Neonatal anemias, when and why do they occur?

Anemia is defined as a decrease in the concentration of hemoglobin (Hb) in the blood. It is measured in grams of hemoglobin per liter of blood (g/L) and normal values during the neonatal period vary widely, making interpretation sometimes difficult. In practice, three aspects should be taken into account:

1. In a newborn (NB) at term the hemoglobin value is usually around 160 g/l.
2. During the first month of life this value decreases significantly to 130/150g/l.
3. After six months the hemoglobin value stabilizes at around 120g/l, so that the lower limit of normality until the child is between 12 and 15 years old is 110g/l.

Can a baby suffer from anemia and what type of anemia will it be?

A newborn baby may be anemic but it is usually due to benign causes such as physiologic anemia, which is normal and does not require extensive evaluation and treatment. Physiological anemia is more common in premature infants and is due to the fact that normal breathing after birth causes a sudden increase in the concentration of oxygen in the tissues and a decrease in the hormone that stimulates the formation of red blood cells or erythropoietin (Epo). As a result, the red blood cell concentration decreases.

What other causes can lead to neonatal anemia?

Apart from physiological anemia, there are three other causes of neonatal anemia:

1. Hemorrhage

Hemorrhage can be prenatal (before birth), perinatal (during delivery) or neonatal (after delivery). When the newborn presents with chronic blood loss there may be a physiologic compensation of anemia that is barely evident and goes unnoticed on conventional clinical examination. However, when the hemorrhage is acute and relatively intense it is usually easily appreciated because the infant presents with pallor of the skin and mucous membranes, increased heart rate, and rapid and shallow breathing.

The most common cause of prenatal and perinatal anemia is feto-maternal hemorrhage, which usually occurs spontaneously or as a result of maternal trauma, amniocentesis, external cephalic version or placental tumors. It occurs in approximately 50% of pregnancies but, in most cases, goes unnoticed because the volume of blood lost is small (about 2 ml). Clinically significant hemorrhage, defined as a blood loss of more than 30 ml, affects 3 out of every 1,000 pregnancies.

Other less frequent causes of prenatal or perinatal anemia are placental anomalies, especially placenta previa and placental abruption. During the neonatal period or shortly after birth the causes of anemia may be diverse but their clinical appreciation depends on the intensity of the anemia so that, in some cases, they may also go unnoticed clinically. Among the most frequent causes are umbilical cord tearing, obstetric accidents and coagulation disorders. Among the latter, hemorrhagic disease of the newborn due to vitamin K deficiency stands out. This is a type of hemorrhage that appears a few days after a normal delivery due to a physiological and transitory deficiency of vitamin K-dependent coagulation factors (II, VII, IX and X). These factors are poorly transferred through the placenta and, as vitamin K is synthesized by intestinal bacteria, its synthesis is very scarce because the newborn’s intestine is sterile. This is why vitamin K supplementation is advised after birth. Other coagulation defects that can cause bleeding in the first days of life are hemophilia (factor VIII deficiency), von Willebrand factor deficiency and disseminated intravascular coagulation caused by bacterial infections (septicemia) or vascular malformations.

2. Defects in red blood cell production

Red cell production defects are due to bone marrow disorders that prevent the formation or maturation of red cell precursor cells or erythroblasts. There are congenital and acquired forms.

Congenital forms are almost always seen during the neonatal or perinatal period, and their clinical manifestations last a lifetime. The best known are:

• Blackfan-Diamond anemia. It is characterized by the virtual absence of erythroblasts in bone marrow and reticulocytes in peripheral blood (
• Fanconi anemia. It is considered an autosomal recessive disorder of the pluripotent stem cell that affects the three lines of hematopoietic differentiation, with predominance of the erythropoietic or red cell-forming lineage. Therefore, its main clinical manifestation is macrocytic anemia (MCV>98 fl) and the virtual absence of reticulocytes (
• Pearson’s syndrome. This is a very rare multisystemic disease due to mitochondrial defects that cause iron accumulation in the mitochondria and intense anemia (sideroblastic anemia), which is resistant to any treatment. This anemia is usually accompanied by leukopenia and/or plateletopenia (pancytopenia) and various systemic insufficiencies: hepatic, renal and pancreatic.
• Congenital Dyserythropoietic Anemia (CDA). It is the most frequent form of hereditary chronic anemia due to a defect in the differentiation and maturation of erythroblasts. As a result, red blood cell production is inefficient (ineffective erythropoiesis) because the vast majority of erythroblasts fail to mature into red blood cells and die in the bone marrow itself (marrow abortion). In CDA, ineffective erythropoiesis is accompanied by significant alterations in erythroblast morphology or dyserythropoiesis and the anemia, usually significant, is almost always macrocytic (MCV>98fl). CDA is due to mutations of genes of the erythropoietic lineage, the study of which is used to make the diagnosis.

Acquired forms are more typical of early childhood or adolescence, with the exception of the following situations:

1. Parvovirus B19 viral infection, which results in a disappearance of erythroblasts or mature red cell precursors and, with it, intense anemia with disappearance of circulating reticulocytes. This situation is generally transitory and disappears spontaneously.
2. Rh incompatibility due to sensitization of Rh (D antigen) positive fetal red blood cells when the mother is Rh (D antigen) negative. Thus, when Rh (antigen) positive fetal red blood cells enter the maternal circulation during the first pregnancy, the production of lgG antibodies against them is stimulated. This means that when the mother has a second pregnancy with an Rh-positive fetus, the sensitization acquired in the first pregnancy is manifested and the lgG antibodies destroy the red blood cells of the fetus, giving rise to neonatal hemolysis, generally severe, known as erythroblastosis fetalis. Sometimes intrauterine hemolysis is severe enough to cause infant death, and therefore maternal desensitization by administration of anti-Rh D serum is very important in these cases. Less frequently, ABO incompatibility (or other antigens) may also occur, causing hemolysis by a similar mechanism. ABO incompatibility is usually less severe than Rh incompatibility, as the initial lgM antibodies remove fetal blood cells from the maternal circulation before sensitization can occur.
3. Intrauterine infections, which can be bacterial or viral, although it can also be triggered by fungi or plasmodium falciparum, which is the malaria parasite.

3. Defects in the components of the red blood cell

These defects are mostly due to congenital causes that alter the fundamental components of the red blood cell, which are hemoglobin, membrane and metabolic enzymes, but they can also have an acquired origin where the alteration of the red blood cell components is due to vascular disorders (microcirculation), alterations of the immune system (autoantibodies) or infections that damage the red blood cell (malaria). Congenital or acquired alterations of the structural components of the red blood cells are always the cause of their premature elimination by the spleen or hemolysis, which is usually accompanied by an increase in plasma bilirubin and jaundice.

Unlike red cell formation defects in the bone marrow, defects in red cell components, both congenital and acquired, are usually diagnosed months after birth, i.e., during childhood or adolescence, something that will be explained in the next article on anemias in these life stages.