Phase IV Study of Oral Administration of Bovine Lactoferrin (bLf) to Prevent and Cure Iron Deficiency (ID) and Iron Deficiency Anemia (IDA) Until Delivery in Hereditary Thrombophilia (HT) Affected Pregnant Women

In industrialized and developing countries, iron deficiency (ID) and iron deficiency anemia (IDA) are highly prevalent in pregnant women. ID and IDA, in pregnant women as a consequence of an increased iron requirement, due to enhanced blood volume and development of fetal-placenta unit, represent a high risk for maternal and infant health: preterm delivery, fetal growth retardation, low birth weight, and inferior neonatal health. However, the degree of fetal ID is not always as severe as that in mother, being iron transfer from the mother to the fetus regulated by the placenta. In particular, the placental syncytiotrophoblast acquires ferric iron bound to maternal transferrin at the apical membrane through transferrin receptors (TfR-1), which noticeably increase in pregnant women suffering of ID and IDA. Recently, it has been suggested that most iron transfer to the fetus, occurring after the 30th week of gestation, also involves placental expression of hepcidin and ferroportin, two proteins known to modulate systemic iron homeostasis in adults. As matter of fact, iron homeostasis is tightly regulated through iron absorption, storage and transport. The absorption of nearly all dietary iron (1-2 mg daily), ensuring iron supplies in the bone marrow, at second and third trimester of pregnancy increases until to about 4 and 8 mg/day, respectively. The iron absorption takes place in the proximal duodenum and includes the following steps: (i) reduction of iron from the ferric state (III) to the ferrous state (II) by a ferrireductase (duodenal cytochrome B; (ii) apical uptake by enterocytes followed by trans-cellular trafficking via divalent metal transporter 1; (iii) storage into ferritin; and (iv) basolateral efflux by the iron transporter ferroportin. Ferroportin, the only known cellular iron exporter from tissues into blood, has been found in all cell types involved in iron export, including the enterocytes, hepatocytes, placental cells and macrophages which require ferroportin to daily recycle 20 mg of iron from lysed erythrocytes for erythropoiesis.

Another pivotal component of systemic iron homeostasis is hepcidin, a circulating peptide hormone synthesized by hepatocytes in iron loading conditions and secreted in plasma and urine. Hepcidin regulates the entry of iron into plasma through ferroportin. Hepcidin, by binding to ferroportin, causes ferroportin phosphorylation, internalization and degradation in lysosomes, thus hindering iron export and enhancing cytosolic iron storage in ferritin. Iron homeostasis disorders appear to arise from hepcidin and/or ferroportin dysregulation. Similarly to the regulation of maternal systemic iron homeostasis, fetal hepcidin controls the transfer of maternal iron across the placenta to the fetus and the enhanced placental-fetal iron transport is related to an increased expression of ferroportin on placental basal fetal-facing membrane, consistent with unidirectional mother-fetus iron transport. Even if the interaction of hepcidin with ferroportin can explain the regulation of iron homeostasis at systemic level, the influence of iron metabolism on critical stage of fetal development, is still unknown.

Regulation of hepcidin expression seems to occur at transcriptional level and its production is increased by iron loading and inflammation and decreased by anemia and hypoxia.

Even if the molecular mechanisms of hepcidin regulation by iron, oxygen and anemia are still unclear, it is known that Interleukin 6 (IL-6) induces transcription of the hepcidin gene in hepatocytes. In inflammatory and infection disorders, cytokine induced hepcidin excess, through ferroportin binding, contributes to development of anemia of inflammation, characterized by ID and IDA despite adequate iron stores. When iron export is hindered, iron is stored in host cells. However, inflammation may contribute to ID and IDA by hepcidin-independent mechanism(s) as the down-regulation of ferroportin. Independently on hepcidin synthesis, high levels of serum IL-6 seem to down-regulate ferroportin mRNA expression, thus sequestering iron inside cells and blocking iron flow into plasma. The inability to export iron leads to hypoferremia, decreased pool of serum transferrin-Fe(III) and iron-limited erythropoiesis.

The recent discovery of hepcidin-ferroportin complex has greatly contributed to clarify the enigmatic mechanism of systemic iron homeostasis. Notwithstanding, iron homeostasis disorders, as ID and IDA, are still treated with oral administration of large quantity of iron as fer¬rous sulfate due to its poor bio-availability. Ferrous sulfate oral administration often fails to exert significant effects on ID and IDA, and frequently causes many adverse effects, including gastrointestinal discomfort, nausea, vomiting, diarrhea, and constipation.