Albertine Donker

General Introduction 25 1 DEVELOPMENTAL ASPECTS OF IRON HOMEOSTASIS Iron homeostasis in early life is fundamentally different from iron homeostasis later in life As stated above, the key hormone hepcidin and the IRE/IRP system collaborate on the systemic and cellular level, respectively, in order to precisely adjust body iron amounts to the needs of the human individual. However, iron homeostasis during the fetal period and infancy differs from iron homeostasis later in life. 57,58 Optimal iron status in utero is essential for the development of the fetus and helps establish birth iron stores that are adequate to sustain growth in early infancy. Consistent with the situation in adults, the majority of the iron in the fetus is dedicated to the production of erythrocytes. However, iron in utero is also crucial for processes involving brain development as neurotransmitter production, neuronal energy metabolism and myelinisation. 59,60 Therefore, ID in the human fetus and infant is associated with a number of short-term and long-term neurodevelopmental deficits that persist after repletion of iron stores because of critical iron-dependent gestational windows during central nervous system development. Approximately 80% of fetal iron accrues in the last trimester of pregnancy by active placental transport from the mother to the fetus. 61 Under most circumstances, maternal iron status modulates the expression of placental iron transporters in favor of the fetal demands. However, evidence exists that the regulatory system can no longer sustain sufficient transfer of iron from the mother to the fetus in case of severely exhausted maternal iron status, resulting in fetal ID. 62-64 The systemic and local mechanisms that sense and regulate placental iron transport are largely unknown, and the possible role of maternal and/ or fetal hepcidin in prenatal iron metabolism still needs clarification. 61,64-68 Also, the molecular pathways of iron trafficking in the placenta on the cellular level are still poorly understood. 65,67,68 Maternal iron status accounts for 6% of the variants in infant iron stores at birth, and the remaining causes of the highly variable size of birth iron endowment are not known, but likely include gestational age, intrauterine growth restriction, time of cord clamping, maternal smoking habits and diabetes. 69 After the fetus has been born, iron demands remain high to meet the large quantities needed for the rapid growth of the newborn (15-20 mg/kg/day), the accompanying increase in circulating blood volume and the ongoing development of the neonatal