“Common red blood cell disorders encountered in the normal newborn nursery include hemolytic disease of the newborn and resultant hyperbilirubinemia, anemia, and polycythemia. A less frequent clinically relevant hematologic issue in newborns to be covered herein is thrombocytopenia.”
Key points
- •
Early clinical jaundice or rapidly developing hyperbilirubinemia are often signs of hemolysis, the differential diagnosis of which commonly includes immune-mediated disorders, red-cell enzyme deficiencies, and red-cell membrane defects.
- •
Knowledge of the maternal blood type and antibody screen is critical in identifying non-ABO alloantibodies in the maternal serum that may pose a risk for severe hemolytic disease in the newborn.
- •
Moderate to severe thrombocytopenia in an otherwise well-appearing newborn strongly suggests immune-mediated (alloimmune or autoimmune) thrombocytopenia.
Introduction
Hematologic problems often arise in the newborn nursery, particularly those related to the red blood cell (RBC), the primary focus of this review. Their timely identification is important to ensure appropriate care of the neonate. Common RBC disorders include hemolytic disease of the newborn, anemia, and polycythemia. Another clinically relevant hematologic issue in neonates to be covered herein is thrombocytopenia. Disorders of white blood cells will not be reviewed.
Introduction
Hematologic problems often arise in the newborn nursery, particularly those related to the red blood cell (RBC), the primary focus of this review. Their timely identification is important to ensure appropriate care of the neonate. Common RBC disorders include hemolytic disease of the newborn, anemia, and polycythemia. Another clinically relevant hematologic issue in neonates to be covered herein is thrombocytopenia. Disorders of white blood cells will not be reviewed.
Red blood cell
Clinical signs of an RBC disorder in the immediate newborn period are jaundice (hemolysis), pallor (anemia), and plethora (polycythemia). Of these RBC disorders, hemolysis is the most frequently encountered and often heralded by early-onset jaundice (≤24 hours of age). In the current era of birth hospitalization, bilirubin screening using total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) measurements, an elevated hour specific bilirubin greater than 75% on the Bhutani nomogram also is a marker for hemolysis. Although there are many diagnostic considerations in the interpretation of RBC disturbances in the neonatal period, a systematic approach based on mechanism(s) of disease highlighted herein make this process more straightforward.
Hemolytic disease of the newborn
Catabolism of RBC-derived heme produces bilirubin that results in jaundice, the most prevalent clinical condition requiring evaluation and management in neonates. Although hepatic and gastrointestinal immaturities that limit bilirubin clearance contribute to neonatal jaundice, it is increasingly clear that accelerated RBC turnover (hemolysis) plays a pivotal role in the risk for subsequent severe hyperbilirubinemia. Moreover, hemolysis potentiates the risk of bilirubin neurotoxicity and treatment interventions are therefore recommended at lower TSB levels when hemolysis is present. Pediatricians must therefore have a strong working knowledge of hemolytic disorders to properly care for the jaundiced neonate. These conditions are outlined in Box 1 and include immune-mediated disorders, red-cell enzyme defects, red-cell membrane abnormalities, and, for completeness but exceedingly rare in neonates, hemoglobinopathies.
- 1.
Immune-mediated (positive direct Coombs test)
- a.
Rhesus blood group: Anti-D, -c, -C, -e, -E, C W , and several others
- b.
Non-Rhesus blood groups: Kell, Duffy, Kidd, Xg, Lewis, MNS, and others
- c.
ABO blood group: Anti-A, -B
- a.
- 2.
Red blood cell (RBC) enzyme defects
- a.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
- b.
Pyruvate kinase deficiency
- c.
Others
- a.
- 3.
RBC membrane defects
- a.
Hereditary spherocytosis
- b.
Elliptocytosis
- c.
Stomatocytosis
- d.
Pyknocytosis
- e.
Others
- a.
- 4.
Hemoglobinopathies
- a.
alpha-thalassemia
- b.
gamma-thalassemia
- a.
Immune-Mediated Hemolytic Disorders
Immune-mediated disorders are the most common cause of hemolysis in neonates and should be suspected when there is (1) a heterospecific mother-infant pair in which the infant expresses a red-cell antigen(s) foreign to the mother, (2) the presence of a maternal antibody directed to the infant RBC antigen, (3) and a positive direct Coombs test in the neonate indicating maternal antibody bound to the infant RBC. An initial priority in evaluating every newborn is therefore knowledge of the maternal blood type and the maternal antibody screen. The latter deserves specific comment and emphasis.
The maternal antibody screen is a routine test performed at maternal registration on pregnancy diagnosis. The goal of screening is to identify non-ABO alloantibodies in the maternal serum that may pose a risk for hemolytic disease in the newborn. A standard screening panel for alloantibodies is shown in Table 1 . In addition, women who are Rh-D negative and have a negative antibody screen at registration will have a repeat screen at 24 to 28 weeks’ gestation before Rhogam (RhD-Ig) administration, and another screen at delivery along with a type and Coombs on the infant to determine the need for postpartum Rhogam. Interpreting the results of the maternal antibody screen by pediatricians is critical in identifying mothers who carry a non-ABO alloantibody, several of which can cause moderate to severe hemolytic disease of the newborn as detailed in Table 2 .
| Alloantibody | Blood Group |
|---|---|
| D, C, c, E, e, f, C W , V | Rhesus |
| K, k, Kp a , Js a | Kell |
| Fy a , Fy b | Duffy |
| Jk a , Jk b | Kidd |
| Xga | Xg |
| Le a , Le b | Lewis |
| S, s, M, N | MNS |
| P1 | P |
| Lu b | Lutheran |
| Within Rh system | Anti-D, -c, -C, -C w , -C x , -e, -E, -E w , -ce, -Ce s , -Rh29, -Rh32, -Rh42, -f, -G, -Go a , -Be a , -Evans, -Rh17, -Hr o , -Hr, -Tar, -Sec, -JAL, -STEM |
| Outside Rh system | Anti-LW, -K, -k, -Kp a , -Kp b , -Jk a , -Js a , -Js b , -Ku, -K11, -K22, -Fy a , -M, -N, -S, -s, -U, -PP 1 pk , -Di b , -Far, -MUT, -En 3 , -Hut, -Hil, -Vel, -MAM, -JONES, -HJK, -REIT |
Indeed, in addition to the classic Rhesus hemolytic disease of the newborn secondary to Rh-D isoimmunization, alloantibodies directed to non-D Rhesus antigens and a broad range of non-Rhesus blood group antigens are seen. Increasingly, the latter 2 categories comprise a clinically relevant proportion of hemolytic disease of the newborn. Identical maternal and infant blood grouping with respect to the ABO system and Rh-D status (“Rh positive” or “Rh negative”) does not preclude the presence of a clinically significant maternal alloantibody. Only a review of the maternal antibody screen and the direct Coombs test on the infant will uncover such cases. Indeed, a type and direct Coombs test are indicated at delivery (cord or infant blood) on all infants born to women with potentially significant alloantibodies.
Table 3 outlines several clinical scenarios in which the maternal antibody screen is positive, accompanied by the likely clinical explanation for the positive screen. It should be readily apparent that the clinical details outlined in each case must be sought out and appreciated by caretakers to identify infants at risk for non-ABO immune-mediated hemolytic disease. The only scenario shown that does not indicate maternal sensitization is that secondary to Rhogam administration. The latter positive anti-D maternal antibody screen finding must be distinguished from the rare occurrence of late Rh-D sensitization by confirming that the mother was anti-D antibody negative before Rhogam administration, and that she did indeed receive the Rhogam. At times, the infant also will have a positive direct Coombs test secondary to maternal Rhogam administration. This finding is generally not thought to indicate a hemolytic risk, albeit one recent case report suggests in rare circumstances it may. The latter has yet to be confirmed.
| Maternal Antibody Status at Beginning of Pregnancy | Maternal Antibody Status at 24–28 wk Before Rhogam | Was Rhogam Administered? | Maternal Antibody Status at Delivery | Maternal Antibody | Diagnosis | Infant at Risk for Hemolytic Disease of the Newborn |
|---|---|---|---|---|---|---|
| Negative | Negative | Yes | Positive | Anti-D | Passive anti-D; Rhogam effect | Unlikely a |
| Negative | Negative | No | Positive | Anti-D | Late sensitization to Rh-D | Yes |
| Negative | Positive | No | Positive | Anti-D | Early sensitization to Rh-D | Yes |
| Positive | Positive | No | Positive | Anti-D | Sensitized pregnancy to Rh-D | Yes |
| Negative | Negative | Yes | Positive | Non-D antibody | Late sensitization to non-D antigen | Yes |
a At times, the infant will also have a positive direct Coombs test secondary to maternal Rhogam administration. This finding is generally not thought to indicate a hemolytic risk, albeit one recent case report suggests in rare circumstances it may. The latter has yet to be confirmed.
It is also important to note that infants who are Rh-D positive and delivered to women who are Rh-D negative during the first isoimmunized pregnancy (conversion from negative to positive maternal antibody titer in that pregnancy) are at an approximately 20% risk of developing hemolytic disease of the newborn requiring treatment, including the possibility of an exchange transfusion. This risk likely holds true for all non-ABO alloantibodies. An infant born of a pregnancy during which maternal antibody conversion occurs will by definition carry the foreign antigen and may have a positive direct Coombs test. Such infants are at risk of hemolytic disease of the newborn, should be monitored closely for the development of severe hyperbilirubinemia with serial TSB measurements, and should not be discharged early from the birth hospital.
ABO hemolytic disease
Hemolytic disease related to ABO incompatibility is generally limited to mothers who are blood group O and infants of blood group A or B. Although this association exists in approximately 15% of pregnancies, only a subset of such infants will develop significant hyperbilirubinemia. Defining which infants will be affected is difficult to predict using standard laboratory screening tests. Ozolek and colleagues observed that of infants who are type A or B born to mothers who are blood group O, approximately one-third had a positive direct Coombs test, and of those with a positive direct Coombs test, approximately 15% had peak serum bilirubin levels greater than 12.8 mg/dL. Others have reported a higher percentage (approximately 50%) of hyperbilirubinemia (defined by an hour specific TSB >95% on the Bhutani nomogram) in infants who are type A or B who demonstrate a positive direct Coombs test born to mothers who are type O. Regardless, only a subset evidence symptomatic hemolytic disease.
Infants born of ABO-incompatible mother-infant pairs who have a negative direct Coombs test as a group appear to be at no greater risk for developing hyperbilirubinemia than their ABO-compatible counterparts and the development of significant hyperbilirubinemia in such neonates should prompt an evaluation for a cause other than isoimmunization. Similarly, infants who are group A or B born to mothers who are, respectively, incompatible group B or A, are not likely to manifest symptomatic ABO hemolytic disease and fewer than 1% will have a positive direct Coombs test.
Despite the difficulty in predicting its development, symptomatic ABO hemolytic disease does occur. Hyperbilirubinemia seen with symptomatic ABO hemolytic disease is often detected within the first 12 to 24 hours of life along with jaundice (“icterus neonatorum praecox”) and accompanied by microspherocytosis on peripheral blood smear and an increased reticulocyte count. Indeed, of infants who were ABO-incompatible direct Coombs positive who developed a TSB greater than 95% on the Bhutani nomogram, 67% did so within the first 24 hours of life and only 1 of 85 such infants developed hyperbilirubinemia after 48 hours. Hyperbilirubinemia in symptomatic ABO hemolytic disease is more often than not controlled with intensive phototherapy alone. Only a few affected infants will develop hyperbilirubinemia to levels requiring exchange transfusion, albeit this must be monitored for.
Some ABO heterospecific mother-infant pairs hold potential for more severe hemolytic disease than others. O-B heterospecificity is associated with greater hyperbilirubinemia risk than O-A, in particular in mothers and neonates of African origin. Although there is some conflicting literature regarding the latter, our recent institutional experience and other reports support the assertion that O-B heterospecificity poses some risk in African American individuals. The last 6 double-volume exchange transfusions we performed for symptomatic ABO hemolytic disease have all been in the context of O-B incompatibility and an African American mother. In each case there were markedly elevated maternal immunoglobulin G (IgG) anti-B titers in the range of 1:1024 to 1:2048, as contrasted with the more typical 1:8 to 1:32 titers in mothers who are type O. None of the affected neonates had coexistent glucose-6-phosphate dehydrogenase (G6PD) deficiency. High-titer anti-B IgG also has been reported in the rare case of ABO hemolytic disease in mothers who are group A.
During robust hemolysis of any cause, the TSB may continue to rise despite intensive phototherapy. Indeed, if not previously considered, failure of phototherapy to produce a prompt decline in TSB should raise the possibility of an underlying hemolytic condition. It follows that in hyperbilirubinemic newborns with symptomatic ABO hemolytic disease, TSB should be monitored during phototherapy to ensure the TSB does not rise to levels that merit exchange transfusion.
Routine screening of all ABO-incompatible cord blood has been recommended in the past and remains common practice in many nurseries. The literature, however, suggests that such screening is not warranted given the cost and low yield, consistent with the tenor of recommendations of the American Association of Blood Banks, the American Academy of Pediatrics, and the implementation of universal newborn bilirubin screening during the birth hospitalization. A blood type and direct Coombs test is indicated, however, in the evaluation of any newborn with early jaundice (<24 hours of age) and/or clinically significant hyperbilirubinemia, including those treated with phototherapy.
Red Blood Cell Enzymopathies
G6PD and pyruvate kinase (PK) deficiency are the 2 most common red-cell enzyme disorders associated with marked neonatal hyperbilirubinemia. Of these, G6PD deficiency is the more frequently encountered and it remains an important cause of kernicterus worldwide, including the United States, Canada, and the United Kingdom, the prevalence in Western countries a reflection in part of immigration patterns and intermarriage. The risk of kernicterus in G6PD deficiency also relates to the potential for unexpected rapidly developing extreme hyperbilirubinemia in this disorder associated with acute severe hemolysis after exposure to oxidative stress. Reported hemolytic triggers in neonates include among others naphthalene (moth balls), methylene blue, antimalarials, sulfonamides, maternal ingestion of fava beans (favism by proxy), and infection. This mode of G6PD-deficiency–associated hazardous hyperbilirubinemia can result in kernicterus that may not always be preventable.
More than 20% of neonates in the United States pilot kernicterus registry, a database of voluntarily submitted information on 125 infants who developed kernicterus between 1992 and 2004, had G6PD deficiency, as contrasted to an estimated 4% to 7% background population prevalence. African American neonates comprised the most (73%), reflecting the high prevalence of this condition (12.2% for boys; 4.1% for girls) and risk for hazardous hyperbilirubinemia (TSB ≥30 mg/dL) in newborns of black race. The latter belies the fact that black race is associated with a lower risk of TSB in the ranges of 13 to 15 mg/dL, 16 to 19 mg/dL, and ≥20 mg/dL. This apparent discrepancy is best explained by G6PD deficiency itself and its potential to predispose to acute hemolysis, resultant rapid rise in TSB, and hazardous hyperbilirubinemia.
G6PD deficiency is an X-linked enzymopathy affecting hemizygous males, homozygous females, and a subset of heterozygous females (via X chromosome inactivation). Hemolysis in G6PD deficient neonates, however, may be self-limited and overt anemia not necessarily noted, masked by other factors that modulate hemoglobin concentration in the immediate newborn period. Severe jaundice rather than anemia may predominate in the clinical presentation. In other neonates, the combination of G6PD deficiency with hepatic bilirubin conjugation defects of Gilbert syndrome significantly increases the risk of hyperbilirubinemia. Pediatricians must have a high index of suspicion for G6PD deficiency in populations with increased risk (Mediterranean region, Africa, the Middle East, Asia), and in particular the African American neonate, with significant hyperbilirubinemia.
PK deficiency typically presents with jaundice, anemia, and reticulocytosis. Such jaundice may be severe, as reflected by one series in which a full third of affected infants required exchange transfusion to control hyperbilirubinemia and kernicterus in PK deficiency, and is well described. The diagnosis of PK deficiency is often difficult, as the enzymatic abnormality is frequently not simply a quantitative defect, but in many cases involves abnormal enzyme kinetics or an unstable enzyme that decreases in activity as the red cell ages. It is inherited as an autosomal recessive disorder, but notably, most affected individuals are compound heterozygotes; that is, they express 2 different disease-causing alleles: 1 maternal and 1 paternal in origin. The diagnosis of PK deficiency should be considered whenever persistent significant hyperbilirubinemia and a picture of nonspherocytic, Coombs-negative hemolytic anemia is observed, particularly in populations in which consanguinity is prevalent, including newborns of Amish descent and in other remote communities where intermarriage is prevalent.
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