Cord Clamping and Placental Transfusion

The timing of cord clamping significantly influences hemoglobin values in the newborn (discussed later). Around the time of birth, placental blood is rapidly transferred to the infant. Approximately a quarter of this transfusion occurs within 15 seconds of birth and half occurs by the end of the first minute after birth. Delayed cord clamping (DCC) typically increases the infant’s blood volume by 30%, because the placental vessels contain between 75 to 125 mL of blood at birth. Holding the infant above the level of the placenta prevents placental transfusion and may even lead to neonatal transfusion into the placenta, resulting in neonatal anemia.

Site of Blood Sampling

Significant variation in hemoglobin levels may exist, depending on the site of blood sampling. Hemoglobin levels from capillary blood samples typically are higher than those obtained from indwelling venous or arterial catheters. Capillary samples may lead to overestimation of the hemoglobin, particularly when the samples are obtained from a poorly perfused extremity. The largest differences between capillary and venous hematocrits exist in very preterm infants, particularly those with acidosis, hypotension, and anemia. In infants younger than 30 weeks’ gestation, capillary hematocrit values are 20% higher than venous hematocrit values, compared with capillary values that are 12% higher than venous hematocrit levels at term. “Arterializing” a capillary sample by prewarming the extremity may improve the correlation between capillary and venous hematocrit levels. Finally, values of samples from similar sources, such as arterial, venous, and capillary samples, correlate independent of the site of sampling. For example, umbilical, radial, and femoral arterial hemoglobin levels show little variation from sample to sample.

Mean Corpuscular Volume

The average volume of circulating erythrocytes is estimated by the MCV. During pregnancy an inverse relationship exists between gestational age and MCV, with MCV values decreasing throughout gestation to 108 to 118 fl at term (see Table 2-1 ). When an MCV less than 95 fl is observed in a term neonate, α-thalassemia trait or iron deficiency should be considered.

Mean Corpuscular Hemoglobin

Similar to the MCV, the mean corpuscular hemoglobin is higher in preterm and term neonates, ranging from 33 to 41 pg/cell compared with 27 to 31 pg/cell in adults.

Mean Corpuscular Hemoglobin Concentration

The mean corpuscular hemoglobin concentration does not vary between neonates and adults. Although neonatal erythrocytes are larger and contain more hemoglobin, the hemoglobin in the erythrocyte is not more concentrated.

Fetomaternal Hemorrhage (FMH)

FMH is the passage of fetal blood into the maternal circulation before or during delivery. Antenatal FMH is associated with variable effects on the fetus and neonate, ranging from none to neurologic injury, hydrops fetalis, and in utero demise of the fetus or, in the neonate, congestive heart failure (CHF), hypovolemic shock, persistent pulmonary hypertension, neurologic injury, and death. The structure of the fetal-placental unit sets up a large pressure gradient from the umbilical artery to the intervillous space. The maternal intervillous space is separated from the pulsatile fetal circulation by a thin, two-cell membrane, with the constant possibility for rupture of the trophoblastic-endothelial juncture and contamination of the maternal intervillous space with fetal blood ( Fig. 2-4, A ). Given this very fragile mechanical relationship, it is surprising that significant FMH does not occur more frequently. Most spontaneous FMH occurs during the third trimester ( Fig. 2-4, B ), most commonly during labor and delivery, although hemorrhage has been reported as early as 3 to 4 months’ gestation ( Fig. 2-4, C ). Approximately 99% of deliveries are associated with FMH of less than 15 mL. However, 3 in 1000 deliveries are associated with FMH greater than or equal to 30 mL, and 1 in 2000 pregnancies is associated with an FMH greater than or equal to 100 mL.

Anatomic issues in fetomaternal hemorrhage. A, Resting state: fragile capillary networks are present. B, A minor small bleed, known to occur in almost all pregnancies. C, A major possibility of significant exchange of fetal and maternal blood as a result of abruption (more severe) or normal childbirth.

Fetal RBCs can be detected in the maternal circulation in a number of ways. The most frequently used test is microscopic demonstration of fetal RBCs in the maternal circulation with use of the Kleihauer-Betke staining procedure. With this method, HbA is denatured and eluted from smears of adult RBCs with an acid solution, leaving behind largely empty RBC membranes. Because HbF resists denaturation and elution, fetal cells stain darkly. Simple observation of the acid-treated maternal blood smear can provide a qualitative picture. The actual amount of fetal blood lost is estimated using the following formula: 2400 × the ratio of fetal to maternal cells = 1 mL of fetal blood. Using this equation, it has been shown that most deliveries result in less than 3 mL of fetal blood in the maternal circulation, and only 0.3% have a fetomaternal transfusion of 10 mL or more. However, the volume of fetal blood in the maternal circulation does not reflect the timing or acuity of the hemorrhage. Anti-HbF–based flow cytometry is an alternative method for detecting and quantifying cells that contain HbF in the maternal circulation. Conditions that elevate maternal HbF production (e.g., thalassemia minor, sickle cell disease, hereditary persistence of HbF, and pregnancy-induced maternal HbF production) confound these analyses. ABO blood group incompatibility can complicate interpretation of testing for FMH because removal of fetal cells from the maternal circulation by maternal anti-A or anti-B antibodies may lead to a false-negative result.

Abruptio Placentae

Placental abruption—that is, separation of the placenta from the uterine wall—occurs in approximately 1% of pregnancies. Abruption is more common in pregnancies complicated by chronic or pregnancy-induced hypertension. The classic triad of placental abruption is vaginal bleeding, uterine contractions, and an irritable, tender uterus. If bleeding occurs in a retroplacental location, recognition and treatment may be delayed. Fetal hypoxemia may develop as a result of decreased placenta surface area and may be worsened by fetal hemorrhage accompanying the maternal bleeding. If fetal hemorrhage is significant, severe anemia, hypovolemia, and heart failure may rapidly develop, leading to in utero fetal demise. Placental abruption is typically an acute event. However, fetal blood loss may occur gradually when the area of placental separation is small with a low-grade, chronic hemorrhage. At birth, these neonates exhibit anemia with compensation of varying degree, marked reticulocytosis, and prominent normoblastosis. In severe cases, iron deficiency may occur.

Placenta Previa

Placenta previa—that is, implantation of the placenta in a low-lying position in advance of the fetal presenting part, usually overlying part or all of the cervical os—occurs in approximately 1 in 250 births. The classic presentation is acute onset of painless vaginal bleeding, with a peak incidence around 34 weeks’ gestation. When placenta previa persists to the third trimester, a cesarean section is indicated. Fetal blood loss of varying amounts occurs in approximately 50% of cases. Signs of fetal anemia include intrauterine growth retardation, abnormal biophysical testing, and tachycardia. Vaginal bleeding may be intermittent and recurrent or massive and acute. In the former situation, the neonate presents with a partially or completely compensated anemia and marked reticulocytosis. In the latter situation, the neonate may present with acute hypovolemic shock with risk of death. Up to 10% of neonates born after the occurrence of placenta previa exhibit significant anemia, making it the most common placental anomaly that causes neonatal anemia.

Vasa Previa

Vasa previa occurs when fetal vessels exiting the placental end of the umbilical cord travel across the fetal membranes and then return to the fetal placental surface. If the fetal vessels are near the cervical os, they may tear when membranes rupture or during labor, when progressive cervical dilatation occurs. In both situations, laceration of the fetal vessels may lead to rapid exsanguination and death of the fetus. Acute onset of vaginal bleeding (usually at the initiation of labor or during the progression of labor) with acute fetal tachycardia is a classic presentation of vasa previa. Prompt recognition of this condition, delivery, and resuscitation of the anemic infant are indicated to prevent peripartum death.

Velamentous Insertion of the Cord

In cases of velamentous insertion of the cord, which occurs in approximately 1% of pregnancies, the umbilical vessels are unprotected and may tear spontaneously or during labor. Rarely the unprotected umbilical vessel crosses the cervical os, combining a velamentous insertion with vasa previa, with a high potential for tearing when the membranes rupture. Velamentous insertion is more common in twins and with low-lying placentas. The presentation of painless vaginal bleeding followed by signs of fetal distress is similar to vasa previa. The incidence of fetal loss is 1% to 2%.

Twin-Twin Transfusion and Related Disorders

Monochorionic twin pregnancies are at high risk for an adverse outcome because of vascular anastomoses that create shared fetal circulations. This situation may lead to complications, including twin-twin transfusion syndrome (TTTS), the twin anemia polycythemia sequence, the twin reversed arterial perfusion sequence, and monoamniotic twinning. TTTS complicates 8% to 15% of twin gestations with monochorionic diamniotic placentation, with the unbalanced transfer of blood from one fetus to the other via vascular anastomoses in the placenta. Classically, the donor twin is small and anemic and the recipient is large and plethoric. Fetal demise may occur from exsanguination of the donor or circulatory overload in the recipient. This condition may be dynamic with varying consequences to the twin fetuses, because the vascular anastomoses may vary in both size and number, as well as proceed in opposite directions. Antenatal factors that may predict outcome include the presence of hydrops fetalis and gestational age. Perinatal therapies have included serial amnioreduction, fetoscopic laser occlusion of communicating placental anastomoses, maternal digoxin therapy, and selective feticide.

At birth, both infants may be critically ill. The anemic donor twin may experience CHF and respiratory failure, whereas the plethoric recipient twin may require treatment for polycythemia hyperviscosity syndrome (PHS) and its complications, including thrombosis, hyperbilirubinemia, and, rarely, disseminated intravascular coagulation (DIC). In the classic presentation of TTTS in which the donor twin has been chronically hemorrhaging into the recipient, the donor anemic twin has marked reticulocytosis and normoblastosis, whereas the plethoric, polycythemic infant weighs greater than or equal to 20% more with a hemoglobin greater than or equal to 5 g/dL higher than its sibling. Acute transfusions, which typically occur closer to the time of delivery, do not lead to significant differences in neonatal weights, and there is an equal chance of either twin being the donor. Despite advances in pregnancy management, mortality in fetuses with TTTS remains high. The risk of long-term neurodevelopmental morbidity in survivors is significant.

Traumatic Fetal Hemorrhage

Fetal bleeding has been described after multiple trauma and after blunt abdominal trauma to the pregnant mother. It has also been described after traumatic amniocentesis or cordocentesis and after external cephalic version.

Placental Lesions

The marked vascularity and unique double circulation of the placenta predisposes it to numerous vascular abnormalities, some of which may lead to fetoplacental hemorrhage and/or FMH. Chorioangioma is the most common vascular anomaly of the placenta associated with neonatal anemia from fetoplacental hemorrhage and/or FMH. Chorioangiomas may number from one to many. In severe cases, they may lead to severe in utero hemorrhage and fetal demise. Other placental lesions associated with neonatal anemia are hemangioma, hematoma, and intraplacental choriocarcinoma.

Other Causes of Fetal Hemorrhage

In utero hemorrhage into fetal organs is uncommon, with intracranial and intraabdominal hemorrhage predominating. Intracranial hemorrhage typically occurs when the pregnancy is complicated by thrombocytopenia (autoimmune or alloimmune), severe fetal hypoxemia, or maternal coumadin use. Intraabdominal bleeding may occur after in utero volvulus, leading to ischemic bowel necrosis with venous hemorrhage.

Placenta

Labor may exaggerate or worsen abnormalities of placentation (such as vasa previa, abruptio placentae, and velamentous insertion of the cord during labor) and lead to significant hemorrhage.

Umbilical Vessels

One in 10,000 deliveries is associated with umbilical cord bleeding or rupture, which is associated with the risk of anemia, hypovolemic shock, and death. Cord rupture is most common in precipitous deliveries. Typically, traction on a shortened or abnormal umbilical cord leads to cord rupture, usually on the fetal side. Abnormalities such as cysts, vascular malformations (including aneurysms, hemangiomas, or varices), funisitis, or a velamentous insertion can weaken the cord and predispose it to rupture. Entrapment of the cord accompanied by direct pressure, for example, by forceps, can also lead to traumatic cord laceration.

Neonates born with a tight nuchal cord can lose up to 20% of their blood volume into the placenta, leading to anemia and hypovolemic shock. In cases of a tight nuchal cord, placental blood is blocked from flowing into the fetus by constriction of the thin-walled umbilical vein, while blood flow out of the fetus into the placenta via the muscular umbilical arteries continues.

Intrapartum Trauma

Neonates may experience varying degrees of anemia as a result of internal bleeding associated with intrapartum trauma. These internal hemorrhages may or may not be obvious at the time of delivery. In severe cases, signs of hypovolemic shock are seen shortly after birth. In other cases the infant may present with sudden pallor, tachycardia, and hypotension later on the first or second day of life. The site of internal bleeding may be discerned by the intrapartum history and other individual characteristics. Marked hyperbilirubinemia may occur.

Neonatal Coagulopathy

Neonatal anemia may result from marked bleeding due to abnormalities in hemostasis, particularly at intracranial and gastrointestinal sites, or after trauma, such as circumcision. Disorders most commonly associated with significant hemorrhage in the neonate include congenital factor deficiencies, particularly hemophilia, and acquired and inherited platelet abnormalities. Neonatal hemorrhage with secondary anemia has occurred in infants with vitamin K deficiency as a result of maternal anticonvulsant therapy or in exclusively breast-fed infants who were not treated with vitamin K at birth. Neonatal anemia has also been reported in infants with Wiskott-Aldrich syndrome and thrombocytopenia–absent radius syndrome.

Iatrogenic Causes

Phlebotomy-associated blood loss leading to anemia may occur in hospitalized neonates, particularly premature infants. It is not surprising that these critically ill premature infants require the most phlebotomy procedures for diagnostic testing or that they experience the most additional blood wastage (phlebotomy overdraw) during this testing. Numerous noninvasive monitoring techniques and microscale laboratory analyses have been developed to avoid these phlebotomy-associated losses. Other iatrogenic causes of hemorrhage and anemia include vascular or tissue damage during diagnostic or therapeutic procedures, accidental disconnection of vascular catheters, and postoperatively associated with operative site or wound.

Other Causes of Hemorrhage

Gastric and intestinal ulceration with hematemesis or hematochezia may cause significant anemia in the neonate. The Apt test permits differentiation of neonatal blood from swallowed maternal blood. Hemorrhage into large tumors such as sacrococcygeal teratomas and bleeding from vascular malformations such as hemangiomas, hemangioendotheliomas, and arteriovenous malformations as causes of neonatal anemia have been described.

Blood Group Incompatibility

Immune-mediated hemolytic anemia due to blood group incompatibility is the most common cause of hemolytic anemia in the newborn period. Details of fetal and neonatal immune hemolytic disease are provided in Chapter 3 .

Other Causes of Extrinsic Hemolysis

Hemolytic anemia is present in some neonates born to mothers with autoimmune disease, particularly systemic lupus erythematosus and rheumatoid arthritis. Neonatal lupus syndrome is associated with the transplacental passage of maternal autoantibodies, including Ro/SS-A, Ro/SS-B, and La, as well as other poorly characterized contributing factors. Clinical findings may include cutaneous lesions, congenital heart block, thrombocytopenia, anemia, neutropenia, hepatobiliary disease, and pericarditis. With the exception of heart block, which is permanent, clinical manifestations, including anemia, are self-limited.

Maternal autoimmune hemolytic anemia has led to neonatal anemia of varying degree with a positive direct antiglobulin test.

Cases of maternal medication administration (including penicillin) reported to cause hemolytic anemia in the newborn have been described.

Angiopathic Anemias

Oxidant Exposure

Oxidant hemolysis in the newborn is not rare, and it is not always associated with an inherited metabolic abnormality of the erythrocyte (see Chapters 17 and 18 ) or with congenital Heinz body anemia (see Chapter 19 ). An acute hemolytic event occurs, presumably related to the oxidant sensitivity of neonatal red cells. Infants present with acute onset anemia and hyperbilirubinemia with “bite” and “blister” cells, spherocytes, and irregularly shaped RBCs on a peripheral blood smear. Typically no obvious source for the presumed oxidant stress is identified and the episode resolves in a few days. Transfusion is rarely required. Infants with ongoing hemolysis warrant further diagnostic evaluation (see Chapters 18 and 19 ).

Other Causes of Hemolysis

Other causes of neonatal hemolysis include galactosemia, prolonged or recurrent metabolic acidosis, lysosomal storage disease, and some amino acidopathies. Although typically associated with a hypoplastic anemia and thrombocytopenia, hemolysis may be found in neonates with osteopetrosis. Maternal ingestion of valproic acid has caused hemolysis and thrombocytopenia in a breastfed infant.

Disorders of Erythrocyte Metabolism

Congenital nonspherocytic hemolytic anemia includes disorders not attributed to immune-mediated disturbances, defects of hemoglobin or the erythrocyte membrane, or other disorders. The disorders in this heterogeneous group are caused by a variety of metabolic abnormalities of the erythrocyte, including enzymopathies of glucose, glutathione, and nucleotide metabolism (see Chapters 17 and 18 ). Significant clinical, laboratory, and genetic heterogeneity exists within individual disorders. Hemolysis develops as a result of enzyme or antioxidant deficiency or impaired enzyme function.

Disorders of the Hexose Monophosphate Shunt and Associated Pathways

Disorders of the hexose monophosphate shunt or the glutathione metabolic pathways impair the ability of the erythrocyte to adequately respond to oxidant stress. In the normal erythrocyte, reduced glutathione detoxifies intracellular oxidants. In glucose-6-phosphate dehydrogenase (G6PD) deficiency, the inability to generate reduced nicotinamide adenine dinucleotide phosphate leads to inadequate levels of reduced glutathione, leaving oxidants free to damage critical erythrocyte proteins. Oxidation of the sulfhydryl groups of hemoglobin produces functionless methemoglobin and intracellular precipitates of hemoglobin called Heinz bodies.

Three clinical syndromes have been described in patients who are deficient in G6PD: neonatal jaundice (NNJ), congenital nonspherocytic hemolytic anemia, and acute hemolysis after an oxidative stress. All three have been observed in the neonatal period. NNJ, which is rarely present at birth, has a peak onset between the second and third day of life. The severity of hyperbilirubinemia is variable, but it may be severe, resulting in kernicterus or even death. Hyperbilirubinemia is usually adequately treated with phototherapy, but occasionally exchange transfusion is necessary. Anemia is rarely severe in neonates with NNJ, and when it is observed, it should prompt investigation for additional abnormalities. The cause of NNJ in neonates with G6PD deficiency is unknown. Contributions from decreased hepatic excretion of bilirubin, low-grade hemolysis, or manifestation of an additional genetic disorder have been suggested. The incidence of NNJ is increased in infants who are deficient in G6PD, with a polymorphism of the uridine diphosphoglucuronosyl transferase gene ( UGT1A ) associated with Gilbert syndrome (see Chapter 4 ).

Hemolytic anemia, even with nonimmune hydrops fetalis, has occurred in the G6PD-deficient fetus or neonate after maternal ingestion of an oxidant agent such as a sulfa drug, ascorbic acid, or fava beans. Hemolysis has occurred in breastfed, G6PD-deficient infants after maternal ingestion of fava beans. These cases have led to the term favism by proxy .

Significant hemolysis after transfusion or exchange transfusion with G6PD-deficient erythrocytes in neonates has been described. In areas endemic for G6PD deficiency, it has been recommended that blood donors be screened for G6PD deficiency prior to neonatal transfusion.

The diagnosis and treatment of G6PD deficiency is discussed in Chapter 18 .

Disorders of the Embden-Meyerhof Pathway

Defects of the Embden-Meyerhof pathway are inherited in an autosomal-recessive fashion, and typically hemolysis is only seen in homozygotes or compound heterozygotes. An exception is phosphoglycerate kinase, an X-linked disorder in which hemolysis is only seen in affected males.

Pyruvate kinase deficiency, which is the most common abnormality of the Embden-Meyerhof pathway, usually presents in the neonatal period or early childhood with anemia and jaundice (see Chapter 17 ). Severe cases have presented with anemia in utero or in the first days of life. Nonimmune hydrops fetalis has been described. Neonatal hyperbilirubinemia is common in persons deficient in pyruvate kinase, and phototherapy or exchange transfusion may be required. Kernicterus has been reported.

Other abnormalities of the Embden-Meyerhof pathway may present in the neonatal period. Glucose phosphate isomerase deficiency is the third most common hemolytic enzymopathy and is frequently manifested in infancy. Marked fetal and neonatal anemia, nonimmune hydrops, hyperbilirubinemia, and perinatal death have been described. Patients with hexokinase deficiency have experienced neonatal anemia and hyperbilirubinemia. Similarly, NNJ and anemia have been associated with 2,3-biphosphoglycerate mutase deficiency and phosphoglycerate kinase deficiency.

Disorders of Glutathione Metabolism

Deficiency of γ-glutamylcysteine synthetase and glutathione synthetase, enzymes involved in erythrocyte glutathione synthesis, has been associated with anemia in the neonatal period.

Disorders of the Erythrocyte Membrane

Disorders of the erythrocyte membrane (see Chapter 16 ) make up an important group of hemolytic anemias that may present in the fetal or neonatal period. HS, hemolytic hereditary elliptocytosis (HE), and hereditary pyropoikilocytosis are the membrane disorders most likely to present in the fetus and newborn.

Hereditary Stomatocytosis Syndromes

The hereditary stomatocytosis (HSt) syndromes are a heterogeneous group of disorders characterized by variable numbers of stomatocytes on a peripheral blood smear and abnormal permeability of erythrocytes to sodium and potassium, with resultant modification of intracellular water content. HSt has presented in the neonatal period with severe hemolysis, anemia, hyperbilirubinemia, and hydrops fetalis. The dehydrated variant of HSt, hereditary xerocytosis, may present in utero with nonimmune hydrops fetalis unrelated to the degree of fetal anemia. Hereditary xerocytosis has been linked to mutations in the mammalian mechanosensory transduction protein PIEZO1.

Hemoglobin Disorders

Significant variation exists in the fetal and neonatal manifestations of α- and β-thalassemia because of developmental differences in globin chain synthesis. α-Globin synthesis is found in the yolk sac by 3 weeks’ gestation. By 9 weeks’ gestation, α-globin is the main α-like globin in the fetus, with only low levels of the major embryonic α-like embryonic hemoglobin, hemoglobin Portland (ζ ₂ γ ₂ ). In contrast, the switch from fetal to adult β-like globin chains, γ to β-globin, is not complete until 6 to 12 months of life. The primary hemoglobin in fetal and neonatal life is fetal hemoglobin, HbF (α ₂ γ ₂ ). Thus abnormalities of α-globin, such as homozygous α-thalassemia, lead to severe anemia in utero, whereas abnormalities of β-globin, such as homozygous β-thalassemia, are typically ameliorated in the first few months of life by sustained production of HbF. (See Chapter 21 for a detailed discussion of the thalassemias.)

α-Globin Defects

Clinical severity of the α-thalassemia syndromes is related to the numbers of functional α-globin genes present. Deletion of a single α-globin gene results in a clinically silent asymptomatic carrier state. Deletion of two α-globin genes results in α-thalassemia trait with marked microcytosis, hypochromia, and mild anemia. Deletion of three α-globin genes results in hemoglobin H (Hb H) disease (see the section on Hb H disease in this chapter) with varying degrees of anemia, ranging from mild to severe. Deletion of all four α-globin genes results in homozygous α-thalassemia, which usually leads to death of the affected fetus in utero from severe hemolytic anemia, CHF, and nonimmune hydrops fetalis.

β-Globin Defects

As previously noted, structural variants of β-globin, including β-thalassemia and sickle cell disease, typically do not present with neonatal anemia. However, the incidence of neonatal hyperbilirubinemia in sickle cell disease is increased. In one rare case of sudden infant death in an infant with sickle cell disease, widespread neonatal vasoocclusion was observed.

Unstable Hemoglobins

Unstable hemoglobins (see Chapter 19 ) due to abnormalities in the α-globin or the β-globin chain have been reported to cause NNJ and hemolytic anemia. Precipitated globin chain fragments form Heinz bodies, thus the name congenital Heinz body hemolytic anemia . Two interesting representative hemoglobin variants that present with hemolytic anemia in the neonate due to congenital Heinz body hemolytic anemia are hemoglobin Hasharon and hemoglobin F Poole. Hemoglobin Hasharon is due to a mutation in the α-globin chain such that, when mutant α-globin chains are paired with γ-globin, an unstable hemoglobin is produced. When mutant α-globin chains are paired with β-globin, it is no longer unstable, presumably because of the tenfold higher affinity between α and β chains than between α and γ chains. Hemoglobin F Poole is an unstable hemoglobin due to mutation in the γ-globin chain. As might be expected, Hemoglobin Hasharon, hemoglobin F Poole, and other hemoglobin variants influencing HbF structure and function produce hemolytic anemia in the neonatal period that resolves as the fetal-to-adult hemoglobin switch occurs.