Anemia in Early Infancy

Symposium on Pediatric Hematology

Anemia in Early Infancy

Frances M. Gill, MD.,* and Elias Schwartz, M.D.**

As in older children and adults, anemia in young infants may result from blood loss, hemolysis, or decreased production of red cells. Special circumstances unique to the newborn may increase the risk of anemia from these causes. There is an increased tendency to bleed because of decreased levels of some clotting factors in the newborn period. 3 In addition, the infant may have intrauterine or intrapartum bleeding. Red cells from the newborn are more mechanically fragile and are especially susceptible to hemolysis. The life span of these cells is approximately two thirds that of adult cells. 30 After the active erythropoiesis during gestation, there is a period of marked erythroid hypoplasia of the bone marrow lasting for several weeks after birth. For all these reasons, stresses which might be adequately met at a later age may lead to anemia in the infant. The premature infant is at an even greater disadvantage, for the red-cell life span is even shorter, the metabolic abnormalities are more pronounced, and there are decreased stores of many substances necessary for normal red cell production and survival, such as iron and vitamin E. Before considering the most common causes of blood loss, hemolysis, and decreased red cell production in early infancy, the normal state of erythropoiesis at this period will be summarized.

NORMAL VALVES The normal hematologic values during the first 6 months of life are listed in Table 1. Since the levels of hemoglobin concentration and hematocrit are higher in capillary blood samples than in venous blood, samples in the newborn from one source, preferably venous, should be used consistently for an accurate picture of change in the infant's status. The heel may be warmed prior to puncture to obtain a sample which reflects venous values more closely than do the values from a standard heel puncture sample. Normally the hemoglobin and hematocrit values rise From the Cardeza Foundation for Hematologic Research and the Department of Pediatrics, Jefferson Medical College, Philadelphia, Pennsylvania "Research Fellow in Pediatric Hematology, Jefferson Medical College '''''Associate Professor of Pediatrics, Jefferson Medical College Supported in part by U.S. Public Health Service Grants AM 05212 and AM 12896.

Pediatric Clinics of North America- VoL 19, No.4, November 1972

841

00 ~

~

Table 1.

Normal Hematologic Values* During Early Infancy 'Tj

~

FULL TERM INFANTS':":'

Z

(")

PARAMETER

Hemoglobin (gm. per 100 ml.) venous capillary Red blood cells x 106 per cu. mm. Hematocrit (%) MCV (11-") MCHC (%) Reticulocytes (%) Nucleated red blood cells per cu. mm. per 100 white blood cells

1

])AY

7

])A YS

2-3

WEEKS

5-6

WEEKS

8-9

WEEKS

11-12

WEEKS

t"l

C/l

~ 17.1 ± 1. 7 19.3 ± 2.2 5.14 ± 61 ± 119 ± 31.6 ± 3.2 ±

0.17 7.4 9.4 1.9 1.4

500 7.3

GJ 17.9 ± 2.5 4.86 ± 0.6 56 ± 9.4 118±11.2 32.0 ± 1.6 0.5 ± 0.4 0

15.6 ± 2.6 4.20 46 111 33.9 0.8

± ± ± ± ± 0

0.6 7.3 8.2 1.9 0.6

11.9 ± 1.5 3.55 ± 0.2 36 ± 6.2 102 ± 10.2 34.1 ± 2.9 1.0±0.7 0

10.7 ± 0.9 3.40 ± 31 ± 93 ± 34.1 ± 1.8 ± 0

0.5 2.5 12.0 2.2 1.0

11.3 ± 0.9 3.70 ± 33 ± 88 ± 34.8 ± 0.7 ± 0

0.3 3.3 2.2 2.2 0.3

t:: t-<

> Z

t:i

trI t-<

:; C/l

III (")

:I: ~

> ::
...,

N

r -.-

-: ~

PREMATURE INFANTS§

~

1 day

5-6 weeks

10-11 weeks

22-23 weeks

:; ""Z

Hemoglobin (gm. per 100 m!.) capillary Hematocrit (%) MCV (!L") MCHC (%) Reticulocytes (%) Nucleated red blood cells per cU.mm. per 100 white blood cells

i:':I

16.4 52.9 103 31 8.8

± ± ± ± ±

2.2 8.1 3.6 1.6 2.3

1000-1500 21

10.6 ± 32.0 ± 93 ± 33 ±

0.8 4.9 4.1 1.8

9.3 28.4 91 33

± ± ± ±

1.1 3.6 3.6 1.5

11.0 ± 34.3 ± 87 ± 32 ±

0.9 2.6 3.7 1.6

;.-

~

t-< ><

[;.Z

a

><

0

0

0

"Average value ±1 S.D. :'Data on full term infants taken primarily from Matoth et a!.21 §Data on premature infants averaging 1840 gm. at birth and fed iron supplemented formula, from Gorten and Cross.' tSamples obtained from puncture of warmed hee!.

00

,j::o.

~

844

FRANCES

M.

GILL AND ELIAS SCHWARTZ

in the first several hours of life because of movement of plasma from the intravascular to the extravascular space."' A venous hemoglobin concentration of less than 14 gm. per 100 mI. or a fall in hemoglobin concentration or hematocrit in the first day of life is abnormal and should be investigated. The hemoglobin level at birth is lower in the premature than in the term infant, and the reticulocyte and nucleated red blood cell counts are higher. The lower the gestational age of the infant, the more pronounced are the differences. Infants with intrauterine growth retardation have reticulocyte levels which are compatible with the gestational age,!S but red cell counts, hemoglobin concentrations, and hematocrits which are frequently elevated." Erythropoietic activity in the marrow decreases markedly during the first week of life in both the term and the premature infant. The reticulocyte count is elevated at birth but falls to less than 1 per cent by the sixth day of life. 37 The red blood cell, hemoglobin, and hematocrit values decrease only slightly during the first week, but in the following 5 to 8 weeks they decline rapidly."! Physiologic anemia of the newborn develops at this time."6 Erythroid hypoplasia is accompanied by an absence of circulating erythropoietin in infants after the first day of life lO until 60 days."· When the hemoglobin concentration falls to a level of about 11 gm. pet 100 mI., erythropoietic activity begins to increase. The lowest hemoglobin values are found in the term infant at about the eighth to the tenth week. In the premature infant, the fall in hemoglobin is more pronounced, and the nadir may be reached by the fifth week of life. The anemia is more marked in the smaller premature infant, falling to about 8 gm. per 100 ml. in those weighing less than 1200 gm. at birth. This physiologic anemia is self-limited and does not respond to iron or to other nutritional supplements. It is usually well tolerated, and transfusion therapy is not normally required. Mter this period the hemoglobin concentration will rise to 10 to 12 gm. per 100 mI. without treatment and normally remains at this level throughout the first year. The red cells of the newborn infant are markedly macrocytic at birth, but the mean cell volume and diameter begin to fall after the first week, reaching adult values by the ninth week.'! The mean cell hemoglobin concentration averages 31.6 per cent at birth and rises thereafter."! A peripheral smear from the 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 and a few per cent of abnormal cells, such as spherocytes, target cells, and schistocytes. Howell-Jolly bodies may be seen because of splenic hypofunction early in life. Nucleated red blood cells are no longer found in the blood by 3 to 5 days, even in premature infants, but they may be markedly increased in association with hemolytic disorders or hypoxia. In the normal term infant, the iron contained in the total initial hemoglobin and in tissue stores is sufficient to allow normal erythropoiesis for 5 to 6 months without dietary supplementation. The premature infant has a lower initial hemoglobin mass and has received only partial iron stores from the mother. Stainable iron is present in small amounts in the bone marrow at birth and increases during the first weeks of life in both term and premature infants. After 2 to 3 months the amount of iron begins to decrease, disappearing in term babies by 4 to 6 months and earlier in premature infants.3s

BLOOD LOSS Anemia present at birth is almost invariably the result of bleeding or hemolysis in utero or of bleeding during delivery. Case 1

A 7 lb., 4 oz. Caucasian boy was born after a normal pregnancy and delivery. The mother was not anemic and had received prenatal vitamins and iron. No abnormal vaginal bleeding was noted, and the gross anatomy of the placenta was normal. The baby was normal except for pallor. Hemoglobin concentration was

ANEMIA IN EARLY INFANCY

845

10 gm. per 100 mI., mother's blood type 0 positive, and the baby's A positive. Direct and indirect Coombs tests were negative. There was no hyperbilirubinemia. The child was seen at the Thomas Jefferson University Hospital on the seventh day of life. Hemoglobin concentration was 9.2 gm. per 100 mI. with a reticulocyte count of 10.3 per cent. Examination of the peripheral smear showed macrocytic, normochrOInic cells. White blood cell count, differential, and platelet count were normal. A smear of the peripheral blood of the mother was examined by the acid elution technique of Kleihauer-Betke, and 1 fetal cell was present per 200 adult cells.

The presence of fetal cells in the maternal circulation as shown by the Kleihauer-Betke technique indicates that bleeding has occurred from the fetus into the mother. Such a transfusion can be demonstrated in 20 per cent of women after delivery of a first child.43 In 1 per cent of pregnancies the volume of blood exceeds 40 mI., an amount large enough to produce anemia in the infant.4 To demonstrate the presence of red cells from the fetus, a smear of maternal blood is prepared, fixed in methyl alcohol, incubated with an acid buffer, and stained. 13 The adult hemoglobin is eluted by the acid, leaving ghost cells. The fetal hemoglobin is acid resistant, and cells containing fetal hemoglobin appear dark among the ghost cells. The number of fetal cells per 100 adult cells may be used as a rough estimate of the volume of the transfusion, a count of 1 per cent corresponding to about 40 ml.4 This test should be done as soon after delivery as possible, since the fetal cells may disappear if there are maternal antibodies against fetal red cell antigens. The amount of Hb F in the mother is not a reliable indicator of transplacental transfusion because quantitation of Hb F is technically difficult and the level is frequently slightly elevated in pregnancy. Transfusion reactions have occurred in mothers when incompatible fetal cells have crossed into the maternal circulation. The marked hemolysis needed to produce a hemoglobin concentration as low as 10 gm. per 100 ml. at birth is almost always the result of . maternal-fetal incompatibility. Rh or minor group sensitization was ruled out in the infant described above by the blood group typing and the negative direct Coombs test. It would be unlikely for ABO incompatibility to produce such a marked anemia at birth without hyperbilirubinemia and without detectable maternal antibody in the baby's serum. The common causes of in utero bleeding are fetal-to-maternal transfusion, fetal-to-fetal transfusion, and bleeding caused by placental disorders, such as placenta previa and placental abruption. 33 If the intrauterine blood loss has been chronic, the infant's cells are often microcytic and hypochromic because of iron deficiency. The baby is usually not in clinical distress even with a severe degree of anemia. Iron replacement therapy should be given in all cases. A transfusion of packed red cells is rarely necessary and should be given carefully to avoid circulatory overload. Acute bleeding may not be recognized if the volume has not been large enough to cause symptoms in the infant. However, the infant with massive acute blood loss may be in shock with pallor, tachycardia, rapid and often irregular respirations, and poor peripheral pulses. Such an infant does not improve with oxygen therapy and requires rapid expansion of intravascular volume with appropriate fluids until a blood transfusion can be given. The initial hemoglobin level may not reflect the true extent of blood loss. If the infant is not in distress clinically and there is a ques-

846

FRANCES

M.

GILL AND ELIAS SCHWARTZ

tion of acute blood loss, the baby should be followed closely over several hours to watch for a fall in the hemoglobin concentration. The morphology of the red cells after a single, recent episode of bleeding is normal. Significant fetal-to-fetal transfusions occur in approximately 15 per cent of all sets of monochorial twins. 32 In all twins of the same sex, hemoglobin levels should be determined. A difference of 5 gm. per 100 ml. between twins indicates a transfusion of major clinical importance. The donor infant, who is usually but not invariably smaller, may have adjusted to the anemia but may occasionally require a transfusion. The recipient baby may need a partial exchange transfusion with plasma to treat erythrocytosis and relieve resultant congestive heart failure, pulmonary distress, seizures, or hyperbilirubinemia. Anomalies in the placental vessels or their insertions may lead to massive bleeding if tearing occurs during delivery. Incision of the placenta during cesarean section may cause significant bleeding. Inspection of the placenta and of the cord and inquiry regarding abnormal vaginal bleeding should be made when investigating anemia noted at birth. The newborn infant may have bleeding into the gastrointestinal tract, lungs, head, or skin, or from a ruptured liver, spleen, or ovarian cyst. A hemoglobin or hematocrit level which continues to fall postnatally in the absence of hemolysis suggests this type of bleeding. If there are petechiae or ecchymoses, or if the bleeding is generalized, a platelet count and coagulation studies should be done to look for severe thrombocytopenia, hemorrhagic disease of the newborn, or disseminated intravascular coagulation. Bleeding as a cause of anemia is unusual in the older infant. Iron deficiency anemia developing during the first 6 months of life in a term infant who had a normal hemoglobin level at birth, and especially in one receiving iron-rich foods, suggests continuing blood loss, usually into the gastrointestinal tract or into the lungs, as in pulmonary hemosiderosis.

HEMOLYSIS In the immediate neonatal period, anemia caused by increased destruction of red blood cells is usually accompanied by hyperbilirubinemia. The anemia may not be detected until marked jaundice is present. The following case illustrates the approach to diagnosis in an infant with hemolytic anemia and jaundice. Case 2 A white girl delivered at term was transferred to Jefferson Hospital at 10 hours of age because of petechiae, jaundice, and hepatosplenomegaly. Pregnancy and delivery were normal. Physical examination revealed no further abnormalities. On initial blood count the hemoglobin concentration was 11.9 gm. per 100 ml., reticulocytes 6.2 per cent, white blood cell count 20,000 per cu. mm., and platelet count was estimated to be less than 20,000 per cu. mm. The bilirubin was 10 mg. per 100 ml. ,Mother's blood type was B positive, the baby's AB positive. The direct Coombs test was negative. At 24 hours of age the hemoglobin concentration was 10 gm. per 100 mI., platelet count 9000, and reticulocytes 12.4 per cent. There were a few spherocytes and poikilocytes and 10 nucleated red blood cells per 100 white blood cells on the peripheral blood smear. Bilirubin reached a maximum

ANEMIA IN EARLY INFANCY

847

level of 22 mg. per 100 mI., of which 7.5 mg. was direct reacting. The hemoglobin was lowest on the tenth day, 9 gm. per 100 mI. No organism was grown from blood cultures. The serum IgA was 32 mg. per 100 mI. and IgM 37 mg. per 100 mI. Cells with intranuclear inclusions characteristic of those produced by cytomegalovirus were seen in the urinary sediment, confirming the clinical diagnosis of cytomegalovirus infection.

The thrombocytopenia, hepatosplenomegaly, elevated IgA and IgM levels, and the hepatic dysfunction indicated by the elevated direct-reacting bilirubin fraction suggested an intrauterine infection with cytomegalovirus, rubella, toxoplasmosis, or syphilis, or a neonatal infection with herpes simplex. Hemolytic anemia, jaundice, and thrombocytopenia resulting from infection may occur without other stigmata of infection. Hemolytic anemia may also be seen in bacterial sepsis, and blood cultures should be done to investigate this possibility. Erythroblastosis fetalis secondary to Rh, ABO, or minor group incompatibility is the most frequent cause of hemolytic disease in the newborn in the United States. The direct Coombs test is always positive in Rh or minor group sensitization. It is often weakly positive but may be negative in ABO incompatibility. Maternal antibodies may be found in the serum of most infants with ABO sensitization in the first 24 hours of life. Hereditary spherocytosis may cause jaundice and anemia within the first 2 days of lifeY The presence of spherocytes, lack of positive direct Coombs reaction, and minimal or absent splenomegaly may lead to confusion with hemolysis caused by ABO incompatibility. A positive family history and the presence of spherocytes in the peripheral blood of one of the parents are helpful in establishing the diagnosis of hereditary spherocytosis. Hereditary elliptocytosis may also cause jaundice and anemia in the neonate,25 and the diagnosis may be made by positive family history and the finding of elliptocytosis in one parent. Occasionally red blood cell enzyme deficiencies cause anemia and hyperbilirubinemia in the neonatal period. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in persons of Oriental17 • 31 or Mediterranean42 extraction may cause severe hyperbilirubinemia, since the enzyme is frequently almost completely absent and even young red blood cells are susceptible to hemolysis. In most of the neonatal cases no drug . has been implicated as a causative agent. In the American Negro with G-6-PD deficiency, sufficient enzyme is present in young red cells to make hemolytic disease in the newborn very uncommon, although hemolysis may occur in some affected premature infants.5 Of the other red cell enzyme deficiencies, pyruvate kinase deficiency has been most often reported as a cause of hemolysis in the neonatal period29 with cases resulting from hexokinase, glutathione-peroxidase, and triosephosphate isomerase deficiencies also reported. The diagnosis of a specific enzyme deficiency may be established in the first few days of life if appropriate laboratory facilities are available. If, because of hyperbilirubinemia, exchange transfusion is necessary before a definitive diagnosis is made, the enzyme deficiency may be confirmed after 3 to 4 months when the transfused red cells have been cleared from the infant's circulation. Infants with erythroblastosis fetalis should be followed carefully, since hemolysis may continue when jaundice is no longer apparent and

848

FRANCES

M.

GILL· AND ELIAS SCHWARTZ

severe anemia may develop after discharge from the hospital. In one group of 47 babies with Rh sensitization 13 had hemoglobin levels below 7.4 gm. per 100 ml. during the first four months of life. 6 The anemia occurred in some babies with only mild manifestations of hemolysis at birth, but it was more frequent in those who were severely affected, despite adequate initial exchange transfusion therapy. Seven of the 13 infants had positive direct Coombs tests at 4 to 6 weeks without a reticulocyte response to increasing anemia. The Coombs test has been known to remain positive for as long as 4 months. As phototherapy for jaundice reduces the number of infants with ABO incompatibility requiring exchange transfusions, late anemia may also become common in this group.40 Anemia in some premature infants in the second month of life has been associated with reticulocytosis, increased in vitro red blood cell hemolysis by hydrogen peroxide, low serum vitamin E (tocopherol) levels,28 thrombocytosis, and edema.34 The incidence is highest in infants with birth weights less than 1500 gm. and gestational ages less than 32 weeks. 23 The deficiency has been ascribed to decreased stores of vitamin E in the premature infant and the low content of the vitamin in many formulas. The smallest premature infants cannot absorb vitamin E efficiently until about the twelfth week even when supplementary doses of vitamin E are given.24 In addition, premature infants receiving therapeutic doses of iron (6 mg. per kg. per day or more) had more marked anemia than did those receiving no iron supplementation, possibly because of increased oxidation and shortened survival of red cells.23 Iron should probably only be given in therapeutic doses to those premature infants in whom the presence of iron deficiency anemia has been clearly established. There is no evidence that the low levels of iron present in supplemented formulas (8 to 12 mg. per quart) have a detrimental effect on red cell survival. Autoimmune hemolytic anemia has been described in infants as young as 6 weeks. The acute onset of anemia with reticulocytosis and a positive direct Coombs test usually suggests the etiology. Most children with this disorder respond to corticosteroid therapy and recover completely. Children with the common hemoglobinopathies may be diagnosed in the first 6 months of life when an adequate level of Hb A fails to appear to replace the decreasing amount of fetal hemoglobin. The initial manifestation in an infant with sickle cell disease may be painful swelling of the hands and feet (the "hand-foot syndrome"). Infants with sickle cell disease are more susceptible to bacterial infections than normal children. Retarded physical growth may be apparent by 6 months. The findings of anemia, abnormal red cell morphology, and splenomegaly suggest a hemoglobinopathy, and hemoglobin electrophoresis should be done. Sickle cells may be demonstrated in all children with sickle cell disease, sickle cell trait, hemoglobin SC disease, and sickle-thalassemia after the first few months of life. The presence of many target cells suggests hemoglobin C disease or trait or hemoglobin SC disease. Hemoglobin abnormalities may be diagnosed in the newborn period by starch gel electrophoresis.

ANEMIA IN EARLY INFANCY

849

Children with homozygous beta thalassemia become anemic before they are 6 months old. Splenomegaly is present, and the peripheral smear shows microcytic, hypochromic cells, marked poikilocytosis, and nucleated red blood cells. In the first few days of life this diagnosis may be made by finding purple inclusion bodies in red cells stained with methyl violet. These inclusion bodies result from precipitated excess alpha chains. As splenic function develops, such cells are removed from the circulating blood, but they may be demonstrated in the bone marrow at any age. Family studies are useful in elucidating the exact nature of hemoglobinopathies in the newborn period. Two forms of thalassemia may cause anemia in the immediate newborn period. In hydrops fetalis associated with homozygous alpha thalassemia, alpha chain production is deficient and excess gamma chains combine to form hemoglobin Barts (04)' This abnormal tetramer has an unusual avidity for oxygen, and the deficient release of oxygen results in severe intrauterine distress. The hydropic fetus is usually stillborn or dies shortly after birth. Although alpha thalassemia trait is common in people of Oriental, Mediterranean, and African descent, no case of hydrops fetalis caused by alpha thalassemia has been described in the American Negro. Another type of thalassemia causing anemia in the newborn was recently described: a baby heterozygous for both gamma and beta thalassemia had hyperbilirubinemia and hemolytic anemia.12

DECREASED PRODUCTION After the immediate neonatal period anemias may result from deficient production of red blood cells as well as from hemolysis and blood loss. Bone marrow examination is important in differentiating disorders of red cell production. Case 3

A 4 month old white girl was admitted to a local hospital after 3 weeks of vomiting and decreasing activity. The baby had had no problems in the neonatal period but had become progressively paler since birth. Hemoglobin concentration was 1.8 gm. per 100 ml., and the reticulocyte count was 0.1 per cent. Direct Coombs test was negative. After transfusion to a hemoglobin level of 8.5 gm. per 100 mI., she developed oliguria, azotemia, and congestive heart failure. She was transferred to Jefferson Hospital where her condition appeared critical, with signs of marked congestive heart failure. Hemoglobin concentration was 7.4 gm. per 100 ml. Peripheral blood smear showed normochromic, normocytic cells without fragmented forms or burr cells. Bone marrow examination showed normal myelopoiesis and thrombopoiesis but only a rare red blood cell precursor. Blood urea nitrogen was 78 mg. per 100 ml. Peritoneal dialysis was followed by prompt relief of heart failure and by a gradual return of normal renal function. She was begun on prednisone, with a gradual rise in reticulocyte count and hemoglobin level. At 14 months of age she still requires prednisone therapy to maintain an adequate hemoglobin level.

The severe anemia developing at this age after a normal newborn period, the absence of reticulocytes, and the extreme paucity of red blood cell precursors in the bone marrow are hallmarks of pure red cell aplasia or the Diamond-Blackfan syndrome. The anemia and renal failure were

850

FRANCES

M.

GILL AND ELIAS SCHWARTZ

suggestive of the hemolytic-uremic syndrome, but the absence of thrombocytopenia and other coagulation abnormalities, the lack of reticulocytosis, and the bone marrow findings did not support this diagnosis. It is important to make the diagnosis of congenital red cell aplasia and begin corticosteroid therapy early, since there is a higher occurrence of responses in children treated within a few months of onset. 1 The anemia and lack of reticulocytes may occasionally be present at birth in these children, but they are more usually noted at 2 to 3 months of age. The most common cause of decreased red cell production in childhood is iron deficiency anemia, which is discussed in detail elsewhere in this volume. The term infant does not normally develop iron deficiency in the first 6 months. The premature infant, however, requires supplementary dietary iron in order to prevent iron deficiency from developing as physiologic anemia resolves. The use of proprietary formula containing 12 mg. of elemental iron per quart has been shown to prevent this iron deficiency.7 Folic acid deficiency is the most common cause of megaloblastic anemia in infancy.19 Although common in many other areas, there are few reports from the United States. The symptoms and signs are irritability, anorexia, pallor, failure to gain weight, diarrhea, and vomiting. The red cells are not always macrocytic, and the bone marrow may not show megaloblastic changes in the red cell series. However, giant metamyelocytes and giant band forms are present, and thrombocytopenia is common. The deficiency in term infants is usually associated with malnutrition or malabsorption, although a congenital defect of transport of folic acid has been described. 16 Infection, especially during the second to fourth months of life, may cause a deficiency of folate even with an adequate dietary intake. In a study of premature infants,39 low serum folic acid levels were found in 60 per cent of those 1 to 2 months old who had weighed less than 1700 gm. at birth. Only 7.7 per cent of the premature infants with birth weights greater than 1700 gm. had low serum levels. Bone marrow examination did not show megaloblastic changes in folate-deficient infants. TranSIent deficiencies of vitamin B12 have occurred in breast-fed infants when the level of B12 in the milk was low. This has been reported in one mother with unrecognized pernicious anemia15 and in another mother who was a vegetarian and had low serum B12.14 True megaloblastic anemia with onset in infancy has also been described in two sisters who had a deficiency of the B12 transport protein, transcobalamin IJ.9 Copper deficiency has been recognized in children with iron deficiency anemia and hypoproteinemia35 and in malnourished children in Peru. s Two cases have been reported recently of premature infants who developed copper deficiency while on a standard prepared formula. 2, 36 In addition to the anemia and lack of reticulocytosis, leukopenia with granulocytopenia, megaloblastic marrow changes with maturation arrest in the white blood cell series, and bone changes similar to those seen in scurvy have been noted. All these changes resolve with the oral administration of copper sulfate. Anemia resulting from decreased production of red cells may be secondary to a baSIC disorder such as hypothyroidism or severe renal disease.

851

ANEMIA IN EARLY INFANCY

Anemia, leukopenia, and thrombocytopenia are found in acquired aplastic anemia and in some cases of malignancy, such as leukemia, neuroblastoma, or the reticuloendothelioses.

SUMMARY Anemia in infancy results from blood loss, hemolysis, or decreased production of red cells. In the newborn infant, blood loss is most commonly the result of fetal-to-maternal transfusion but may result from twin-to-twin transfusion, placental bleeding, or internal bleeding. Hemolysis in the neonatal period is usually caused by Rh, ABO, or minor group incompatibility. Intrauterine and neonatal infections, red cell enzyme deficiencies, and red cell membrane abnormalities, such as hereditary spherocytosis or elliptocytosis, may cause hemolysis in the newborn infant. In the older infant blood loss is an unusual cause of anemia. Continuing hemolysis in infants with blood group incompatibilities may cause a late and severe anemia. In some premature infants a hemolytic anemia has been observed in association with low serum vitamin E levels. Decreased erythrocyte production owing to iron deficiency may be seen in term infants who had intrauterine or neonatal blood loss or in premature infants who had not received supplementary iron. Other causes of decreased production are congenital red cell aplasia, copper deficiency, and megaloblastic anemias resulting from deficiencies of folic acid or vitamin B 12 • Anemia may also be secondary to hemoglobinopathies, hypothyroidism, aplastic anemia, renal failure, intravascular coagulation, or malignancies. The cause of the anemia can usually be found by careful history and physical examination and the use of a few standard laboratory examinations. Genetic studies in some cases are helpful in determining the correct diagnosis. Establishing a specific diagnosis avoids unnecessary medications and transfusions and allows early initiation of appropriate therapy.

REFERENCES 1. Allen, D. M., and Diamond, L. K.: Congenital (erythroid) hypoplastic anemia: cortisone treated. Amer. J. Dis. Child., 102:416, 1961. 2. AI-Rashid, R. A., and Spangler, J.: Neonatal copper deficiency. New Eng. J. Med., 285 :841, 1971. 3. Bleyer, W. A., Hakami, N., and Shepard, T. H.: The development of hemostasis in the human fetus and newborn infant. J. Pediat., 79:838, 1971. 4. Cohen, F., Zuelzer, W. W., Gustafson, D. C., et al.: Mechanism of isoimmunization. I. The transplacental passage of fetal erythrocytes in homospecific pregnancies. Blood, 23:621, 1964. 5. Eshaghpour, E., Oski, F. A., and Williams, M.: The relationship of erythrocyte glucose-6-phosphate dehydrogenase deficiency to hyperbilirubinemia in Negro premature infants. J. Pediat., 70:595, 1967. 6. Fraser, I. D., Oppe, T. E., Tovey, G. H., et aI.: Post-exchange anemia in RH haemolytic disease. Lancet, 2:1309,1964.

852

FRANCES

M.

GILL AND ELIAS SCHWARTZ

7. Gorten, M. K, and Cross, E. R.: Iron metabolism in premature infants. II. Prevention of iron deficiency. J. Pediat., 64:509, 1964. 8. Graham, G. G., and Cordano, A.: Copper depletion and deficiency in the malnourished infant. Johns Hopkins Med. J., 124:139,1969. 9. Hakami, N., Neiman, P. E., Canellos, G. P., et al.: Neonatal megaloblastic anemia due to inherited transcobalamin. II. Deficiency in two siblings. New Eng. J. Med., 285:1163, 1971. 10. Halvorsen, S.: Plasma erythropoietin levels in cord blood and in blood during the first week of life. Acta Paediat. Scand., 52:425, 1963. 11. Humbert, J. R., Abelson, H., Hathaway, W. E., et aL: Polycythemia in small for gestational age infants. J. Pediat., 75:812, 1969. 12. Kan, V. W., Forget, B. G., and Nathan, D. G.: Gamma-beta thalassemia: A cause of hemolytic disease of the newborn. New Eng. J. Med., 286:129,1972. 13. Kleihauer, E., and Betke, K: Praktische Anwendung des Nachweises von Hb F-haltingen Zellen in fixierten Blut-ausstrichen. Internist, 6:292, 1960. 14. Lampkin, B. C., and Saunders, E. F.: Nutritional B12 deficiency in an infant. J. Pediat., 75:1053, 1969. 15. Lampkin, B. C., Shore, N. A., and Chadwick, D.: Megaloblastic anemia of infancy secondary to maternal pernicious anemia. New Eng. J. Med., 274:1168,1966. 16. Lanzkowsky, P.: Congenital malabsorption of folate. Amer. J. Med., 48:580,1970. 17. Lee, T., Wei, H., and Blackwell, R. Q.: Increased incidence of severe hyperbilirubinemia among newborn Chinese infants with G-6-PD deficiency. Pediatrics, 37:994, 1968. 18. Lockridge, S., Pass, R., and Cassady, G.: Reticulocyte counts in intrauterine growth retardation. Pediatrics, 47:919, 1971. 19. MacIver, J. E.: Megaloblastic anemias. PEDIAT. CLIN. N. AMER., 9:727, 1962. 20. Mann, D. L., Sites, M. L., Donati, R. M., et al.: Erythropoietin stimulatory activity during the first ninety days of life. Proc. Roy. Soc. Exper. BioL Med., 118:212,1965. 21. Matoth, Y., Zaizor, R., and Varsano, I.: Postnatal changes in some red cell parameters. Acta Paediat. Scand., 60:317, 1971. 22. McCue, C. M., Garner, F. B., Hurt, W. G., et al.: Placental transfusion. J. Pediat., 72:15, 1968. 23. Melhorn, D. K, and Gross, S.: Vitamin E-dependent anemia in the premature infant. 1. Effects of large doses of medicinal iron. J. Pediat., 79:569, 1971. 24. Melhorn, D. K, and Gross, S.: Vitamin E-dependent anemia in the premature infant. II. Relationships between gestational age and absorption of vitamin E. J. Pediat., 79:581, 1971. 25. Nielson, J. A., and Strunk, K W.: Homozygous hereditary elliptocytosis as a cause of hemolytic anemia in infancy. Scand. 1. Haemat., 5:486,1968. 26. O'Brien, R. T., and Pearson, H. A.: Physiologic anemia of the newborn infant. J. Pediat., 79:132,1971. 27. Oettinger, 0., Jr., and Mills, W. B.: Simultaneous capillary and venous hemoglobin determinations in the newborn infant. J. Pediat., 35:362,1949. 28. Oski, F. A., and Barness, L. A.: Vitamin E deficiency: a previously unrecognized cause of hemolytic anemia in the premature infant. 1. Pediat., 70:211, 1967. 29. Oski, F. A., and Diamond, L. K: Erythrocyte pyruvate kinase deficiency resulting in congenital nonspherocytic hemolytic anemia. New Eng. J. Med., 269:763, 1963. 30. Pearson, H. A.: Life-span of the fetal red blood cell. J. Pediat., 79:838, 1967. 31. Phornphutkul, C., Whitaker, J. A., and Worathumrong, N.: Severe hyperbilirubinemia in Thai newborns in association with erythrocyte G-6-PD deficiency. Clin. Pediat., 8:275, 1969. 32. Rausen, A. R.. Seki, Moo and Strauss. L.: Twin transfusion syndrome. A review of 19 cases studied at one institution. J. Pediat., 66:613, 1965. 33. Raye, J. R., Gutberlet, R. L., and Stahlman, M.: Symptomatic posthemorrhagic anemia in the newborn. PEDIAT. CLIN. N. AMER., 17:401, 1970. 34. Ritchie, J. H., Fish, M. B., McMasters, V., et al.: Edema and hemolytic anemia in premature infants. New Eng. J. Med., 279:1185,1968. 35. Schubert, W. K, and Lahey, M. E.: Copper and protein depletion complicating hypoferric anemia of infancy. Pediatrics, 24:710, 1959. 36. Seely, J. R., Humphrey, G. B., and Matter, B. J.: Copper defiCiency in a premature infant fed on iron-fortified formula. New Eng. J. Med., 286:109,1972. 37. Seip, M.: The reticulocyte level and the erythrocyte production judged from reticulocyte studies in newborn infants during the first week of life. Acta Paediat. Scand., 44:355, 1955. 38. Seip, M., and 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 Paediat. Scand., 45:600, 1956. 39. Shojania, A. M., and Gross, S.: Folic acid deficiency and prematurity. J. Pediat., 64:323, 1964.

ANEMIA IN EARLY INFANCY

853

40. Sisson, T. R. C., Kendall, N., Glauser, S. C., et al.: Phototherapy of jaundice in newborn infants. I. ABO blood group incompatibility. J. Pediat., 79:904, 1971. 41. Stamey, C. C., and Diamond, L. K.: Congenital hemolytic anemia in the newborn. Relationship to kernicterus. A.M.A. J. Dis. Child., 94:616, 1957. 42. Valaes, T., Karaklis, A., Stravrakakis, D., et al.: Incidence and mechanism of neonatal jaundice related to glucose-6-phosphate dehydrogenase deficiency. Pediat. Res., 3:448, 1969. 43. Woodrow, J. C., and Finn, R.: Transplacental hemorrhage. Brit. J. Haemat., 12:297, 1966. Children's Hospital of Philadelphia 1740 Bainbridge Street Philadelphia, Pennsylvania 19146