Robert D. Christensen, MD

Normal Erythrocyte Values of Neonates

Expected values, also called “reference ranges,” for Hgb and hematocrit on the day of birth are a function of gestational age, increasing gradually through the second and third trimesters. Studies with very large sample sizes of neonates on the day of birth reveal no differences in Hgb or hematocrit associated with the infants’ sex. Reference ranges for blood Hgb concentrations are shown as Figure 12-1. The fifth percentile value (the lowest expected limit) at term is 14 g/dL. Thus the value of 11.8 g/dL in this patient is low. ¹

The 95th percentile reference range at term is 22.5 g/dL (see Figure 12-1). The value of 24 g/dL in this patient is therefore high.

Yes. Values from capillary beds (heel stick) are generally about 15% higher and also more variable than venous or arterial values. This observation is due in part to the changing peripheral perfusion in the hours after birth. Poorly perfused heels seem to have capillary pooling or sludging of red blood cells (RBCs) that result in higher values. This phenomenon of higher Hgb level in capillary as opposed to central blood sources is not so significant in older children and adults. If the Hgb value of 24 g/dL in the patient in Question 2 was drawn from a heel stick, you would want to repeat it using a central vascular determination before you decide whether the neonate is truly polycythemic.

The MCV and the MCH both diminish gradually through the second and third trimesters, as shown in Figure 12-2. The MCHC, however, does not change during this period but remains in the range of 31 to 34 g/dL. MCHC values greater than 36 g/dL should alert you to the possibility of hereditary spherocytosis or pyropoikilocytosis, two conditions that generally present with a low MCV and a high MCHC. They commonly also demonstrate hyperbilirubinemia and sometimes a diminishing Hgb concentration. If the MCV is consistently greater than 36 g/dL you should assess the morphology of the RBCs, and you will need to ask whether other family members have abnormally shaped RBCs and have had anemia, neonatal jaundice, or early cholelethiasis (bilirubin stones).

NRBCs can be reported as the number of NRBCs per 100 WBCs or as NRBCs per μL. The latter provides a more accurate accounting because of changing WBC counts over the first several days. The former is more commonly used in clinical practice. Reference ranges for NRBCs per 100 WBCs are shown in Figure 12-3. For term infants on the day of birth, the 95th percentile (highest expected limit) is 15 per 100 WBCs. Therefore the value of 100 in this patient is abnormally high.

A value of zero (0) NRBCs per 100 WBCs is always within the reference range, regardless of gestational age. Thus the value of 0 in this patient is within the expected (normal) range.

Hgb is a tetramer of globin chains, usually of two distinct types, bound to a heme moiety. Adult hemoglobin (Hgb A) consists of two alpha chains and two beta chains, whereas fetal hemoglobin (Hgb F) consists of two alpha chains and two gamma chains ( Figure 12-4).

Embryonic Hgbs are present in the first 8 weeks after conception and consist of Hgb Gower 1 (zeta 2, epsilon 2), Hgb Gower 2 (alpha 2, epsilon 2), and Hgb Portland (zeta 2, gamma 2). Hgb Barts consists of four gamma chains and occurs in the absence or deficiency of alpha chains. Thus 10% of the Hgb observed as Barts is abnormal and suggests a deficiency of at least one, and probably two, of the four alpha chain genes. Deletion of one alpha gene results in a phenotypically normal individual, and deletion of two can result in mild microcytic anemia with the presence of Barts Hgb during the fetal and early newborn period. Deletion of three genes gives rise to Hgb H disease; deletion of all four gives rise to a lethal syndrome of hydrops fetalis with all or most of the Hgb being Barts, and no Hgb A or F or alpha 2 (because there are no alpha chains). ²

Hgb F binds oxygen more avidly. The oxyhemoglobin dissociation curve for Hgb F is shifted to the left of the adult curve. The higher affinity for oxygen facilitates transfer of oxygen from maternal Hgb A but also results in decreased oxygen release to the fetal tissues. The latter situation is not a disadvantage, however, because fetal tissues use oxygen primarily for growth; metabolic functions are mostly handled by the mother.

Factors that shift the oxyhemoglobin dissociation curve to the right (increasing oxygen delivery to tissues) include increased temperature, increased partial pressure of carbon dioxide in the blood (PaCO₂), increased RBC 2,3-diphosphoglycerate content, and decreased pH.

Anemia in the Fetus and Newborn Infant

None of the four is normal. The bilirubin and the MCHC are high, and the Hgb and the MCV are low.

All the preceding steps may be helpful in the diagnosis and management of this case. Consider the following:

The initially stable Hgb level does not exclude the diagnosis of a subgaleal hemorrhage. Hemorrhage itself does not lower the Hgb and hematocrit. The fall occurs only when extravascular fluid moves into the vascular space as a physiologic response to hypovolemia.

Although much less common than a caput, a subgaleal hemorrhage can be life-threatening and therefore demands aggressive monitoring and support. Head wrapping has been attempted in the past as a potential method for tamponade, but in general this approach has not been successful because it tends to increase the intracranial pressure.

With signs of hypovolemia, transfusion support may be warranted. Coagulopathy can occur, generally secondary to shock and disseminated intravascular coagulopathy (DIC), and can worsen the hemorrhage. Portable cranial ultrasound will generally confirm the presence of a subgaleal hemorrhage. Computed tomography or magnetic resonance imaging will provide more accurate and detailed information, but these are usually not needed to make the diagnosis of a subgaleal hemorrhage.

False. Most neonatal subgaleal hemorrhages do indeed follow vacuum extraction, but some follow forceps delivery and some occur with nonoperative delivery. However, in a series from Intermountain Healthcare, we found that every neonate with a subgaleal hemorrhage that required one or more RBC transfusions was delivered by either vacuum or forceps extraction.

All neonates who had a “spontaneous” subgaleal hemorrhage (not delivered by vacuum or forceps extraction) lacked signs of shock, had no transfusions, and generally had a good outcome. Thus vacuum delivery is the most significant risk factor for developing a neonatal subgaleal hemorrhage. ⁴

True. In a recent report from Taiwan, one in 218 vacuum deliveries developed a subgaleal hemorrhage. In a study from Intermountain Healthcare, a subgaleal hemorrhage was diagnosed in one in 598 vacuum deliveries. A subgaleal hemorrhage is therefore rare, even after a vacuum delivery, but because of the vigilance needed for proper diagnosis and management, the possibility of a subgaleal hemorrhage should be considered after any operative delivery in which scalp fluctuance is observed.

False. Some publications describing cases from the 1980s and earlier did indeed report a mortality rate this high, but more recent series suggest the mortality rate is 5% to 10%. Regardless, this injury is devastating. Vigilance and aggressive management are likely responsible for the observed improvement in outcome.

Neonatal hemolytic jaundice is typical, particularly manifesting in the following ways:

HDFN resulting from maternal anti-Kell antibody presents with fetal or neonatal anemia but no reticulocytosis, no evidence of hemolysis, and no hyperbilirubinemia. These cases present with hyporegenerative anemia. The explanation is that the Kell antigen is expressed on erythroid progenitor cells, whereas most other blood group antigens are not expressed until the cells clonally mature. As a consequence of maternal anti-Kell antibody binding to fetal erythroid progenitors, fetal RBC production is reduced and hyporegenerative anemia results. The KEL gene (7q33) encodes a 93 kilodalton transmembrane zinc-dependent endopeptidase that is responsible for cleaving endothelin-3. The Kell protein has recently been designated CD238.

True. Women lacking the A and the B erythrocyte antigens often have anti-A and anti-B antibodies even before pregnancy. In the case of women with blood type O, their anti-A and anti-B antibodies are sometimes of the immunoglobulin G type and therefore can cross the placenta and bind to fetal antigens. Unlike the situation observed with maternal anti-D, in neonates with ABO hemolytic disease the principal problem is usually jaundice. Anemia, erythroblastosis, and hydrops are all very rare. The ABO locus is on chromosome 9 and has three main allelic forms: A, B, and O. The A and B alleles encode glycosyltransferases. The O allele differs from the A allele by deletion of only one nucleotide—guanine at position 261. This deletion causes a frame shift and results in premature termination of translation of the mRNA. ⁶

The H antigen is the precursor to the ABO blood group antigens. The H locus is on chromosome 19 and encodes the H antigen, which is expressed on the RBC surface. The H antigen is then modified by the A or the B antigen to produce the final A, B, or O antigen. Very rarely an individual lacks the H antigen because of a mutation in the H gene. This results in type O blood, but because the precursor molecule (the H antigen) is also missing, even type O blood cannot be transfused because the individual recognizes the H antigen in the type O blood as foreign. This unusual O blood type is called Bombay blood group and occurs in approximately four per million people, except in parts of India where it may be as common as 1 in 10,000. Neonates who are type O on the basis of Bombay can hemolyze if transfused with type O blood.