tumor necrosis factor

During embryogenesis, hematopoiesis occurs in spatially and temporally distinct sites, including the extraembryonic yolk sac, the fetal liver, and the preterm bone marrow. Erythropoiesis is established soon after implantation of the blastocyst, with primitive erythroid cells appearing in yolk sac blood islands by day 18 of gestation.1,2 The origin of hematopoietic cells in mammals is tied closely to gastrulation and the formation of mesoderm. Inducers of mesoderm, including transforming growth factor b (TGF-b), fibroblast growth factor, and bone morphogenetic protein-4 (BMP-4), likely are important molecules regulating the onset of hematopoiesis.3 Yolk sac erythroblasts arise in close association with the first embryonic blood vessels, suggesting that endothelial cells and blood cells arise from a common hemangioblast precursor.
The development of primitive erythroblasts in the yolk sac is critical for embryonic survival. In the mouse, targeted disruption of the murine transcription factors SCL (TAL1), LMO2 (RBTN2), and GATA-1 each abrogates primitive erythropoiesis in the yolk sac and leads to early embryonic death.4,5 and 6 Yolk sac erythroblasts have several characteristics distinguishing them from their later definitive counterparts. Primitive erythroblasts differentiate within the vascular network rather than in the extravascular space and remain nucleated as they circulate. Primitive erythroblasts are characterized by more rapid maturation, increased sensitivity to erythropoietin, and a shortened life span compared to fetal and adult erythroblasts.7 Yolk sac erythroblasts are extremely large red cells (megaloblasts) with an estimated mean cell volume (MCV) of >450 fl/cell.
The erythroid progenitors, burst-forming units-erythroid (BFU-E), and the later erythroid progenitors, colony-forming units-erythroid (CFU-E), are present in the yolk sac at 4 weeks gestation.8 Primitive erythroblasts and erythroid progenitors then enter the embryo proper through the circulation. BFU-E appear in the fetal liver as early as 5 weeks of gestation, and CFU-E are evident soon thereafter.8 Erythroid and nonerythroid progenitors are evident also in the nonliver regions of the embryo proper.9 After 7 weeks gestation, hematopoietic progenitors are no longer detected in the yolk sac.10 Yolk sac derived primitive erythroblasts continue to circulate until approximately 12 weeks of gestation.
The liver serves as the primary source of red cells from the 9th to the 24th weeks of gestation. Between 7 and 15 weeks gestation, 60 percent of the liver cells are hematopoietic.11 Erythroid cells differentiate in close association with macrophages and extrude their nuclei prior to entering the blood stream. These fetal liver-derived definitive “macrocytes” are smaller than yolk sac megaloblasts and contain one-third the amount of hemoglobin. Differentiation of erythroid cells in the fetal liver is dependent on erythropoietin signaling through its receptor and the JAK2 kinase.12,13 Fetal liver-derived erythroid progenitors will differentiate in vitro with erythropoietin alone, in contrast to adult bone marrow-derived BFU-E that require erythropoietin plus interleukin-3 (IL-3).14,15 Erythropoietin transcripts are present during the first trimester in the liver.9 The liver remains the primary site of erythropoietin transcription throughout fetal life.16 Erythropoietin transcripts also are present in the developing human kidney as early as 17 weeks of gestation and increase after 30 weeks.16 Erythropoietin is expressed both in the fetal liver and in the postnatal kidney.16 Like primitive erythropoiesis in the yolk sac, definitive erythropoiesis in the fetal liver is necessary for continued survival of the embryo. Targeted disruption of the c-myb and EKLF transcription factors in the mouse each blocks fetal liver erythropoiesis and leads to fetal death.17,18 These mutations do not effect yolk sac erythropoiesis, indicating fundamental differences in the transcriptional regulation of these distinct forms of erythropoiesis.
In contrast to the yolk sac, where hematopoiesis is restricted to erythroid and macrophage cells, hematopoiesis in the fetal liver also includes other myeloid as well as lymphoid lineages. Megakaryocytes are present in the liver by 6 weeks of gestation. Platelets are first evident in the circulation at 8–9 weeks gestation.11 Small numbers of circulating leukocytes are present at the 11th week of gestation.2 Granulopoiesis is present in the liver parenchyma and in some areas of connective tissue as early as 7 weeks gestation. Despite the low number and immature appearance of hepatic neutrophils, the fetal liver contains abundant hematopoietic progenitor cells, including colony-forming unit–granulocyte-erythroid-monocyte-macrophage (CFU-GEMM) and colony-forming unit–granulocyte-monocyte (CFU-GM).19,20 CFU-GM growth depends upon several cytokines, including granulocyte colony stimulating factor (G-CSF), granulocyte-monocyte colony stimulating factor (GM-CSF), and interleukins.21 When compared to adult bone marrow-derived myeloid progenitors, these fetal liver derived myeloid progenitors have a similar dose response in vitro to G-CSF.22 G-CSF is expressed by hepatocytes at 14 weeks gestation.23
Hematopoietic cells are first seen in the marrow of the 10- to 11- week embryo,1,2 and they remain confined to the diaphyseal regions of long bones until 15 weeks gestation.24 Initially there are approximately equal numbers of myeloid and erythroid cells in the fetal marrow. However, myeloid cells predominate by 12 weeks gestation, and the myeloid to erythroid ratio approaches the adult level of 3 to 1 by 21 weeks gestation.11 Macrophage cells in the fetal marrow, but not in the fetal liver, express the lipopolysaccharide receptor CD14.23 The marrow becomes the major site of hematopoiesis after the 24th week of gestation.
Lymphopoiesis is present in the lymph plexuses and the thymus beginning at 9 weeks gestation.11 B cells with surface IgM are present in the liver, and circulating lymphocytes also are seen at 9 weeks gestation.2 Lymphocyte subpopulations are detected by 13 weeks gestation in fetal liver.25 Absolute numbers of major lymphoid subsets in 20–26-week-old fetuses, as defined by the antigens CD2, CD3, CD4, CD8, CD19, CD20 and CD16 (see Chapter 14 for functional significance of these phenotypes), are similar to those in newborns (see “Neonatal Lymphopoiesis”).26,27
The reconstitution of hematopoiesis by transplantation with cord blood indicates that hematopoietic stem cells are present at birth.28 However, the developmental origin of hematopoietic stem cells has not yet been defined. It was first postulated that hematopoietic stem cells originate independently in each hematopoietic site (yolk sac, liver, and bone marrow) of the embryo.29 However, experiments in the mammalian embryo indicate that the liver rudiment is seeded by exogenous hematopoietic cells.30,31 The marrow also is seeded by exogenously derived blood cells. Fetal liver provides a source of stem cells for myeloid and lymphoid reconstitution of fetal sheep and monkey transplant recipients.32 The immunological reconstitution of an immunodeficient human fetus with fetal liver-derived cells also indicates that hematopoietic stem cells exist in the fetal liver.13
Yolk sac stem cells were first thought to seed the liver and eventually the bone marrow.33 However, later experiments in avian and amphibian embryos indicated that the hematopoietic stem cells that seed the marrow arise within the body of the embryo proper rather than from the yolk sac.34,35 Investigations in the mouse embryo also suggest that prior to the fetal liver, the aorta-gonad-mesonephros (AGM) region of the embryo proper contains stem cells capable of engrafting myeloablated adult recipients.36 This correlates anatomically with the transient appearance of CD34-positive blood cells closely associated with the ventral wall of the aorta in several mammalian species, including the 5-week gestation human embryo.37,38 These studies suggest that the AGM-region-derived stem cells seed the liver and the marrow to provide lifelong hematopoiesis. The underlying relationship of primitive hematopoiesis in the yolk sac to definitive hematopoiesis in the fetal liver and the marrow is unclear.
Human hemoglobin is a tetramer composed of two a-type and two b-type globin chains (Table 7-1). The a-globin gene cluster is located on chromosome 16 and contains the z gene 5′ to the pair of a-globin genes. The b-globin gene cluster is located on chromosome 11 and contains five globin genes oriented 5′ to 3′ as e-gA-gG-d-b.39 During embryogenesis the genes on both chromosomes are activated sequentially from the 5′ to the 3′ end. This globin “switching” is related not only to the relative positions of the globin genes within their respective chromosomal clusters, but also to interacting upstream “locus control regions.”40


Hb Gower 1 (z2e2), is the major hemoglobin in embryos less than 5 weeks of gestation (see Table 7-1).41 Hb Gower 2 (a2e2) has been found in embryos with a gestational age as young as 4 weeks and is absent in embryos older than 13 weeks.42 Hb Portland (z2g2) is found in young embryos but persists in infants with homozygous a thalassemia.11 Synthesis of the z and e chains decreases as that of a and g chains increases (Figure 7-1). The z to a globin switch precedes the e to g globin switch as the liver replaces the yolk sac as the main site of erythropoiesis.43,44

FIGURE 7-1 Changes in hemoglobin tetramers (a) and in globin subunits (b) during human development from embryo to early infancy. (Reproduced from HF Bunn and BG Forget, Hemoglobin: Molecular, Genetic and Clinical Aspects, Saunders, Philadelphia, 1986, with permission.)

Hb F (a2g2) is the major hemoglobin of fetal life45 (see Figure 7-1). Synthesis of Hb A can be demonstrated in fetuses as young as 9 weeks of gestation.46,47 In fetuses of 9 to 21 weeks of gestation, the amount of Hb A (a2b2) rises from 4 to 13 percent of the total hemoglobin.47 These levels of Hb A have enabled the antenatal diagnosis of b thalassemia using globin chain synthesis. After 34 to 36 weeks of gestation the percentage of Hb A rises, while that of Hb F decreases (see Figure 7-1). The mean synthesis of Hb F in term infants was 59.0 ± 10 percent (1 SD) of total hemoglobin synthesis as assessed by 14C-leucine uptake.48 The amount of Hb F in blood varies in term infants from 53 to 95 percent of total hemoglobin.49,50
The fetal hemoglobin concentration in blood decreases after birth by approximately 3 percent per week and is generally less than 2 to 3 percent of the total hemoglobin by 6 months of age. This rate of decrease in Hb F production is closely related to the gestational age of the infant and is not affected by the changes in environment and oxygen tension that occur at the time of birth.51 Hb A2 (a2d2) has not been detected in fetuses. Normal adult levels of Hb A2 are achieved by four months of age.52 Increased proportions of Hb F at birth have been reported in infants who are small for gestational age, who have experienced chronic intrauterine hypoxia, or who have trisomy 13.53,54,55 and 56 Decreased levels of Hb F at birth are found in trisomy 21.57 Persistence of the embryonic Hb Gower-1, Hb Gower-2, and Hb Portland has been described in some infants with developmental abnormalities, while persistently elevated levels of fetal hemoglobin have been observed in infants dying from the sudden infant death syndrome (SIDS).58
The fetal blood composition changes markedly during the second and third trimesters. The mean hemoglobin in fetuses progressively increases from 9.0 ± 2.8 g/dl at age 10 weeks to 16.5 ± 4.0 g/dl at 39 weeks.59 There is a concomitant decrease in the MCV of fetal red cells from a mean of 134 fl/cell at 18 weeks to 118 fl/cell at 30 weeks gestation.60 The total white blood cell count during the middle trimester is between 4 and 4.5 × 109/liter, with an 80 to 85 percent preponderance of lymphocytes and 5 to 10 percent neutrophils.60 The percentage of circulating nucleated red cells decreases from a mean of 12 percent at 18 weeks to 4 percent at 30 weeks.60 The platelet count remains greater than 150,000/µl from 15 weeks gestation to term.60,61
Large numbers of committed hematopoietic progenitors circulate in the fetal blood. Blood samples obtained by fetoscopy at 12 to 19 weeks of gestation reveal a mean of 20,450 BFU-E/ml and 12,490 CFU-GM/ml.62 This is in striking contrast to adult peripheral blood, which contains essentially no erythroid progenitors and 30 to 250 CFU-GM/ml.63 The cycling rate of 26 to 28 week gestation fetal hematopoietic progenitors is nearly maximal (70–80%) compared to the relative quiescence (0–5%) of adult marrow-derived progenitors.63
Hemoglobin, Hematocrit, and Indices The mean hemoglobin level in cord blood at term is 16.8 g/dl, with 95 percent of the values falling between 13.7 and 20.1 g/dl.64 This variation reflects perinatal events, particularly asphyxia,65 and also the amount of blood transferred from the placenta to the infant after delivery. Delay of cord clamping may increase the blood volume and red cell mass of the infant by as much as 55 percent.66,67 The mean total blood volume after birth is 86.3 ml/kg for the term infant and 89.4 ml/kg for the premature infant.68 The blood volume per kilogram decreases over the ensuing weeks, reaching a mean value of about 65 ml/kg by 3 to 4 months of age.
Normally the hemoglobin and hematocrit values rise in the first several hours after birth because of the movement of plasma from the intravascular to the extravascular space.69 A venous hemoglobin concentration of less than 14 g/dl in a term infant and/or a fall in hemoglobin or hematocrit level in the first day of life are abnormal. Normal red cell values from capillary blood samples are shown in Table 7-2 for term infants in the first 12 weeks of life.70 Capillary hematocrit values in newborns are higher than those in simultaneous venous samples, particularly during the first days of life, and the capillary/venous ratio is approximately 1.1:.71 This difference reflects circulatory factors and is greater in preterm and sick infants.


The red cells of the newborn are macrocytic, with a mean cell volume (MCV) in excess of 110 fl/cell. The MCV begins to fall after the first week, reaching adult values by the ninth week (see Table 7-2).70,72 The blood film from a newborn infant shows macrocytic normochromic cells, polychromasia, and a few nucleated red blood cells. Even in healthy infants there may be mild anisocytosis and poikilocytosis.73 Three to 5 percent of the red cells may be fragments, target cells, or distorted. By 3 to 5 days after birth, nucleated red blood cells are not found normally in the blood of term or premature infants, but they may be present in markedly elevated numbers in the presence of hemolysis or hypoxic stress.
There are significant numbers of circulating progenitor cells in cord blood.74,75,76 and 77 Cord blood BFU-E and CFU-E differentiate more rapidly than their adult counterparts.78 Furthermore, the proportion of cord blood hematopoietic progenitors in the mitotic cycle is approximately 50 percent, intermediate between the proportions found in fetal and adult progenitor cells.76
In several,79,80 but not all, studies81 premature infants at birth had lower hemoglobin levels, higher reticulocyte counts, and higher nucleated red cell counts than the term infants. The reticulocyte counts of premature infants are inversely proportional to their gestational age, with a mean of 8 percent reticulocytes evident at 32 weeks gestation and 4 to 5 percent at term.82 Infants who are small for their gestational ages have higher red cell counts, hematocrit levels, and hemoglobin concentrations compared to infants whose size is appropriate for their gestational age.80,83
Erythropoietin and Physiologic Anemia of the Newborn Erythropoietin is the primary regulator of erythropoiesis. While erythropoietin is present in cord blood, it falls to undetectable levels after birth in healthy infants.84 Subsequently, the reticulocyte count falls to less than one percent by the sixth day of life.85 The red cell, hemoglobin, and hematocrit values decrease only slightly during the first week but decline more rapidly in the following 5 to 8 weeks (see Table 7-2),70 producing the physiologic anemia of the newborn.86 The lowest hemoglobin values in the term infant occur at about 2 months of age.72 When the hemoglobin concentration falls below 11 g/dl, erythropoietic activity begins to increase. Erythropoietin can be measured after the 60th day of life,87 corresponding to the recovery from physiologic anemia. If there is sufficient stimulus, such as hemolytic anemia or cyanotic heart disease, the newborn infant is able to produce erythropoietin during the first several months of life.84
In the premature infant the fall in hemoglobin level is more pronounced. In one study of premature infants the mean hemoglobin level at 2 months was 9.4 g/dl, with a 95 percent range of 7.2 to 11.7 g/dl.88 In healthy premature infants erythropoietin becomes detectable when the hemoglobin level falls to about 12 g/dl. In infants with a lower percentage of Hb F (as from transfusion) and consequently better oxygen delivery, erythropoietin does not rise until the hemoglobin falls to about 9.5 g/dl.89 The mean values for iron-sufficient premature infants reached those of term infants by 4 months for red cell count, 5 months for hemoglobin level, and 6 months for mean corpuscular volume and mean corpuscular hemoglobin.88
Blood Viscosity The viscosity of blood increases logarithmically in relation to the hematocrit.90,91 Hyperviscosity has been found in 5 percent of infants in one series92 and in 18 percent of infants who are small for gestational age in another.93 Newborn infants with hematocrit values of greater than 65 to 70 percent may become symptomatic because of increased viscosity.94 Of 45 infants with documented hyperviscosity and a mean hematocrit greater than 65 percent, 17 (38%) had symptoms of irritability, hypotonia, tremors, or poor suck reflex.95 Partial plasma exchange transfusion reduced blood viscosity, improved cerebral blood flow, and relieved the symptoms. However, cerebral blood flow was normal in the asymptomatic infants with hyperviscosity, and there consequently was no benefit from exchange transfusion.95
Red Cell Antigens The blood group antigens on neonatal red cells differ from those of the older child and adult. The i antigen is expressed strongly while the I antigen and the A and B antigens are expressed only weakly on neonatal red cells. The i antigen is a straight-chain carbohydrate which is replaced by the branched-chain derivative, I antigen, as a result of the developmental acquisition of a glycosyltransferase.96 By one year of age the i antigen has become undetectable, and the ABH antigens increase to adult levels by age 3. The ABH, Kell, Duffy and Vel antigens can be detected on the cells of the fetus in the first trimester and are present at birth.97 The Lua and Lub antigens also are detectable on fetal red cells and are more weakly expressed at birth, increasing to adult levels by age 15.97 The Xg antigen is variably expressed in the fetus and is weaker on newborn than adult red cells. Moreover, particularly poor expression of Xg has been noted in newborns with trisomy 13, 18, and 21.97 The Lewis group (Lea/Leb) antigens are adsorbed on the red cell membrane and become detectable within 1 to 2 weeks after birth as the receptor sites develop. Anti-A and anti-B as isohemagglutinins develop during the first 6 months of life, reaching adult levels by 2 years of age.
Red Cell Life Span The life span of the red cells in the newborn infant is shorter than that of red cells in the adult. The average of several studies of mean half-life of newborn red cells labeled with chromium was 23.3 days in term infants and 16.6 days in premature infants. When corrected for the elution rate of chromium from newborn cells, the estimate of mean red cell survival in the newborn is 60 to 80 days.98 The reasons for this shortened survival are unclear, but the known susceptibility to oxidant injury of newborn red cells may be a contributing factor.
Iron and Transferrin The serum iron level in cord blood of the normal infant is elevated compared to maternal levels. The mean value is about 150 ± 40 µg/dl (1 SD).99 Infants on an iron-supplemented diet have a median serum iron level of 125 µg/dl at 1 month of age and of about 75 µg/dl at 6 months of age. The total iron- binding capacity rises throughout the first year of life. The median transferrin saturation falls from almost 65 percent at 0.5 months to 25 percent at 1 year, and saturations as low as 10 percent may be observed in the absence of iron deficiency.100 The mean serum ferritin levels in iron-sufficient infants are high at birth, 160 µg/l, rise further during the first month, and then fall to a mean of 30 µg/l by 1 year of age.101 The amount of stainable iron in the marrow at birth is small but increases in both term and premature infants during the first weeks of life. Stainable marrow iron begins to decrease after 2 months and is gone by 4 to 6 months in term infants and earlier in premature infants.102
Oxygen Delivery The oxygen affinity of cord blood is greater than that of maternal blood, since the affinity of Hb F for 2,3-bisphosphoglycerate (2,3-BPG) is less than that of Hb A.103 Levels of 2,3-BPG are lower in newborn red cells than in adult cells and even more decreased in the red cells of premature infants,104 and this low 2,3-BPG level further heightens the oxygen affinity of newborn red cells. Thus, the red cell oxygen equilibrium curve of the newborn is shifted to the left of that of the adult (Figure 7-2). The mean partial pressure of oxygen at which hemoglobin is 50 percent saturated with oxygen at 1 day of age in term infants is 19.4 ± 1.8 torr, as compared with the normal adult value of 27.0 ± 1.1 torr.105 This results in a decrease in the oxygen released at the tissue level, as shown in Figure 7-2. As the PO2 falls from 90 torr in arterial to 40 torr in the venous blood, 3.0 ml/dl of oxygen are released from newborn blood, while 4.5 ml/dl are released from adult, Hb A-containing blood. The shift to the left of the oxygen equilibrium curve is even more pronounced in the premature infant, requiring a larger fall in PO2 to release an equivalent amount of oxygen. After birth the oxygen equilibrium curve shifts gradually to the right, reaching the position of the adult curve by 6 months of age. The position of the curve in the premature infant correlates with gestational age rather than with postnatal age,105 and its shift to the adult position is more gradual.

FIGURE 7-2 The oxygen equilibrium curves are based on the assumption that the Hb concentration is 15 g/dl and that there is full O2 saturation of Hb at a PO2 of 100 torr. The O2 released is the difference in O2 content between a PO2 of 90 torr and the mixed venous PO2 of 40 torr. The O2 available is the difference in O2 content between a PO2 of 90 torr and a mixed venous PO2 of 20 torr. This is the maximum O2 available without evoking compensatory mechanisms such as increased cardiac output.

Metabolism Many differences have been found between the metabolism of the red cells of newborn infants and that of adults.106,107 Some of the differences may be explained by the younger mean cell age in the newborn, but others seem to be properties of the fetal cell. The glucose consumption in newborn cells is lower than that in adult cells.108 Elevated levels of glucose phosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase beyond those explainable by the young cell age have been found in neonatal cells.104,109 The level of phosphofructokinase is low in red cells of term and premature infants.104,109,110 The pentose phosphate shunt is active in red cells of term and premature infants,111 but there is glutathione instability and a heightened susceptibility to oxidant injury. Furthermore, there is relative instability of the 2,3-BPG concentration. Lower-than-adult activities have been found for several other red cell enzymes, including NADP-dependent methemoglobin reductase112 and glutathione peroxidase.113 The levels of ATP and ADP are higher in the red cells of term and preterm infants110 but may merely reflect the younger age of the erythrocyte population.114
Membrane The membrane of the newborn red cell also is different from that of the adult red cell. Ouabain-sensitive ATPase is decreased,115 and active potassium influx is significantly less in neonatal red cells.116 Newborn cells are more sensitive to osmotic hemolysis and to oxidant injury than are adult cells. Newborn red cell membranes have higher total lipid, phospholipid, and cholesterol per cell than adult red cells.117,118 The patterns of phospholipid and phospholipid fatty acid composition also differ from those in adult red cells. Red cells of newborns have the same pattern of membrane proteins on polyacrylamide gel electrophoresis119 and the same rate of mobility in an electric field120 as do red cells from adults. After trypsin treatment of newborn and adult cells, however, there is a difference in electrophoretic mobility, indicating that the surface trypsin-resistant proteins are different.120 The relationship of the metabolic and membrane alterations in neonatal red cells to their shorter life span is not clear.
Colony-Stimulating Factors and Granulo-monopoiesis The absolute number of neutrophils in the blood of term and premature infants is usually greater than that found in older children (Table 7-3).121 The neutrophil count tends to be lower in the premature than in the term infant, and the proportion of myelocytes and band neutrophils is higher.122 Serum and urinary colony-stimulating activity are elevated during the period of neutrophilia.123,124 When granulopoiesis was studied in cord blood, blood, and marrow of infants, the macrophage colony-forming unit was predominant in spite of the clinical neutrophilia, and this pattern was not altered by different sources of colony-stimulating factors.125,126 The endogenous cytokines produced by mononuclear cells from cord or systemic venous blood support the growth of neutrophil colonies in assays using marrow from adults.125 However, there is diminished GM-CSF, G-CSF, and IL-3 production and diminished mRNA expression in stimulated newborn compared to adult mononuclear cells,127,128 and 129 which may limit the response to bacterial infection in the newborn. Smaller numbers of CFU-GM colonies were observed in the blood of sick infants, who have diminished endogenous production of CSF in culture.126 Dysregulation of neonatal granulopoiesis may impair the neonatal response to infection.130 The administration of stem cell factor with G-CSF to newborn rats reduces the mortality of experimental group B streptococcal infection, and this approach may be useful in human disease.131


White Cell and Differential Counts The values for the white cell and differential counts during the first 2 weeks of life are given in Table 7-3. The absolute number of segmented neutrophils rises in both term and premature infants in the first 24 h of life.132 In term infants the mean value increases from 8 × 109/liter (8000/µl) to a peak of 13 × 109/liter (13,000/µl) and then falls to 4 × 109/liter (4000/µl) by 72 h of age, remaining at this level through the following 7 days. In the premature infant the mean values for neutrophils are 5 × 109/liter (5000/µl) at birth, 8 × 109/liter (8000/µl) at 12 h, and 4 × 109/liter (4000/µl) at 72 h. The mean count then falls gradually to 2.5 × 109/liter (2500/µl) by the 28th day of life. The level after the first 72 h is very stable for an individual infant, whether term or premature. Immature forms, including an occasional promyelocyte and blast cell, may be seen in the blood of healthy infants in the first few days of life and are more frequent in premature infants than in term infants.132 Segmented granulocytes are the predominant cells in the first few days of life. As their number decreases, the lymphocyte becomes the most numerous cell and remains so during the first 4 years of life. An absolute eosinophil count of greater than 0.7 × 109/liter (700/µl) was found in 76 percent of premature infants at 2 to 3 weeks of age. The onset of the eosinophilia coincided with the establishment of steady weight gain in the infants.133 It is increased by the use of total parenteral nutrition, endotracheal intubation, and blood transfusions.
Bacterial infections are a major cause of morbidity and mortality in the newborn period.134 The infections are frequently due to organisms of low virulence in normal children and adults, including Staphylococcus, Lancefield group B b-hemolytic streptococci, Pseudomonas, and other gram-negative bacilli. Cellular defense mechanisms and humoral immunity of the newborn differ from those found later in life, and these undoubtedly contribute to the unusual susceptibility to infection noted in the neonatal period.134
Opsonins and Complement Engulfment and destruction of bacteria by neutrophils depend on opsonic activity of the plasma and on chemotaxis, phagocytosis, and the bacteriocidal capacity of the leukocyte. The serum factors necessary for optimal phagocytosis (opsonins) include the immunoglobulins and complement components. In term infants, opsonic activity is normal for Staphylococcus aureus,135,136 but it is low for yeast137 and Escherichia coli.136 Diminished opsonic antibody has been associated with group B streptococcal infection and represents one risk factor for neonatal infection.138
In premature infants, opsonic activity is low for Staphylococcus aureus and Serratia marcescens135 but is normal for Pseudomonas aeruginosa.139 When serum concentrations of fibronectin and IgG subclasses C3 and C4 were measured at birth, 1 month, 3 months, and 6 months, early gestational age was correlated with lower initial levels.140 The decreased opsonic activity for some organisms in premature infants has been attributed to diminished IgG levels, since additional IgG will correct the opsonic defect both in vivo and in vitro.135 The added IgG improves bacterial opsonization by serum of premature infants in part because complement consumption and deposition of C3 on the bacterial surface is augmented.141,142
Complement components appear in fetal blood before 20 weeks of gestation and increase markedly during the third trimester. However, in many newborns both the classical and alternative complement pathways are decreased in activity and in levels of individual components.143 The mean level of C3, the first common component of the two pathways of complement activation, is about 65 percent of that in normal adults.144,145 and 146 There is no transplacental transfer of this protein, and levels in infants are lower than those in their mothers.144 Total hemolytic complement (CH50) and alternative pathway activity (PH50) in newborns are lower than in adults, as are mean levels of C1q, C2–C9, properdin, and factors B, I and H.145,146 and 147 In general, the mean levels in full-term infants are greater than 50 percent of those in normal adult controls and may be somewhat less in premature infants. There is considerable overlap, however, between levels in infants and in controls. A functional deficiency in the alternative pathway has been detected in infants.148
Fibronectin mediates more efficient interactions between phagocytes and infectious agents. Fibronectin, a 450 kD glycoprotein found in plasma and in the intercellular matrix, promotes the attachment of staphylococci to neutrophils149 and enhances opsonic activity of antibodies against group B streptococci.150 Since both these bacteria are common pathogens for neonates, the deficiency in fibronectin observed in neonates151 may further compromise opsonic capacity and hence bactericidal activity in the neonate.
The administration of intravenous IgG may be useful in the treatment or prophylaxis of infection in preterm infants based on the reduced placental transfer of maternal antibody and the restricted endogenous synthesis of IgG.152 IgG administered to septic neonates appears to enhance serum opsonic capacity as well as to increase the quantity of circulating neutrophils.153 Added IgG heightens phagocytosis of granulocytes from premature neonates,154 and intravenous IgG has been reported to effectively treat infected premature neonates, but these reports involved small numbers of subjects.155,156 The clinical efficacy of IgG prophylaxis against neonatal pathogens is not firmly established.157,158 New IgG preparations with consistent, adequate levels of antibodies directed against neonatal pathogens can be achieved by selection of sera with high levels of functional antibodies,159 or potentially by the addition of monoclonal antibodies, and these may prove more clearly effective.
Chemotaxis Chemotactic function of leukocytes is low in neonates, while random motility is normal.160,161 and 162 Neonatal serum does not generate as much chemotactic factor as does adult serum, even after the addition of purified C3. The defect in chemotaxis may be related to decreased granulocyte deformability and impaired capping of cell surface receptors.163 The role of observed cAMP and membrane potential alterations in the defective chemotaxis is not clear.163
The densities of the C3bi receptor (CD11b/CD18) and of the low-affinity receptor for immunoglobulin, FcRIII (CD16), are decreased on neutrophils of premature infants, whereas term infants’ cells show a lesser impairment.164,165,166 and 167 The deficient up-regulation of C3bi has been correlated with decreased adherence and chemotaxis by neonatal neutrophils.168 Low FcRIII was associated with impaired chemotaxis of neonatal neutrophils,169 although decreased FcRIII might also be responsible for subtle defects in adherence and subsequent phagocytosis of opsonized159 and unopsonized170 organisms by neutrophils.
Phagocytic and Bactericidal Activity Phagocytosis of bacteria and latex granules by neutrophils from premature and term infants is normal.135,136,137,138 and 139,172,173 Bactericidal activity varies according to the conditions of testing and the clinical status of the neonates. The intracellular killing of Staphylococcus aureus and Serratia marcescens in cells from most term and low-birth-weight infants is normal,135,174 as is that of Escherichia coli in term infants.136 Similar studies have shown defective bactericidal activity against S. aureus in some infants in the first 12 h of life,172 P. aeruginosa in cells from premature infants,139 and Candida albicans in granulocytes from term and premature infants.175 With bacteria/neutrophil ratios of 1:1, newborn cells kill S. aureus and E. coli as effectively as controls; however, at the higher ratio of 100:1 killing and oxidative response as measured by chemiluminescence are markedly depressed, although phagocytosis is normal.173 Depressed activity also has been found in cells from newborns who have had clinical stress, either from infection or other disorders, shown both as decreased chemiluminescence and impaired bactericidal activity against S. aureus, E. coli, and group B streptococci.176,177 and 178 The decreased granulocyte function shown in these studies also is found in liquid culture, where neutrophils from newborns do not survive as long as those from adults, perhaps because of decreased resistance to autoxidation.179 Although superoxide dismutase levels are normal and superoxide production is normal or increased in neutrophils from newborns, glutathione peroxidase and catalase levels are decreased.180,181 The relationship of these in vitro cellular defects to bacterial infections in the newborn is still not clear.
Monocytes from newborn infants have normal nitroblue tetrazolium (NBT) reduction,182 normal antibody-dependent cellular cytotoxicity,183 and normal in vitro killing of S. aureus and E. coli.184 However, they are slower than monocytes from adults in phagocytosis of polystyrene spheres,185 and they have reduced ATP production.186 Furthermore, chemotaxis to serum-derived factors is decreased, as is monocyte appearance in skin windows.187 These functional aspects may contribute to the observed susceptibility of newborns to a variety of infectious agents.
Cytokine Effects on Neonatal Phagocytic Function There is a complex interaction between cytokines produced by lymphocytes and macrophages, and the activation status of neutrophils during infection. There is decreased production of g-interferon by neonatal leukocytes.188,189 and 190 g-interferon causes the up-regulation of the C3bi receptor and induces the surface expression of the high-affinity immunoglobulin receptor FcRI (CD64)191 on neutrophils. C3bi is required for adherence and efficient chemotaxis by neutrophils. Complement-mediated phagocytosis and oxidative metabolism also are impaired by low levels of this receptor. FcRI mediates oxidative responses as well, and appears on neutrophils of adults during infection. The diminished production of G-CSF and GM-CSF by neonatal mononuclear cells127,128 and 129 may not only limit progenitor colony growth but also impair neonatal neutrophil functions, including chemotaxis, superoxide production, and C3bi expression, which are enhanced by these factors.192,193 Tumor necrosis factor alpha (TNF-a) and interleukin 4 (IL-4), cytokines which modulate neutrophil functions, also may be produced at lower levels in neonates.194 Interleukin 8 (IL-8), a cytokine that enhances neutrophil functions, has not been adequately studied in neonates.
The platelet counts in term and preterm infants are between 150 and 400 × 109/liter (150,000 to 400,000/µl), comparable to adult values.195 and 196 Thrombocytopenia of less than 100 × 109/liter (100,000/ µl) may occur in high-risk infants with respiratory distress or sepsis,197 small-for-date infants,198 and newborns with trisomy syndromes.199 Even normal newborns are unable to regulate thrombopoiesis and myelopoiesis in a totally effective manner.200 Although committed megakaryocyte progenitors (CFU-Meg) are increased in the marrow and cord blood of newborns, they are less able to produce adequate numbers of platelets when severely stressed. Thrombopoiesis-stimulating activity appears lower in cord serum than in adult serum,201 and reduced levels of G-CSF, GM-CSF, IL-3, and IL-11 may play a role in the impaired response.202 IL-11 and IL-3 act synergistically to enhance mouse CFU-Meg, and the role of these growth factors and others, such as TPO, IL-6, and Steel factor are currently being explored.
Bleeding Time The expected inverse relationship between the platelet count and bleeding time has been described in term and preterm newborns.203 However, the bleeding time often is longer than would be predicted by the platelet count because of sepsis or respiratory distress resulting in impaired platelet function, aggravating the effects of thrombocytopenia.
The bleeding time reflects platelet function and capillary integrity as well as the platelet count and traditionally has been used to assess these parameters. However, there are technical difficulties in applying a technique for measuring bleeding time to neonates or preterm infants because of the need for venous occlusion of the forearm, where the test normally is performed, and for a minimal incision to avoid scarring of the skin. Bleeding times were measured using an automatic device to minimize trauma in normal neonates, with venous occlusion of 20 torr for infants less than 1000 g, 25 torr for those 1000 to 2000 g, and 30 torr for those over 2000 g. In 82 observations, 97 percent of the measurements were below 3.5 min, which was suggested as the upper limit for normal in these infants.204 A similar upper limit (200 s) for the bleeding time of normal infants has been obtained using an automated device and vertical incisions.205 Generally, newborn infants have shorter bleeding times than those of children and adults, and this may reflect their higher hematocrit, increased concentration of von Willebrand factor, and higher proportion of high molecular weight multimers of von Willebrand factor.206 Children have longer bleeding times than either adults or newborns,207 and the upper limit measured with an automated pediatric device may be as high as 13 min before age 10, compared to an upper limit of 7 min in adults measured with the same device.207
The bleeding times in newborns may be prolonged for a variety of reasons, including neonatal infection and respiratory distress syndrome, which do not necessarily result in thrombocytopenia.208 The use of indomethacin for treatment of patent ductus arteriosus in preterm infants has been questioned because this agent interferes with prostaglandin metabolism and the production of thromboxane A2, an important initiator of platelet aggregation. Although bleeding times are prolonged from a normal of 3.5 min to approximately 9 min in indomethacin-treated patients,209 indomethacin did not result in an increase in periventricular or intraventricular hemorrhage in preterm infants treated for patent ductus arteriosus.
Platelet Aggregation and Metabolism A variety of differences have been described in the platelet function of neonates. These include decreased ADP release, platelet factor 3 activity, platelet adhesiveness, and platelet aggregation in response to ADP, epinephrine, collagen, or thrombin.210,211 These defects result from intrinsic differences in neonatal compared to adult platelets.212 Paradoxically, these insufficiencies have little effect on the bleeding time of neonates. The in vitro findings do not appear related to a significant defect in prostaglandin synthesis or to storage pool deficiency of adenine nucleotides.210 Further, electron micrographs of neonatal platelets do not differ from those of platelets from normal adults.213 This leaves unexplained the in vitro observations in neonatal platelets, which may be related to platelet membrane immaturity. These in vitro abnormalities may aggravate the impairment in platelet function and the predisposition to bleeding which results from neonatal diseases, particularly respiratory distress syndrome and sepsis.
Aspirin ingestion by mothers also results in abnormalities in platelet aggregation in response to collagen.214,215 However, aspirin has been studied extensively in patients with preeclampsia, and there is no significant bleeding in the fetus or newborn.216,217
Newborn infants commonly have petechiae, particularly on the head, neck, and shoulders after vertex deliveries. They are presumably due to trauma associated with passage through the birth canal and disappear within a few days. Petechiae usually are not present in infants delivered by cesarean section.
Platelet Antigens and Glycoproteins The glycoprotein complex GPIIb/IIIa represents about 15 percent of platelet surface protein and exhibits two allelic forms, PlA1 and PlA2.218 The PlA1 antigen can be identified on fetal platelets by 16 weeks gestation.210 PlA1 antigen is observed in a higher percentage of fetuses between 18 and 26 weeks than in adults. Approximately 2 percent of the population in the United States of European descent is homozygous for PlA2 and hence PlA1 negative. The complete expression of the PlA1 antigen during early gestation likely permits early sensitization in women who are PlA1 negative even during their first pregnancy.219 The membrane glycoprotein GPIb, as well as the GPIIb/IIIa complex, is expressed by 18 weeks of gestation.219 The gene for GPIIb/IIIa has been cloned, and the difference between PlA1 and PlA2 is a leucine 33/ proline 33 amino acid polymorphism in glycoprotein IIIA.218 Prenatal diagnosis of the glycoprotein genotype using DNA from amniocytes and the polymerase chain reaction can establish the potential for neonatal alloimmune thrombocytopenia220 as well as the diagnosis of Glanzmann’s thrombasthenia. Rarely, other fetal platelet antigens such as PlE2, DUZOa, Koa and Baka have caused maternal sensitization and neonatal alloimmune thrombocytopenia.221 The gestational ages for expression of these antigens have not been defined but are sufficiently early to permit sensitization.
The absolute number of lymphocytes in the newborn is equivalent to that in older children (Table 7-4), with lower values in premature infants at birth. Thymus-derived cells (T cells) develop early in gestation.222 The various lymphocyte subsets in newborns are shown in Table 7-4.223 The absolute number of CD3+ and CD4+ (helper/ inducer phenotype) T-cell subsets in blood of newborns is significantly higher than in adults.13,224 This is due to an increased total lymphocyte count in neonates (and older children) compared to adults.225 The percentages of major lymphoid subsets (CD2, CD3, CD4, CD8, CD19, CD16) are not markedly different in neonates, children, and adults when measured by flow cytometry methods.226 There is a trend to increased CD4 and decreased CD8 lymphocytes in newborns and children, resulting in an increased CD4/CD8 ratio.227,228 In spite of this, T-cell suppressor activity may be increased in newborns.229 Most responses of the cellular immunity system, such as antigen recognition and binding, antibody-dependent cytotoxicity and graft-versus-host reactivity are present in the newborn,229 although some are decreased in comparison with adults.230 The in vitro response to phytohemagglutinin of cord blood lymphocytes is increased,231,232 but the response of the newborn to 2,4-dinitrofluorobenzene, a potent inducer of delayed hypersensitivity, is not as consistent as that seen in older children.233 Impaired T-cell production of g interferon and other lymphokines may be related to immature macrophage rather than T-lymphocyte function, since intercellular cooperation is a requisite for these processes.234 Further, cord blood T-lymphocytes form a functional IL-2 receptor complex and have normal IL-2 receptors, but they do not up-regulate g interferon in response to IL2.235


Humoral (B-cell) immunity also develops early in gestation,222 but it is not fully active until after birth. In the newborn, about 15 percent of lymphocytes have immunoglobulin on their surface, with all Ig isotypes represented.236 A percentage of these cells are CD5+ B cells (B-1 cells), which produce polyreactive autoantibodies whose function is yet unclear.237 The proportion of CD5+ B cells is markedly higher in the fetus compared to adults. The percentages of B cells expressing specific immunoglobulin isotypes are not related to the plasma levels of those isotypes. Variation in antibody response to specific antigens relates to the interaction of macrophages, T cells, and B cells; B lymphocytes are well represented in newborns.238
Fetal lymphocytes synthesize little immunoglobulin, presumably because of the sheltered environment in utero. Animals kept germ-free after birth have few plasma cells and markedly decreased production of immunoglobulins.239 IgG levels of term infants are similar to maternal levels because of transplacental transfer.240 IgM, IgD, and IgE do not cross the placenta,240,241 and the levels of these immunoglobulins and of IgA are low or not detectable at birth. Breast feeding provides some transfer of antibodies, particularly secretory IgA, lysozyme, and lactoferrin. Large numbers of lymphocytes and monocytes (106 cells/ml) are found in colostrum and milk during the first two months postpartum.242 These may provide local gastrointestinal protection against infection,243 and there is some evidence for absorption of immunoglobulin and transfer of tuberculin sensitivity to the infant.
Although the newborn infant can produce specific IgG antibody,244 only small amounts of IgG are usually produced by the fetus. IgG levels in premature infants are reduced in relation to gestational age because of the low placental transport early in pregnancy.245,246 and 247 The ability of the fetus to produce IgM and IgA with appropriate stimuli is indicated by the presence of these antibodies in many newborn infants who have had prenatal infections248 and by the presence of IgM isohemagglutinins in more than one-half of term newborn infants.249 In human newborns and in fetal animals the IgM response is predominant, and the appearance of IgG after exposure to specific antigens is delayed. These differences from the adult may relate to functional immaturity of B and T lymphocytes,250,251 and 252 to increased activity of suppressor T cells239,250 and perhaps to altered macrophage function.253
Newborns also may have relative splenic hypofunction, suggested by the large number of “pocked” red cells seen in the blood films of neonates, particularly premature infants. These “pocks” represent residual intraerythrocyte inclusions, which remain because of monocyte and macrophage hypofunction.254,255
When the term newborn is compared to older children and adults, several differences in the coagulation and fibrinolytic systems have been described.256,257,258,259,260 and 261 A comprehensive evaluation of the developmental changes in the levels of clotting factors and coagulation tests in preterm and term infants has been published.262,263 The term newborn has reduced mean plasma levels (<60% of adult levels) of factors II, IX, X, XI, XII, prekallikrein, and high molecular weight kininogen (Table 7-5). In contrast, the plasma concentration of factor VIII is similar and von Willebrand factor is increased compared to older children and adults. In spite of the lower levels of factors, the functional tests (prothrombin and partial thromboplastin times) are only slightly prolonged compared to adult normal values (see Table 7-5). Although different coagulation factors show different postnatal patterns of maturation, near-adult values are achieved for most components by 6 months of life.259


Factor II (prothrombin), VII, IX, and X require vitamin K for the final gamma glutamyl carboxylation step in their synthesis.264 These factors decrease during the first 3 to 4 days after birth. This fall may be lessened by administration of vitamin K,265 effectively preventing classical, early-occurring (first few days of life) hemorrhagic disease of the newborn. Inactive prothrombin molecules have been found in the plasma of some newborns, but they disappear after administration of vitamin K.266 Early-occurring hemorrhagic disease is most often associated with maternal administration of medications such as phenytoin (Dilantin)267 and warfarin268 which reduce the vitamin K-dependent factors. In rare cases no contributing factor is found.
A hemorrhagic diathesis also may occur later, 2 to 12 weeks after birth, due to lack of vitamin K and is called late hemorrhagic disease of the newborn, or acquired prothrombin complex deficiency.269,270 The etiology of the vitamin K lack is unclear but may result from poor dietary intake, particularly related to breast feeding, alterations in liver function with cholestasis and decreased vitamin K absorption, or a toxic or infectious impairment of hepatic utilization.269 Unfortunately, intracranial hemorrhage frequently is the presenting event in this condition. This problem can be prevented by parenteral or oral vitamin K, but the preferred route of administration remains controversial.271 The parenteral route may result rarely in neuromuscular complications,272 and an association of intramuscular vitamin K prophylaxis and cancer in infancy was suggested but not substantiated. Oral administration, however, may be less reliable and require repeated doses.269 The most current recommendation of the Scientific and Standardization Subcommittee on Perinatal Haemostasis suggests that present practice should not be changed at this time.270 Many institutions in the United States administer 1 mg vitamin K1 intramuscularly at birth with effective prophylaxis. A new mixed micellar vitamin K1 preparation is particularly well absorbed273 and may permit prophylaxis with a single oral dose.
The values for coagulation factors in healthy 30- to 36-week- gestation premature infants are shown in Table 7-5. More prominent decreases in factors IX, XI, and XII are noted, which tend to prolong the partial thromboplastin time. The values for coagulation factors in 28- to 31-week-gestation infants also are shown in Table 7-5. All of the coagulation factors are lower at earlier gestational ages.
There are no significant differences in mean prothrombin time determinations between 30- to 36-week-premature and full-term infants who have not received vitamin K.274 Premature infants given vitamin K have a longer mean prothrombin time than term infants similarly treated. In some small infants there is no improvement in prothrombin time or levels of prothrombin and factors VII and X after the intramuscular administration of vitamin K.265,275 These results suggest a greater degree of “immaturity” of the liver in the small infants.
Significant bleeding occurs more often in low-birth-weight infants than in term newborn infants. Increased capillary fragility is frequently found in premature infants in the first 2 days after birth and is not associated with thrombocytopenia.265 Bleeding under the scalp or in other superficial areas may be due to trauma coupled with increased capillary fragility. The more serious disorders of periventricular-intraventricular hemorrhage and pulmonary hemorrhage probably are not primarily due to coagulation disorders, although such disorders may increase the bleeding.276 Hypoxia seems to affect the clotting status of low birth weight infants.277 Many infants with markedly abnormal prothrombin times have had hypoxia during delivery or shortly thereafter.274 Cardiovascular collapse seen with episodes of cardiac arrest or with profound shock may cause disseminated intravascular coagulation and generalized bleeding. In many sick premature infants, a combination of shock, sepsis, liver immaturity, hypoxia, and other factors may contribute to the pathogenesis of coagulation abnormalities.
Arterial and venous thromboses are relatively frequent in newborns compared to other age groups, but greater than 90 percent of arterial and greater than 80 percent of venous clots are related to catheters. Spontaneous thromboses are much less common, and most involve the renal veins or rarely the pulmonary vasculature.278 Relative hypercoagulability in the newborn could result from a difference in the vascular endothelium, activation of the coagulation cascade, diminished coagulation inhibitor activity, or a defect in fibrinolysis. Inhibitors of coagulation include antithrombin, heparin cofactor II, protein C, and protein S.263,279 The levels of proteins C and S, which are vitamin K-dependent, as well as antithrombin and heparin cofactor II, are low in the newborn; they are in a range associated with thrombotic episodes in adults with inherited deficiencies.279 In addition, the presence of factor V Leiden may occur in as many as 6 percent of newborns.280 This produces resistance to the action of protein C and may heighten the susceptibility to thrombosis. Further, hyperprothrombinemia secondary to the 20210A allele prothrombin gene may affect 1 percent of the population281 and has been associated with heightened venous thrombosis.282 The combined deficiency of these anticoagulant proteins may further intensify the thrombotic risk. However, the precise role of these inhibitors of coagulation in newborn hypercoagulability is uncertain, since a proportionate decrease in vitamin K dependent procoagulant factors (II, VII, IX, X) also is present, and an additional inhibitor, a2-macroglobulin, is increased. The values for plasma inhibitors of coagulation in premature and term infants are shown in Table 7-6.


A number of maternally administered pharmacologic agents have been implicated in hematologic abnormalities of the fetus or newborn (Table 7-7). Maternal aspirin ingestion results in impaired platelet aggregation but does not foster neonatal bleeding. Other agents taken by the mother, including diazoxide and thiazides, may be associated with neonatal thrombocytopenia.283,284 and 285


The newborn’s plasma coagulation factors may be depressed by maternal warfarin ingestion.268 This drug is best avoided during pregnancy, as it is teratogenic (first trimester) and may cause growth retardation of the fetus as well as bleeding.268 In contrast, heparin does not cross the placenta, and maternal treatment with heparin appears to be safe for the fetus.286
Dilantin and/or phenobarbital also may reduce the newborn’s vitamin-K dependent factors, possibly by microsomal enzyme induction, which enhances their degradation.267 Furthermore, phenytoin (Dilantin) may depress the platelet count as a result of prenatal exposure287 and cause teratogenic effects, e.g., the fetal hydantoin syndrome.288 The decision to use this agent during pregnancy should reflect an assessment of the need for this specific drug, and also the risk of maternal seizures to the fetus and mother versus the potential side effects of treatment. Newborns of mothers taking rifampin and isoniazid also may have depressed vitamin K-dependent factors.289
Nitrofurantoin and nalidixic acid may cause oxidant injury to the red cell membrane and hemoglobin.290,291 If there is glucose-6-phosphate dehydrogenase deficiency or if reduced glutathione is diminished, as in newborn red cells, these drugs have the potential to induce hemolysis and heighten neonatal hyperbilirubinemia. Although this problem has not been documented by transplacental transfer of nitrofurantoin or nalidixic acid, hemolysis has occurred in glucose-6-phosphate dehydrogenase–deficient infants who acquired the drugs from breast milk.291,292 Alternatively, sulfonamides may cause displacement of bilirubin bound to albumin and heighten the risk of kernicterus.293 Salicylates, phenylbutazone, and naproxen may have a similar effect at very high plasma concentrations.293
Ideally, all these medications should be avoided during pregnancy unless their indication outweighs the potential risk to the fetus and newborn.

Bloom W, Bartelmez GW: Hematopoiesis in young human embryos. Am J Anat 67:21, 1940.

Gilmour JR: Normal hemopoiesis in intrauterine and neonatal life. J Pathol 52:25, 1942.

Zon L: Developmental biology of hematopoiesis. Blood 86:2876, 1995.

Shivdasani RA, Mayer EL, Orkin SH: Absence of blood formation in mice lacking T-cell leukemia oncoprotein tal-1/SCL. Nature 373:432, 1995.

Warren AJ, Colledge WH, Carlton MBL, Evans M, Smith AJH, Rabbitts TH: The oncogenic cysteine-rich LIM domain protein is essential for erythroid development. Cell 78:45, 1994.

Fujiwara Y, Browne CP, Cuniff K, Goff SC, Orkin SH: Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci 93:12355, 1996.

Peschle C, Migliaccio AR, Migliaccio G, Ptrini M, Calandrini M, Russo G, et al: Embryonic to fetal Hb switch in humans: studies on erythroid bursts generated by embryonic progenitors from yolk sac and liver. Proc Natl Acad Sci USA 81:2416, 1984.

Migliaccio G, Migliaccio AR, Petti S, et al: Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac—liver transition. J Clin Invest 78:51, 1986.

Huyhn A, Dommergues M, Izac B, Croisille L, Katz A, Vainchenker W, Coulombel L: Characterization of hematopoietic progenitors from human yolk sacs and embryos. Blood 86:4474, 1995.

Dommergues M, Aubeny E, Dumez Y, Durandy A, Coulombel L: Hematopoiesis in the human yolk sac: quantitation of erythroid and granulopoietic progenitors between 3.5 and 8 weeks of development. Bone Marrow Transplant 9:23, 1992.

Keleman E, Calvo W, Fliedner TM: Atlas of Human Hemopoietic Development, Springer-Verlag, Berlin, 1979.

Lin C-S, Lim S-K, D’Agati V, Constantini F: Differential effects of an erythropoietin receptor gene disruption on primitive and definitive erythropoiesis. Genes Dev 10:154, 1996.

Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K: Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 93:397, 1998.

Valtieri M, Gabbianelli M, Pelosi E, Bassano E, Petti S, Russo G, et al: Erythropoietin alone induces erythroid burst formation by human embryonic but not adult BFU-E in unicellular serum-free culture. Blood 74:460, 1989.

Emerson SG, Shanti T, Ferrara JL, Greenstein JL: Developmental regulation of erythropoiesis by hematopoietic growth factors: analysis on populations of BFU-E from bone marrow, peripheral blood, and fetal liver. Blood 74:49, 1989.

Dame C, Fahnenstich H, Feitag P, Hofmann D, Abdul-Nour T, Bartmann P, Fandrey J: Erythropoietin mRNA expression in human fetal and neonatal tissue. Blood 92:3218, 1998.

Mucenski ML, McLain K, Kier AB, Swerdlow SH, Schreiner MC, Miller TA, et al: A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65:677, 1991.

Nuez B, Michalovich D, Bygrave A, Ploemacher R, Grosveld F: Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene. Nature 375:316, 1995.

Hann IM, Bodger MP, Hoffbrand AV: Development of pluripotent hematopoietic progenitor cells in the human fetus. Blood 62:118, 1983.

Porcellini A, Manna A, Manna M, et al. Ontogeny of granulocyte- macrophage progenitor cells in the human fetus. Int J Cell Clon 1:92, 1983.

Nicola NA, Metcalf D: Specificity of action of colony-stimulating factors in the differentiation of granulocytes and macrophages. CIBA Found Symp 118:7, 1986.

Ohls RK, Li Y, Abdel-Mageed A, Buchanan G Jr., Mandell L, Christensen RD. Neutrophil pool sizes and granulocyte colony-stimulating factor production in human mid-trimester fetuses. Pediatric Res 37(6):806, 1995.

Slayton WB, Juul SE, Calhoun DA, Li Y, Braylan RC, Christensen RD: Hematopoiesis in the liver and marrow of human fetuses at 5 to 16 weeks postconception: quantitative assessment of macrophage and neutrophil populations. Pediatric Res 43:774, 1998.

Charbord P, Tavian M., Humeau L, Peault B: Early ontogeny of the human marrow from long bones: an immunohistochemical study of hematopoiesis and its microenvironment. Blood 87:4109, 1996.

Gupta S, Pahwa R, O’Reilly R, et al: Ontogeny of lymphocyte subpopulation in human fetal liver. Proc Natl Acad Sci USA 73:919, 1976.

Rainaut M, Pagniez M, Hercend T, Daffos F, Forestier F: Characterization of mononuclear cell subpopulations in normal fetal peripheral blood. Hum Immunol 18:331, 1987.

Hann IM, Gibson BES, Letsky EA: Fetal and Neonatal Haematology, Baillaire Tindale, Philadelphia, 1991.

Cairo MS, Wagner JE: Placental and/or umbilical cord blood: an alternative source of hematopoietic stem cells for transplantation. J Am Soc Hematol 90:4665, 1997.

Maximow AA: Relation of blood cells to connective tissues and endothelium. Physiol Rev IV(4):532, 1924.

Houssaint E: Differentiation of the mouse hepatic primordium. II. Extrinsic origin of the haemopoietic cell line. Cell Differ 10:243, 1981.

Cudennec CA, Johnson GR: Presence of multipotential hemopoietic cells in teratocarcinoma cultures. J Embryol Exp Morphol 61:51, 1981.

Gupta S, Pahwa R, O’Reilly R, et al: Ontogeny of lymphocyte subpopulation in human fetal liver. Proc Natl Acad Sci USA 73:919, 1976.

Moore MAS, Owen JJT: Stem-cell migration in developing myeloid and lymphoid systems. Lancet i:658, 1967.

Dieterlen-Lievre F: On the origin of hematopoietic stem cells in the avian embryo: an experimental approach. J Embryol Exp Morphol 33:607, 1975.

Carpenter KL, Turpen JB: Experimental studies on hemopoiesis in the pronephros of Rana pipiens. Differentiation 14:167, 1979.

Muller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E: Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1:291, 1994.

Smith RA, Glomski CA: “Hemogenic endothelium” of the embryonic aorta: does it exist? Dev Comp Immunol 6:359, 1982.

Tavian M, Coulombel L, Luton D, San Clemente H, Dieterlen-Lievre F, Peault B: Aorta-associated CD-34+ hematopoietic cells in the early human embryo. Blood 87:67, 1996.

Proudfoot NJ, Shander MH, Manley JL, Gefter ML, Maniatis T: Structure and in vitro transcription of human globin genes. Science 209:1329, 1980.

Grosveld F, van Assendelft GB, Greaves DR, Kolias B: Position independent, high-level expression of the human b globin gene in transgenic mice. Cell 51:975, 1987.

Hecht F, Motulsky AG, Lemire RJ, et al: Predominance of hemoglobin Gower 1 in early human embryonic development. Science 152:91, 1966.

Huehns ER, Dance N, Beaven GH, et al: Human embryonic hemoglobins. Cold Spring Harbor Symp Quant Biol 29:327, 1964.

Gale RE, Clegg JB, Huehns ER: Human embryonic haemoglobins Gower 1 and Gower 2. Nature 280:162, 1979.

Peschle C, Mavilio F, Care A, Migliaccio G, Migliaccio AR, Salvo G, et al: Haemoglobin switching in human embryos: asynchrony of the z to a and e to g globin switches in primitive and definitive erythropoietic lineage. Nature 313:235, 1985.

Pataryas HA, Stomatoyannopoulos G: Hemoglobins in human fetuses: evidence of adult hemoglobin production after the 11th gestational week. Blood 39:688, 1972.

Thomas ED, Lochte HL Jr, Greenough WB III, et al: In vitro synthesis of foetal and adult haemoglobin by foetal haematopoietic tissues. Nature 185:396, 1960.

Kazazian HH, Woodhead AP: Hemoglobin A synthesis in the developing fetus. N Engl J Med 289:58, 1973.

Bard H: The effect of placental insufficiency on fetal and adult hemoglobin synthesis. Am J Obstet Gynecol 120:67, 1974.

Kirschbaum T: Fetal hemoglobin content of cord blood determined by column chromatography. Am J Obstet Gynecol 84:1375, 1962.

Armstrong D, Schroeder WA, Fenninger W: A comparison of the percentage of fetal hemoglobin in human umbilical cord blood as determined by chromatography and by alkali denaturation. Blood 22:554, 1963.

Bard H: Postnatal fetal and adult hemoglobin synthesis in early preterm newborn infants. J Clin Invest 52:1789, 1973.

Metaxotou-Mavromati AD, Antonopoulou HK, Laskari SA, Tsiarta HK, Ladis VA, Kattamis CA: Developmental changes in hemoglobin F levels during the first two years of life in normal and heterozygous b-thalassemia infants. Pediatrics 69:734, 1982.

Bard H, Makowski EL, Meschia G, et al: The relative rates of synthesis of hemoglobins A and F in red cells of newborn infants. Pediatrics 45:766, 1970.

Bromberg YN, Abrahamov A, Salzberger M: The effect of maternal anoxemia on the foetal haemoglobin of the newborn. J Obstet Gynaecol Br Commonw 63:875, 1956.

Huehns ER, Hecht F, Keil JV, et al: Developmental hemoglobin anomalies in a chromosomal triplication. Proc Natl Acad Sci USA 51:89, 1964.

Lee CSN, Boyer SH, Bowen P, et al: The D1 trisomy syndrome: three subjects with unequally advancing development. Johns Hopkins Med J 118:374, 1966.

Wilson MG, Schroeder WA, Graves DA: Postnatal change of hemoglobins F and A2 in infants with Down’s syndrome (G trisomy). Pediatrics 42:349, 1968.

Giulian GG, Gilbert EF, Moss RL: Elevated fetal hemoglobin levels in sudden infant death syndrome. N Engl J Med 316:1122, 1987.

Brown MS: Fetal and neonatal erythropoieses, in Developmental and Neonatal Hematology, edited by JA Stockman, III and C Pochedly, pp 39. Raven Press, New York, 1988.

Forestier F, Daffos F, Galacteros F, et al: Haematological values of 163 normal fetuses between 18 and 30 weeks of gestation. Paediat Res 20:342, 1986.

Millar DS, Davis LR, et al. Normal blood cell values in the early mid- trimester fetus. Prenat Diagn, 5:367, 1985.

Linch DC, Knott LJ, et al. Studies of circulating hemopoietic progenitor cells in human fetal blood. Blood 59:976, 1982.

Christensen RD. Hematopoiesis in the fetus and neonate. Pediatr Res 26:531, 1989.

Marks J, Gairdner D, Roscoe JD: Blood formation in infancy. III. Cord blood. Arch Dis Child 30:117, 1955.

Linderkamp O, Versmold HT, Messow-Zahn K, et al: The effect of intrapartum and intra-uterine asphyxia on placental transfusion in premature and full-term infants. Eur J Pediatr 127:91, 1978.

Yao AC, Hirvensalo M, Lind J: Placental transfusion rate and uterine contraction. Lancet 1:380, 1968.

Usher R, Shepard M, et al: The blood volume of the newborn and placental transfusion. Acta Paediatr 52:497, 1963.

Bratteby LE: Studies on erythro-kinetics in infancy. XI. The change in circulating red cell volume during the first five months of life. Acta Paediatr Scand 57:215, 1968.

McCue CM, Garner FB, Hurt WG, et al: Placental transfusion. J Pediatr 72:15, 1968.

Matoth Y, Zaizor R, Varsano I: Postnatal changes in some red cell parameters. Acta Paediatr Scand 60:317, 1971.

Linderkamp O, Versmold HT, Strohhacker I, et al: Capillary-venous hematocrit differences in newborn infants. Eur J Pediatr 127:9, 1977.

Saarinen UM, Simmes MA: Developmental changes in red blood cell counts and indices of infants after exclusion of iron deficiency by laboratory criteria and continuous iron supplementation. J Pediatr 92:412, 1978.

Zipursky A, Brown E, Palko J, et al: The erythrocyte differential count in newborn infants. Am J Pediatr Hematol Oncol 5:45, 1983.

Shannon KM, Naylor GS, Torkildson JC, et al: Circulating erythroid progenitors in the anemia of prematurity. N Engl J Med 317:728, 1987.

Linch DC, Knott LJ, Rodeck CH, Huehns ER: Studies of circulating hemopoietic progenitor cells in human fetal blood. Blood 59:976, 1983.

Christensen RD: Circulating pluripotent hematopoietic progenitor cells in neonates. J Pediatr 11:622, 1987.

Clapp DW, Baley JE, Gerson SL: Gestational age dependent changes in circulating hematopoietic stem cells in newborn infants. J Lab Clin Med 113:422, 1989.

Holbrook SR, Christensen RD, Rothstein G: Erythroid colonies derived from fetal blood display different growth patterns from those derived from adult marrow. Pediatr Res 24:605, 1988.

Burman D, Morris AF: Cord hemoglobin in low birth weight infants. Arch Dis Child 49:382, 1974.

Meberg A: Haemoglobin concentrations and erythropoietin levels in appropriate and small for gestational age infants. Scand J Haematol 24:162, 1980.

Zaizov R, Matoth Y: Red cell values on the first postnatal day during the last 16 weeks of gestation. Am J Hematol 1:275, 1976.

Lockridge S, Pass R, Cassidy G: Reticulocyte counts in intrauterine growth retardation. Pediatrics 47:919, 1971.

Humbert JR, Abelson H, Hathaway WE, et al: Polycythemia in small for gestational age infants. J Pediatr 75:1812, 1969.

Halvorsen S, Finne PH: Erythropoietin production in the human fetus and newborn. Ann NY Acad Sci 149:576, 1968.

Seip M: The reticulocyte level and the erythrocyte production judged from reticulocyte studies in newborn infants during the first week of life. Acta Paediatr Scand 44:355, 1955.

Stockman JA III, Oski FA: Physiological anaemia of infancy and the anaemia of prematurity. Clin Haematol 7:3, 1978.

Mann DL, Sites ML, Donati RM, et al: Erythropoietic stimulating activity during the first ninety days of life. Proc Soc Exp Biol Med 118:212, 1965.

Lundstrom U, Simmes MA: Red blood cell values in low-birth-weight infants: Ages at which values become equivalent to those of term infants. J Pediatr 96:1040, 1980.

Stockman JA III, Garcia JF, Oski FA: The anemia of prematurity: factors governing the erythropoietin response. N Engl J Med 296:647, 1977.

MackIntosh TF, Walker CHM: Blood viscosity in the newborn. Arch Dis Child 48:547, 1973.

Bergqvist G: Viscosity of the blood in the newborn infant. Acta Paediatr Scand 63:858, 1974.

Wirth FH, Goldberg WR, Lubchenco L: Neonatal hyperviscosity. I. Incidence. Pediatrics 63:833, 1979.

Hakanson DO, Oh W: Hyperviscosity in the small-for-gestational age infant. Biol Neonate 37:190, 1980.

Ramamurthy RS, Berlanga M. Postnatal alteration in hematocrit and viscosity in normal and polycythemic infants. J Pediatr 110:929, 1987.

Bada HS, Korones SB, Pourcyrous M, et al: Asymptomatic syndrome of polycythemic hyperviscosity: Effect of partial plasma exchange transfusion. J Pediatr 120:579, 1992.

Bierhuizen MFA, Mattei MG, Fukuda M: Expression of the developmental I antigen by a cloned human cDNA encoding a member of a b-1,6-N-acetylglucosaminyltransferase gene family. Gene Dev 7:468, 1993.

Race RR, Sanger R: Blood Groups in Man, 6th ed. Blackwell Scientific Publications, London, 1975.

Pearson HA: Life-span of the fetal red blood cell. J Pediatr 70:166, 1967.

Weipple G, Pantlitschko M, Bauer P, et al: Normal values and distribution of serum iron in cord blood. Clin Chim Acta 44:147, 1973.

Saarinen UM, Siimes MA: Developmental changes in serum iron, total iron-binding capacity, and transferrin saturation in infancy. J Pediatr 91:875, 1977.

Saarinen UM, Siimes MA: Serum ferritin in assessment of iron nutrition in healthy infants. Acta Paediatr Scand 67:745, 1978.

Seip M, Halvorsen S: Erythrocyte production and iron stores in premature infants during the first months of life. The anemia of prematurity—etiology, pathogenesis, iron requirement. Acta Paediatr Scand 45:600, 1956.

Bauer C, Ludwig I, Ludwig M: Different effects of 2,3-diphosphoglycerate and adenosine triphosphate on oxygen affinity of adult and fetal hemoglobin. Life Sci 7:1339, 1968.

Oski FA: Red cell metabolism in the newborn infant. V. Glycolytic intermediates and glycolytic enzymes. Pediatrics 44:84, 1969.

Oski FA, Delivoria-Papadopoulos M: The red cell, 2, 3-diphosphoglycerate, and tissue oxygen release. J Pediatr 77:941, 1970.

Zipursky A: The erythrocytes of the newborn infant. Semin Hematol 2:167, 1965.

Oski FA, Komazawa M: Metabolism of the erythrocytes of the newborn infant. Semin Hematol 12:209, 1975.

Oski FA, Smith CA: Red cell metabolism in the premature infant. III. Apparent inappropriate glucose consumption for cell age. Pediatrics 41:473, 1968.

Konrad PN, Valentine WN, Paglia DE: Enzymatic activities and glutathione content of erythrocytes in the newborn: comparison with red cells of older normal subjects and those with comparable reticulocytosis. Acta Haematol 48:193, 1972.

Gross RT, Schroeder EAR, Brounstein SA: Energy metabolism in the erythrocytes of premature infants compared to full term newborn infants and adults. Blood 21:755, 1963.

Oski FA: Red cell metabolism in the premature infant. II. The pentose phosphate pathway. Pediatrics 39:689, 1967.

Ross JD: Deficient activity of DPNH-dependent methemoglobin diaphorase in cord blood erythrocytes. Blood 21:51, 1963.

Gross RT, Bracci R, Rudolph N, et al: Hydrogen peroxide toxicity and detoxification in erythrocytes of newborn infants. Blood 29:481, 1967.

Travis SF, Kumar SP, Delivoria-Papadopoulos M: Red cell metabolic alterations in postnatal life in term infants: glycolytic intermediates and adenosine triphosphate. Pediatr Res 15:34, 1981.

Whaun JM, Oski FA: Red cell stromal adenosine triphosphatase (ATPase) of newborn infants. Pediatr Res 3:105, 1969.

Blum SF, Oski FA: Red cell metabolism in the newborn infant. IV. Transmembrane potassium flux. Pediatrics 43:396, 1969.

Crowley J, Ways P, Jones JW: Human fetal erythrocyte and plasma lipids. J Clin Invest 44:989, 1965.

Neerhout RC: Erythrocyte lipids in the neonate. Pediatr Res 2:172, 1968.

Shapiro DL, Pasqualini P: Erythrocyte membrane proteins of premature and full-term infants. Pediatr Res 12:176, 1978.

Kosztolanyi G, Jobst K: Electrokinetic analysis of the fetal erythrocyte membrane after trypsin digestion. Pediatr Res 14:138, 1980.

Altman PL, Dittmer, DS: Blood and Other Body Fluids. Federation of American Societies for Experimental Biology, Washington, DC, 1961.

Coulombel L, Dehan M, Tchernia G, Hill C, et al: The number of polymorphonuclear leukocytes in relation to gestational age in the newborn. Acta Paediatr Scand 68:709, 1979.

Barak Y, Blachar Y, Levin S: Neonatal neutrophilia: Possible role of a humoral granulopoietic factor. Pediatr Res 14:1026, 1980.

Laver J, Duncan E, Abboud M, et al: High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates. J Pediatr 116:627, 1990.

Ijima H, Suda T, Miura Y: Predominance of macrophage-colony formation in human cord blood. Exp Hematol 10:234, 1982.

Prindull G, Ben-Ishay Z, Gabriel M, et al: A comparison of spontaneous and CSF added CFU-MG colony formation in healthy, sick and hypotrophic pre-term infants. Blut 45:167, 1982.

Cairo MS, Suen Y, Knoppel E, Van De Ven C, Nguyen A, Sender L: Decreased stimulated GM-CSF production and GM-CSF gene expression but normal numbers of GM-CSF receptors in human term newborns compared with adults. Pediatr Res 30:362, 1991.

English BK, Hammond WP, Lewis DB, Brown CB, Wilson CB: Decreased granulocyte-macrophage colony-stimulating factor production by human neonatal blood mononuclear cells and T cells. Pediatr Res 31:211, 1992.

Cairo MS, Suen Y, Knoppel E, et al: Decreased G-CSF and IL-3 production and gene expression from mononuclear cells of newborn infants. Pediatr Res 31:574, 1992.

Rosenthal J, Cairo MS: The role of cytokines in modulating neonatal myelopoiesis and host defense. Cytokin Mol Ther 1:165, 1995.

Cairo MS, Plunkett JM, Nguyen A, Van De Ven C: Effect of stem cell factor with and without granulocyte colony-stimulating factor on neonatal hematopoiesis: in vivo induction of newborn myelopoiesis and reduction of mortality during experimental group B streptococcal sepsis. Blood 80:96, 1992.

Xanthou M: Leucocyte blood picture in healthy full-term and premature babies during neonatal period. Arch Dis Child 45:242, 1970.

Gibson EL, Vaucher Y, Corrigan JJ Jr: Eosinophilia in premature infants. Relationship to weight gain. J Pediatr 95:99, 1979.

Siegel JD, McCracken GH Jr: Sepsis neonatorum. N Engl J Med 304:642, 1981.

Forman ML, Stiehm ER: Impaired opsonic activity but normal phagocytosis in low-birth-weight infants. N Engl J Med 281:926, 1969.

Dossett JH, Williams RC Jr, Quie PG: Studies on interaction of bacteria, serum factors and polymorphonuclear leukocytes in mothers and newborns. Pediatrics 44:49, 1969.

Miller ME: Phagocytosis in the newborn infant: humoral and cellular factors. J Pediatr 74:255, 1969.

Hill HR, Shigeoka AO, Pincus S, Christensen RD: Intravenous IgG in combination with other modalities in the treatment of neonatal infection. Pediatr Inf Dis 5:180, 1986.

Cocchi P, Marianelli L: Phagocytosis and intracellular killing of Pseudomonas aeruginosa in premature infants. Helv Paediatr Acta 22:110, 1967.

Drossou V, Kanakoudi F, Diamanti E, et al: Concentrations of main serum opsonins in early infancy. Arch Dis of Childhood (Fetal and Neonatal Edition) 72:F172, 1995.

Yang KD, Bathras JM, Shigeoka AO, James J, Pincus SH, Hill HR: Mechanisms of bacterial opsonization by immune globulin intravenous correlation of complement consumption with opsonic activity and protective efficacy. J Infect Dis 159:701, 1989.

Shaio MF, Yang KD, Bohnsack JF, Hill HR: Effect of immune globulin intravenous on opsonization of bacteria by classic and alternative complement pathways in premature serum. Pediatr Res 25:634, 1989.

Hill H: Host defenses in the neonate: prospects for enhancement. Semin Perinatol 9:2, 1985.

Propp RP, Alper CA: C3 synthesis in the human fetus and lack of transplacental passage. Science 162:672, 1968.

Johnston RB Jr, Altenburger KM, Atkinson AW Jr, et al: Complement in the newborn infant. Pediatrics 64:781, 1979.

Strunk RC, Fenton LJ, Gaines JA: Alternative pathway of complement activation in full term and premature infants. Pediatr Res 13:641, 1979.

Davis CA, Vallota EH, Forristal J: Serum complement levels in infancy: age related changes. Pediatr Res 13:1043, 1979.

Mills EL, Bjorksten B, Quie PG: Deficient alternative complement pathway activity in newborn sera. Pediatr Res 13:1341, 1979.

Proctor RA, Prendergast E, Mosher DF: Fibronectin mediates attachment of Staphylococcus aureus to human neutrophils. Blood 59:681, 1982.

Hill HR, Shigeoka AO, Augustine NH, Pritchard D, Lundblad JL, Schwartz RS: Fibronectin enhances the opsonic and protective activity of monoclonal and polyclonal antibody against group B streptococci. J Exp Med 159:1618, 1984.

Harris MC, Levitt J, Douglas SD, Gerdes JS, Polin RA: Effect of fibronectin on adherence of neutrophils from newborn infants. J Clin Microbiol 21:243, 1985.

Hill HR, Shigeoka AO, Gonzales LA, Christensen RD: Intravenous immune globulin use in newborns. J Allergy Clin Immunol 84:617, 1989.

Christensen RD, Brown MS, Hall DC, Lassiter HA, Hill HR: Effect on neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis. J Pediatr 118:606, 1991.

Fujiwara T, Taniuchi S, Hattori K, Kobayashi T, Kinoshita Y, Kobayashi Y: Effect of immunoglobulin therapy on phagocytosis by polymorphonuclear leucocytes in whole blood of neonates. Clin Exp Immunol 107:435, 1997.

Weisman LE, Stoll BJ, Kueser TJ, et al: Intravenous immune globulin therapy for early-onset sepsis in premature neonates. J Pediatr 121:434, 1992.

Schreiber JR, Berger M: Intravenous immune globulin therapy for sepsis in premature neonates. J Pediatr 121:401, 1992.

Baker CJ, Melish ME, Hall RT, et al: Intravenous immune globulin for the prevention of nosocomial infection in low-birth-weight infants. N Engl J Med 327:213, 1992.

Fanaroff A, Wright E, Korones S, Wright L: A controlled trial of prophylactic intravenous immunoglobulin to reduce nosocomial infections in VLBW infants. Pediatr Res 31:202A, 1992.

Fischer GW, Weisman LE, Hemming VG: Directed immune globulin for the prevention or treatment of neonatal group B streptococcal infections: A review. Clin Immunol Immunopathol 62:S92, 1992.

Miller ME: Chemotactic function in the neonate. Humoral and cellular aspects. Pediatr Res 5:487, 1971.

Klei RB, Fischer TJ, Gard SE, et al: Decreased mononuclear and polymorphonuclear chemotaxis in human newborns, infants, and young children. Pediatrics 60:467, 1977.

Tono-oka T, Nakayama M, Uehara H, et al: Characteristics of impaired chemotactic function in cord blood leukocytes. Pediatr Res 13:148, 1979.

Hill HR, Augustine NH, Newton JA, Shigeoka AO, Morris E, Sacchi F: Correction of a developmental defect in neutrophil activation and movement. Am J Pathol 128:307, 1987.

Bruce MC, Baley JE, Medvik KA, Berger M: Impaired surface membrane expression of C3bi but not C3b receptors on neonatal neutrophils. Pediatr Res 21:306, 1987.

Anderson DC, Freeman KLB, Heerdt B, Hughes BJ, Jack RM, Smith CW: Abnormal stimulated adherence of neonatal granulocytes: impaired induction of surface MAC-1 by chemotactic factors or secretagogues. Blood 70:740, 1987.

Smith JB, Campbell DE, Ludomirsky A, et al: Expression of the complement receptors CR1 and CR3 and the type III Pc-gamma receptor on neutrophils from newborn infants and from fetuses with Rh disease. Pediatr Res 28:120, 1990.

Carr R, Davies JM: Abnormal PcRIII expression by neutrophils from very preterm neonates. Blood 76:607, 1990.

Anderson DC, Rothlein R, Marlin SD, Krater SS, Smith CW: Impaired transendothelial migration by neonatal neutrophils: abnormalities of Mac-1(CD11b/CD18)-dependent adherence reactions. Blood 76:2613, 1990.

Masuda K, Kinoshita Y, Kobayashi Y: Heterogeneity of Fc expression in chemotaxis and adherence of neonatal neutrophils. Pediatr Res 25:6, 1989.

Tosi MF, Berger M: Functional differences between the 40 kDa and 50 kDa IgG Fc receptors on human neutrophils revealed by elastase treatment and antireceptor antibodies. J Immunol 141:2097, 1988.

Salmon JE, Kapur S, Kimberly RP: Opsonin-independent ligation of Fc-gamma receptors. J Exp Med 166:1798, 1987.

Coen R, Grush O, Kander E: Studies of bactericidal activity and metabolism of the leukocyte in full-term neonates. J Pediatr 78:400, 1969.

Mills EL, Thompson T, Bjorksten B, et al: The chemiluminescence response and bactericidal activity of polymorphonuclear neutrophils from newborns and their mothers. Pediatrics 63:429, 1979.

Park BH, Holmes B, Good RA: Metabolic activities in leukocytes of newborn infants. J Pediatr 76:237, 1970.

Xanthou M, Valassi-Adam E, Kintronidou E, et al: Phagocytosis and killing ability of Candida albicans by blood leucocytes of healthy term and preterm babies. Arch Dis Child 50:72, 1975.

Wright WC Jr, Ank BJ, Herbert J, et al: Decreased bactericidal activity of leukocytes of stressed newborn infants. Pediatrics 56:569, 1975.

Shigeoka AO, Santos JI, Hill HR: Functional analysis of neutrophil granulocytes from healthy, infected, and stressed neonates. J Pediatr 95:454, 1979.

Shigeoka AO, Charette RP, Wyman ML, et al: Defective oxidative metabolic responses of neutrophils from stressed neonates. J Pediatr 98:392, 1981.

Strauss RG, Snyder EL: Neutrophils from human infants exhibit decreased viability. Pediatr Res 15:794, 1981.

Strauss RG, Snyder EL, Wallace PO, et al: Oxygen-detoxifying enzymes in neutrophils of infants and their mothers. J Lab Clin Med 95:897, 1980.

Yamazaki M, Matsuoka T, Yasui K, Komiyama A, Akabane T: Increased production of superoxide anion by neonatal polymorphonuclear leukocytes stimulated with a chemotactic peptide. Amer J Hematol 27:169, 1988.

Kretschmer RR, Papierniak CK, Stewardson-Krieger P, et al: Quantitative nitrobluetetrazolium reduction by normal newborn monocytes. J Pediatr 91:306, 1977.

Milgrom H, Shore SL: Assessment of monocyte function in the normal newborn infant by antibody-dependent cellular cytotoxicity. J Pediatr 91:612, 1977.

Orlowski JP, Sieger L, Anthony BF: Bactericidal capacity of monocytes of newborn infants. J Pediatr 89:797, 1976.

Schuit KE, Powell DA: Phagocytic dysfunction in monocytes of normal newborn infants. Pediatrics 65:501, 1980.

Das M, Henderson T, Feig SA: Neonatal mononuclear cell metabolism: Further evidence for diminished monocyte function in the neonate. Pediatr Res 13:632, 1979.

Mills EL: Mononuclear phagocytes in the newborn: their relation to the state of relative immunodeficiency. Am J Pediatr Hematol 5:189, 1983.

Bryson YJ, Winter HS, Gard SE, Fisher TJ, Stiehm ERL: Deficiency of immune interferon production by leukocytes of normal newborns. Cell Immunol 55:191, 1987.

Frenkel L, Bryson YJ: Ontogeny of phytohemagglutinin-induced gamma interferon by leukocytes of healthy infants and children: evidence for decreased production in infants younger than 2 months of age. J Pediatr 111:97, 1987.

Wilson CB, Westall J, Johnston L, Lewis DB, Dower SK, Alper AR: Decreased production of interferon-gamma by human neonatal cells. J Clin Invest 77:860, 1986.

Perussia B, Dayton ET, Lazarus R, Fenning V, Trinchieri G: Immune interferon induces the receptor for monomeric IgG on human monocytic and myeloid cells. J Exp Med 158:1092, 1983.

Cairo MS: Review of G-CSF and GM-CSF effects on neonatal neutrophil kinetics. Am J Pediatr Hematol Oncol 11:238, 1989.

Cairo MS, VandeVen C, Toy C, Suen Y, Mauss D, Sender L: GM- CSF primes and modulates neonatal PMN motility: up-regulation of C3bi (Mol) expression with alteration in PMN adherence and aggregation. Am J Pediatr Hematol Oncol 13:249, 1991.

Sautois B, Fillet G and Beguin Y. Comparative cytokine production by in vitro stimulated mononucleated cells from cord blood and adult blood. Exp Hematol 25:103, 1997.

Fogel BJ, Arais D, Kung F: Platelet counts in healthy premature infants. J Pediatr 73:108, 1968.

Sell EJ, Corrigan JJ: Platelet counts, fibrinogen concentrations and factor V and factor VIII levels in healthy infants according to gestational age. J Pediatr 82:1028, 1973.

Mehta P, Vasa R, Neumann L, Karpatkin M: Thrombocytopenia in the high-risk infant. J Pediatr 97:791, 1980.

Meberg A, Halvorsen S, Orstavik I: Transitory thrombocytopenia in small-for-dates infants, possibly related to maternal smoking. Lancet 2:303, 1977.

Thuring W, Tonz O: Neonatale Thrombozytenwere be: Kindern mit Down-Syndrom und anderen autosomalen Trisomien. Helv Paediatr Acta 34:545, 1979.

Cairo, MS: The regulation of hematopoietic growth factor production from cord mononuclear cells and its effect on newborn rat hematopoiesis. J Hematother 2:217, 1993.

Sirota L, Bessler H, Weissman Z, Dulitzky F, Djaldetti M: Thrombopoietic activity in preterm newborns and infants. Arch Dis Childhood 61:585, 1986.

Suen Y, Chang M, Lee SM, Buzby JS, Cairo MS: Regulation of interleukin-11 protein and mRNA expression in neonatal and adult fibroblasts and endothelial cells. Blood 84:4125, 1994.

Feusner JH: Normal and abnormal bleeding times in neonates and young children utilizing a fully standardized template technic. Am Soc Clin Pathol 74:73, 1980.

Rennie JM, Gibson T, Cooke RWI: Micromethod for bleeding time in the newborn. Arch Dis Child 60:51, 1985.

Andrew M, Paes B, Bowker J, Vegh P: Evaluation of an automated bleeding time device in the newborn. Am J Hematol 35:275, 1990.

Weinstein MJ, Blanchard R, Moake JL, Vosburgh E, Moise K: Fetal and neonatal von Willebrand factor (vWF) is unusually large and similar to the vWF in patients with thrombotic thrombocytopenic purpura. Br J Haematol 72:68, 1989.

Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L: Maturation of the hemostatic system during childhood. Blood 80:1998, 1992.

Andrew M, Castle V, Saigal S, et al: Clinical impact of neonatal thrombocytopenia. J Pediatr 110:457, 1987.

Corazza MS, Davis RF, Merritt TA, et al: Prolonged bleeding time in preterm infants receiving indomethacin for patent ductus arteriosus. J Pediatr 105:292, 1984.

Stuart MJ: Platelet function in the neonate. Am J Pediatr Hematol Oncol 1:227, 1979.

Israels SJ, Daniels M, McMillan EM: Deficient collagen-induced activation in the newborn platelet. Pediatr Res 27:337, 1990.

Rajasekhar D, Kestin AS, Bednarek FJ, Ellis PA, Barnard MR, Michelson AD: Neonatal platelets are less reactive than adult platelets to physiological agonists in whole blood. Thromb Haemost 72:957, 1994.

Ts’ao C, Green D, Schultz K: Function and ultrastructure of platelets of neonates; enhanced ristocetin aggregation of neonatal platelets. Br J Haematol 32:225, 1976.

Blieyer WA, Breckenridge RT: Studies on the detection of adverse drug reactions in the newborn. II. The effects of prenatal aspirin on newborn hemostasis. JAMA 213:2049, 1970.

Corby DG, Schulman I: The effects of antenatal drug administration on aggregation of platelets of newborn infants. J Pediatr 79:307, 1971.

Hauth JC, Goldenberg RL, Parker CR Jr, Cutter GR, Cliver SP: Low- dose aspirin: lack of association with an increase in abruptio placentae or perinatal mortality. Obstet Gynecol 85:1055, 1995.

Sibai BM, Caritis SN, Thom E, Shaw K, McNellis D: Low-dose aspirin in nulliparous women: safety of continuous epidural block and correlation between bleeding time and maternal-neonatal bleeding complications. National Institute of Child Health and Human Developmental Maternal-Fetal Medicine Network. Am J Obstet Gynecol 172:1553, 1995.

Newman PJ, Derbes RS, Aster RH: The human platelet alloantigens, PIA1 and PIA2, are associated with a leucine 33/proline 33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 83:1778, 1989.

Gruel Y, Boizard B, Daffos F, Forestier F, Caen J, Wautier JL: Determination of platelet antigens and glycoproteins in the human fetus. Blood 68:488, 1986.

McFarland JG, Aster RH, Bussel JB, Gianopoulos JG, Derbes RS, Newman PJ: Prenatal diagnosis of neonatal alloimmune thrombocytopenia using allele-specific oligonucleotide probes. Blood 78:2276, 1991.

Shulman NR, Jordan JV Jr: Platelet immunology, in Hemostasis and Thrombosis: Basic Principles and Clinical Practice, 2nd ed, edited by RW Colman, J Hirsh, VJ Marder, EW Salzman, pp 476–483. JB Lippincott, Philadelphia, 1987.

Pabst HF: Ontogeny of the immune response as a basis of childhood diseases. J Pediatr 97:519, 1980.

Erkeller-Yuksel FM, Deneys V, Yuksel B, et al: Age related changes in human blood lymphocyte subpopulations. J Pediatr 120:216, 1992.

De Waele M, Foulon W, Renmans W, et al: Hematologic values and lymphocyte subsets in fetal blood. Am J Clin Pathol 89:742, 1988.

Hicks MJ, Jones JF, Minnich LL, Weigle KA, Thies AC, Layton JM: Age-related changes in T- and B-lymphocyte subpopulations in the peripheral blood. Arch Pathol Lab Med 107:518, 1983.

Kotylo PA, Baenzinger JC, Yoder MC, Engle WA, Bolinger CD: Rapid analysis of lymphocyte subsets in cord blood. Am J Clin Pathol 93:263, 1990.

Slukvin II, Chernishov VP: Two-color flow cytometric analysis of natural killer and cytotoxic T-lymphocyte subsets in peripheral blood of normal human neonates. Biol Neonate 61(3):156–61, 1992.

Neubert R, Delgado I, Abraham K, Schuster C, Helge H: Evaluation of the age-dependent development of lymphocyte surface receptors in children. Life Sci 62:1099, 1998.

Miller ME: Immune-inflammatory response in the human neonate. Am J Pediatr Hematol 3:199, 1981.

Stiehm ER, Winter HS, Bryson YF: Cellular (T cell) immunity in the human newborn. Pediatrics 64:814, 1979.

Carr MC, Stites DP, Fudenberg HH: Cellular immune aspects of the human fetal-maternal relationship. I. In vitro response of cord blood lymphocytes to phytohemagglutinin. Cell Immunol 5:21, 1972.

Papiernick M: Comparison of human foetal with child blood lymphocytic kinetics. Biol Neonate 19:163, 1971.

Uhr JW, Dancis J, Newmann CG: Delayed-type hypersensitivity in premature neonatal humans. Nature 187:1130, 1960.

Blaese RM, Poplack DG, Muchmore AV: The mononuclear phagocyte system: Role in expression of immunocompetence in neonatal and adult life. Pediatrics 64(suppl):829, 1979.

Von Freeden U, Zessack N, Van Valen F, Burdach S: Defective interferon gamma production in neonatal T cells is independent of interleukin-2 receptor binding. Pediatr Res 30:270, 1991.

Sterm CMM: Changes in lymphocytes subpopulations in the blood of healthy and sick newborn infants. Pediatr Res 13:792, 1979.

Raveche ES: Possible immunoregulatory role for CD5+ B cells. Clin Immuno Immunopath 56:135, 1990.

Lawton AR, Cooper MD: B cell ontogeny: immunoglobulin genes and their expression. Pediatrics 64:750, 1979.

Gustafsson BE, Laurell CB: Gamma globulin production in germ free rats after bacterial contamination. J Exp Med 110:675, 1959.

Gitlin D: The differentiation and maturation of specific immune mechanisms. Acta Pediatr Scand 172(suppl):60, 1967.

Stiehm ER: Fetal defense mechanisms. Am J Dis Child 129:438, 1975.

Goldman AS, Garza C, Nichols BL, Goldblum RM: Immunological factors in human milk during the first year of lactation. J Pediatr 100:563, 1982.

Goldman AS, Ham Pong AJ, Goldblum RM: Host defenses: development and maternal contributions. Adv Pediatr 32:71, 1985.

Rothberg RM: Immunoglobulin and specific antibody synthesis during the first weeks of life of premature infants. J Pediatr 75:391, 1969.

Harworth JC, Norris M, Dilling L: A study of the immunoglobulins in premature infants. Arch Dis Child 40:243, 1965.

Thom H, McKay E, Gray DWG: Protein concentrations in the umbilical cord plasma of premature and mature infants. Clin Sci 33:433, 1967.

Yeung CY, Hoffs JR: Serum g-G-globulin levels in normal, premature, postmature, and “small-for-dates” newborn babies. Lancet 1:1167, 1968.

Sever JH: Immunological responses to perinatal responses to perinatal infections. J Pediatr 75:1111, 1969.

Thomaidis T, Agathopoulos A, Matsaniotis N: Natural isohemagglutinin production by the fetus. J Pediatr 74:39, 1969.

Morito T, Bankhurst AD, Williams RC Jr: Studies of human cord blood and adult lymphocyte interactions with in vitro immunoglobulin production. J Clin Invest 64:990, 1979.

Miyagawa Y, Sugita K, Komiyama A, et al: Delayed in vitro immunoglobulin production by cord lymphocytes. Pediatrics 65:497, 1980.

Ferguson AC, Cheung SC: Modulation of immunoglobulin M and G synthesis by monocytes and T lymphocytes in the newborn infant. J Pediatr 98:385, 1981.

Blaese RM, Poplack DG, Muchmore AV: The mononuclear phagocyte system: role in expression of immunocompetence in neonatal and adult life. Pediatrics 64:829, 1977.

Holroyde CP, Oski FA, Gardner FH: The “pocked” erythrocyte. N Engl J Med 281:516, 1969.

Freedman RM, Johnston D, Mahoney MJ, et al: Development of splenic reticuloendothelial function in neonates. J Pediatr 96:466, 1980.

Gross SJ, Stuart MJ: Hemostasis in the premature infant. Clin Perinatol 4:259, 1977.

Barnard DR, Hathaway WE: Neonatal thrombosis. Am J Pediatr Hematol Oncol 1:235, 1979.

Bleyer WA, Hakami N, Shepard TH: The development of hemostasis in the human fetus and newborn infant. J Pediatr 79:838, 1971.

Andrew M, Paes B, Milner B, et al: Development of the human coagulation system in the full-term infant. Blood 70:165, 1987.

Andrew M, Paes B, Milner R, et al: Development of the human coagulation system in the healthy premature infant. Blood 72:1651, 1988.

Corrigan JJ Jr: Neonatal thrombosis and the thrombolytic system: pathophysiology and therapy. Am J Pediatr Hematol Oncol 10:83, 1988.

Andrew M, Paes B, Johnston M: Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol Oncol 12:95, 1990.

Andrew M: The relevance of developmental hemostasis to hemorrhagic disorders of newborns. Semin Perinatol 21:70, 1997.

Furie B, Furie BC: Molecular basis of gamma-carboxylation. Role of the propeptide in the vitamin K-dependent proteins. Ann NY Acad Sci 614:1, 1991.

Aballi AJ, deLamerens S: Coagulation changes in the neonatal period and in early infancy. Pediatr Clin North Am 9:785, 1962.

Muntean W, Petek W, Rosanelli K, et al: Immunologic studies of prothrombin in newborns. Pediatr Res 13:1262, 1979.

Lane PA, Hathaway WE: Vitamin K in infancy. J Pediatr 106:351, 1985.

Stevenson RE, Burton OM,, Ferlauto GJ, et al: Hazards of oral anticoagulants during pregnancy. JAMA 243:1549, 1980.

Shearer MJ: Annotation: Vitamin K and vitamin K-dependent proteins. Br J Haematol 75:156, 1990.

von Kries R, Hanawa Y: Neonatal vitamin K prophylaxis. Report of Scientific and Standardization Subcommittee on Perinatal Haemostasis. Thromb Haemost 69:293, 1993.

Sutor AH, Gobel U, Kries RV, Kunzer W, Landbeck G: Vitamin K prophylaxis in the newborn. Blut 60:275, 1990.

Hathaway WE, Isarangkura PB, Mahasandana C, et al: Comparison of oral and parenteral vitamin K prophylaxis for prevention of late hemorrhagic disease of the newborn. J Pediatr 119:461, 1991.

Amadee-Manesme O, Labert WE, Alagille D, De Leenheer AP: Pharmacokinetics and safety of a new solution of vitamin K1 (20) in children with cholestasis. J Pediatr Gastroenterol Nutr 14:160, 1996.

Aballi AJ: The action of vitamin K in the neonatal period. South Med J 58:48, 1965.

Gray OP, Ackerman A, Fraser AJ: Intracranial haemorrhage and clotting in low birth weight infants. Lancet 1:543, 1968.

Volpe JJ: Neonatal intraventricular hemorrhage. N Engl J Med 304:886, 1981.

Appleyard WJ, Cottom DG: Effect of asphyxia on thrombotest values in low birthweight infants. Arch Dis Child 45:705, 1970.

Schmidt B, Zipursky A: Thrombotic disease in newborn infants. Clin Perinatol 2:461, 1984.

Rodgers GM, Shuman MA: Congenital thrombotic disorders. Am J Hematol 21:419, 1986.

Sifontes MT, Nuss R, Hunger SP, Jacobson LJ, Waters J, Manco-Johnson MJ: Correlation between the functional assay for activated protein C resistance and factor V Leiden in the neonate. Pediatr Res 42:776, 1997.

Leroyer C, et al: Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 80:49, 1998.

Poort SR, Rosendaal FR, Reitsma PH, Bertina RM: A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 88:3698, 1996.

Miller RK, Kellogg CR, Saltzman RA: Reproductive and perinatal toxicology, in Handbook of Toxicology, edited by TJ Haley, WO Berndt, pp 195–309. Hemisphere Publishing, Washington, DC, 1987.

Gray MJ: Use and abuse of thiazides in pregnancy. Clin Obstet Gynecol 11:568, 1968.

Leikin SL: Thiazide and neonatal thrombocytopenia. N Engl J Med 271:161, 1964.

Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R: Heparin therapy during pregnancy. Arch Intern Med 149:2233, 1989.

Page TE, Hoyme HE, Markarian M, et al: Neonatal hemorrhage secondary to thrombocytopenia: an occasional effect of prenatal hydantoin exposure. Birth Defects 18:47, 1982.

Hanson JW, Buehler BA: Fetal hydantoin syndrome: current status. J Pediatr 101:816, 1982.

Eggermont E, Logghe N, van de Casseye W, et al: Haemorrhagic disease of the newborn in the offspring of rifampin and isoniazid treated mothers. Acta Pediatr Belg 29:87, 1976.

Powell RD, DeGowin RL, Alving AS, et al: Nitrofurantoin-induced hemolysis. J Lab Clin Med 62:1002, 1963.

Belton EM, Jones RV: Haemolytic anaemia due to nalidixic acid. Lancet 2:691, 1965.

Varsano I, Fischl J, Tikvah P, et al: The excretion of orally ingested nitrofurantoin in human milk. J Pediatr 82:886, 1973.

Brodersen R: Prevention of kernicterus, based on recent progress in bilirubin chemistry. Acta Paediatr 66:625, 1977.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology


FREE downloads:

i will be here

shot caller

side by side



  1. KZt1NE lwnlzshpjtxn, [url=http://lbnsulteyecb.com/]lbnsulteyecb[/url], [link=http://ktidgqwqzyzw.com/]ktidgqwqzyzw[/link], http://olfschdzzbbn.com/

  2. Just want to know what is the life span of fetal Rbc and is any difference from newborn rbc(ie 80 days).

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )


Connecting to %s

%d bloggers like this: