Bovine Lactoferrin to Prevent and Cure Iron Deficiency and Iron Deficiency Anemia in Complicated Pregnancies
Condition: Pregnancy; Iron Deficiency; Iron Deficiency Anemia
MeSH terms: Anemia; Anemia, Iron-Deficiency; Iron Deficiencies; Deficiency Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to determine whether bovine lactoferrin is effective in
      preventing and curing iron deficiency and iron deficiency anemia in Hereditary Thrombophilia
      affected women during pregnancy.

      The proposed clinical trial is considered as PHASE IV because in Italy bLf is commercialized
      by Grunenthal, as Lattoglobina® (capsules with 100 mg of bLf), to prevent and cure iron
      deficiency and iron deficiency anemia in pregnant women.
    

Detailed description: 
      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.

      Recently, a significant decrease of total serum iron and serum ferritin concentrations
      related with an increase of serum IL-6 concentration has been observed in pregnant women and
      in hemodialysis patients, orally treated with ferrous sulfate. Therefore, it can be
      hypothesized that supplemented iron was not exported from cells to circulation, but it was
      accumulated inside the cells, thereby increasing inflammatory status, similarly to that
      reported in animals treated with ferrous sulfate.

      The weight of evidences, which let to doubt on the efficacy and safety of ferrous sulfate
      oral administration, has stimulated the research of more effective approaches to prevent ID
      and toxicity associated with iron overload. The treatment of ID and IDA during pregnancy
      should be entirely reconsidered taking into account not only the enhanced blood volume and
      development of fetal-placenta unit, but also other factors, as IL-6, which, inducing hepcidin
      up-regulation and ferroportin down-regulation, can play a pivotal role in iron homeostasis
      disorders.

      For this purpose, lactoferrin (Lf), a cationic iron-binding glycoprotein, able to chelate at
      high affinity (KD w10/20 M) two ferric ions per molecule (30), is emerging as an important
      regulator of systemic iron homeostasis, able to cure ID and IDA. Lf is synthesized by
      exocrine glands and neutrophils in infection and inflammation sites. In humans, free iron
      does not exceed 10-18 M to avoid precipitation, microbial growth and formation of reactive
      oxygen species. Lf in tissues and secretions and transferrin in blood assure that iron was
      bound and scarcely available as free-ion.

      Even if several functions, dependent and independent on its iron binding ability, have been
      attributed to Lf, our recent clinical trials have demonstrated that this natural compound may
      represent an interesting approach in the therapy for ID and IDA in pregnant women. As matter
      of fact, a milk derivative bovine lactoferrin (bLf) restores the physiological transport of
      iron from tissues to circulation, thus curing ID and IDA. Moreover, differently from ferrous
      sulfate, bLf oral administration exerts an anti-inflammatory effect by decreasing serum IL-6
      concentration in uncomplicated pregnancies.

      The hypercoagulable state represents one of the physiological changes occurring during
      pregnancy. The hereditary thrombophilia (HT), a genetic predisposition to inappropriately
      form clots, significantly increases adverse outcomes including recurrent miscarriages,
      intrauterine fetal death and growth retardation, preeclampsia and placental abruption. It is
      well known that inflammation promotes coagulation and IL-6 high levels in plasma of HT
      affecting pregnant women with severe preeclampsia have been found. Moreover, elevated
      intra-amniotic IL-6 and IL-8 levels have been correlated to preterm birth.

      Therefore, iron supplementation via oral administration of ferrous sulfate increasing serum
      IL-6 levels in uncomplicated pregnancies, could be deleterious in HT affecting pregnant women
      and could contribute to enhance iron overload in tissues, inflammation and cell damages.

      The bLf capability to prevent and cure ID and IDA together with its ability of decreasing
      serum IL-6 concentration could be effective even in the treatment of ID and IDA in pregnant
      women affected by HT.

      In this clinical trial, pregnant women affected by hereditary thrombophilia (HT), suffering
      of ID and IDA, receive an oral administration of bovine Lf (bLf) 100 mg/twice a day or
      ferrous sulfate 520 mg/day. The number of red blood cells, the values of hemoglobin, total
      serum iron, serum ferritin, haematocrit, serum Interleukin-6 (IL-6) and prohepcidin are
      assayed before therapy, every 30 days until delivery.
    

Intervention name(s): Lattoglobina (Grunenthal) containing bLf; FerroGrad by Abbott
Intervention type(s): Dietary Supplement; Drug
Intervention description(s): One capsule of Lattoglobina contains 100 mg of bLf. Dosage: one capsule twice a day before meals. In twin pregnancy or in severe anemia the dosage is increased to 2 capsules twice a day before meals; Dosage: one tablet/day containing 540 mg of ferrous sulfate during meals
Other intervention name(s): Commercialization by Grunenthal Italy; Manifacture by Giellepi; Licence Microbo srl, Rome, Italy; FerroGrad; Abbott
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lactoferrin; Pregnancy; Hereditary Thrombophilia; Iron deficiency; Iron deficiency anemia