Fetal and Neonatal Iron Metabolism

Introduction

Iron is the fourth most abundant element and constitutes approximately 0.0075% of human body composition. It is a cofactor in some of the most basic biologic reactions, yet its beneficial effects are tempered by the fact that iron can be highly toxic, particularly in its unbound state since it participates in the generation of reactive oxygen species (ROS). An average normal newborn has a total body iron content of 75 mg/kg body weight, 55 mg/kg of which is complexed in hemoglobin. In addition to its predominant role in erythropoiesis, iron is important for normal growth and function of all rapidly developing organ systems. An important principle of iron biology is that rapidly dividing cells require more iron to support their metabolism. Thus the rapidly growing fetus and neonate has higher iron requirements on a body weight basis than do older children and adults.

The clinical signs of iron deficiency are highly variable because iron-containing proteins are important in many facets of human biology. These processes include cellular energetics, DNA replication, tissue oxygenation, neurotransmitter synthesis, maintenance of thyroid status, white cell function, and fatty acid synthesis. The signs and symptoms of iron deficiency result not only from the hypoxia of anemia but the effect of tissue-level iron deficiency in the heart, skeletal muscle, gastrointestinal tract, and brain.

Negative iron balance occurs most commonly during three time periods in child development: the late fetal–early neonatal period (up to 6 months postnatal age), 6 to 24 months of age, and the teenage years. The acute clinical effects and long-term hematologic and nonhematologic sequelae of iron deficiency in the fetal and neonatal period have received intense study in the past 15 years. The previous lack of investigation in this field was a consequence of the misperception that neonatal iron deficiency occurs only secondary to severe maternal iron deficiency. The incidence of fetal iron deficiency anemia as a consequence of maternal iron deficiency anemia is relatively low in high-income countries because most mothers are supplemented with iron during pregnancy and because of prioritization of iron to the fetus by active placental iron transport (see further on). Nevertheless, the rate of maternal iron deficiency with or without anemia in high-income countries is 40% to 50%. The rate approaches 80% among mothers in low- and middle-income countries. Maternal iron deficiency during pregnancy is associated with an increased risk of adverse pregnancy outcome as defined by increased rates of prematurity and intrauterine growth failure. Moreover, a relatively high incidence of reduced iron stores and frank iron deficiency has been found in specific groups of infants born to otherwise iron-sufficient mothers. Iron deficiency in these groups is due to reduced placental iron transport (e.g., maternal hypertension or cigarette smoking) or to increased fetal iron demand that exceeds the capacity of placental iron transport (e.g., maternal glucose intolerance).

Iron overload is also a potential in the fetus and neonate. This condition is rarely due to nutritional iron overload but can result from excessive red cell transfusions, congenital hemochromatosis, or reperfusion injuries. Iron overload of any cause is dangerous because free iron reacts with oxygen to create ROS. Iron overload has been proposed to play a role in neonatal diseases characterized by oxidative injury such as bronchopulmonary dysplasia, necrotizing enterocolitis, and retinopathy of prematurity. ^,

This chapter begins with a review of the biochemistry of iron-containing proteins, their biologic functions, and the regulation of cellular iron accretion. The subsequent discussion of fetal iron balance emphasizes the mechanisms of maternal-fetal iron transport with particular attention to the relative contributions of maternal and fetal iron status to regulating placental iron transport proteins. The section on postnatal iron balance addresses the various sources of iron and the overall iron requirements of term and preterm infants. Finally, the potential physiologic consequences of fetal and neonatal iron deficiency and iron excess are discussed.

General Principles of Iron Metabolism