Evaluation of Antioxidant Activity of Oral Lutein in Preterm and Term Newborn
Condition: Infant, Newborn, Diseases; Other Lipid Storage Disorders
MeSH terms: Infant, Newborn, Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The balance of the redox state is important for normal embryonic and fetal development .
      During the perinatal period, a variety of conditions are responsible for an excessive
      production of free radicals. The following oxidative stress is exacerbated by a lack of
      antioxidant substances that have not yet matured. At the moment there are no therapeutic
      strategies with single or combined antioxidants that have been shown to be clinically
      effective.

      Breastfeeding is important for the contribution of the antioxidant defenses of the newborn
      and the nutritional status of the mother plays a key role because it influences the
      nutritional status of the newborn. Lutein is a carotenoid that is not produced by the body ,
      but taken with food or supplements. The molecule carries out different activities :
      antioxidant, anti-inflammatory, anticancer , neuroprotective. Its main activity of inhibition
      of peroxidation of membrane lipids is peculiarly important for the photoreceptors and neurons
      whose membranes are rich with polyunsaturated fatty acids. Current evidence on its role as an
      antioxidant indicate that supplementation with lutein may play a significant role in the
      prevention of free radical disease in the newborn
    

Detailed description: 
      In recent years many scientific studies demonstrated that lutein, a nutrient belonging to the
      family of carotenoids, may constitute a valid and important preventive and protective factor
      against a large number of chronic diseases affecting millions of people around the world .
      Studies from literature highlight and confirm that lutein is able to reduce the risk of
      developing some ocular diseases or slow down their progression. Lutein is a fat-soluble
      derivative of polar hydroxylated xanthophyll which belongs to the family of carotenoids.
      Carotenoids are linear polyenes, ie double bonds conjugated hydrocarbons containing 40 atoms
      of carbon. Today there are 35 known carotenoids that are ingested, absorbed, metabolised and
      found in human serum. Lutein is the most important corotenoid and it is only in the retina,
      in the macula and in the lens. In tissues and serum lutein is found together with its isomer,
      the zeaxanthin. Lutein, commonly ingested with other foods, is partially eliminated directly
      in the faeces (50-90%) and partially absorbed with fatty foods. It is incorporated into
      chylomicrons reaching the blood where it binds some lipoprotein and thanks to its fat
      solubility it reaches different organs: liver, breast, colon, cervix, lens, iris and the
      retina where it is concentrated in the central region: the macula. Inside cells Lutein is
      placed through the lipid bilayer binding its polar groups with those of cell membranes.
      Lutein and zeaxanthin are present in the umbilical cord and pass through the placental
      barrier. They are also found in high concentrations in breast milk (higher than in plasma),
      particularly in colostrum; indicating an active secretion in milk. The rates of lutein in
      blood increases of 67% versus 14% for beta-carotene after the intake of foods rich in
      carotenoids. Coordinated and interdisciplinary studies, conducted both in vitro and in vivo,
      have shown that lutein plays a role in tissues defense through a functional mechanisms using
      the phenomenon of deactivation (quenching) of singlet oxygen and of reactive oxygen species
      (ROS). This action gives the molecule different activities: antioxidant and anti-inflammatory
      properties, promotion of anti-carcinogenic effects, induction of detoxifying enzymes and
      promotion of proteins with a positive effect on the junctional communication (up-regulation).
      New chemical and experimental data show that oxidative stress and harmful effects of ROS may
      play an important role in the pathogenesis of some neurological diseases like Alzheimer,
      Parkinson, etc.. This could be explained by the fact that the central nervous system is
      characterized by membranes rich of polyunsaturated lipids that are the first target of ROS
      attack (lipid peroxidation). A similar mechanism may occur in some ocular tissues (macula,
      lens, retina), which are more vulnerable than other tissues to oxidative damage being
      particularly rich in polyunsaturated fatty acids. The photo-protective action seems to be
      predominant in the iris, while in the retinal pigment epithelium may operate both light
      filtering and antioxidant mechanisms. The development of the human eye includes a complex
      series of consecutive events beginning with the first differentiation of the fertilized egg
      cell and continuing after birth until the first years of life. The eye of the newborn,
      although smaller than that of adults, has a well developed and mature dioptric apparatus,
      consisting of cornea, aqueous humor, lens and vitreous, transparent structures that allow the
      passage of light and focus images on the retina. Contrariwise the macula and its central part
      (fovea), useful for vision and color discrimination, are not yet mature at birth. The full
      development of the fovea occurs only after the 4 / 5 month of life. This process along with
      the development of more sensitive ways, gives to the child a greater resolving power and a
      distinct vision. The partial pressure of blood gases that regulates blood flow to the retina
      has the same importance. Indeed oxygen consumption by the retina is constant and a defect or
      an excess of this gas can be highly detrimental for the natural development of retinal
      structures. An example of the importance of oxygen partial pressure in regulating retinal
      blood flow is represented by retinopathy of prematurity (ROP), an usually bilateral
      condition, affecting the immature retinal vessels. ROP has been one of the major cause of
      blindness in infants in the past. Nowadays the use of oxygen concentrations based on the
      levels of its partial pressure in the arterial blood, has reduced the incidence of
      retinopathy. The vascularization of the retina begins on the 4th month of gestation. The
      vessels progress from the center to the periphery, reaching the nasal area at the 8th month
      and the temporal at the 9th month of intrauterine life. In the retinopathy of prematurity,
      the development of retinal vasculature is impaired because the increase in PA02 levels leads
      to an arteriolar vasoconstriction and to the obliteration of the newly formed capillaries.
      Consequently the mesenchyme stops to proliferate, forming a marginal tissue. The arteries and
      veins of this margin does not drain their blood in capillaries, but in small arteriovenous
      anastomosis forming shunt. The endothelium of these new vessels is also very permeable
      because it is immature and incomplete. The capillary bed of the shunt is largely obliterated,
      and this causes anomalies of pressure responsible of dilation and tortuosity, microaneurysms,
      neovascularization and resulting in exudative and haemorrhagic phenomena with the possibility
      of developing vitreous traction and retinal detachment. This represents the active phase of
      the disease, which often regresses spontaneously, and the magnitude of which depends on the
      precocity of hyperoxia. The evolution could be the regression, the scarring, or more
      frequently, a combination between the two. During pregnancy, the percentage of fatty acids in
      maternal plasma increases to 51%. The polyunsaturated fatty acids are significantly prone to
      oxidation, the changes in their plasma levels affect the status of the antioxidant systems in
      pregnant and consequently in the newborn. Several studies reported that the increased
      susceptibility to peroxidation of polyunsaturated fatty acids in pregnancy is accompanied by
      an equivalent increase in plasma tocopherol levels but its level decreases dramatically
      immediately after birth. Plasma antioxidant levels of the newborn were found lower if
      compared with those of the mother. Tocopherols and carotenoids levels are significantly lower
      in the umbilical cord than those recorded in maternal plasma and the concentration of
      polyunsaturated fatty acids in the newborn is higher than that of the mother. Many scientific
      studies have also shown an increasing interest in oxidative stress and reactive oxygen
      species that accumulate after birth. OS is assessed by the quantification of thiobarbituric
      acid reactive species (TBRS) in plasma. TBRS levels were significantly increased in premature
      infants after the exposure to blue light for 96 hours. Studies on premature infants have
      shown a correlation between low plasma levels of antioxidants and an increased risk of
      free-radical relates diseases. Therefore it could be useful to increase antioxidant defenses
      in infants in order to restore the redox unbalance and to prevent the damage caused by a
      prolonged exposure to high levels of free radicals and reactive oxygen species. Oxidative
      stress is considered one of the main determinants of retinal damage as in age-related
      diseases. A proper balance between oxidant and antioxidant factors may help to prevent or
      reduce eye damage that can occur in newborns, especially in preterm infants, such as ROP.
      Indeed preterm babies are often exposed to potentially harmful concentrations of oxygen due
      to respiratory problems or undergo phototherapy with high intensity blue light. These
      therapies are sources of free radicals. Lutein and zeaxanthin in the macular pigment, may
      play an important role in protecting the eyes of the newborn from the damage of light thanks
      to their ability to absorb blue light and their antioxidant action. Lutein increases macular
      pigment density and can protect through two synergistic mechanisms: the absorption of blue
      light before it reaches the sensitive retinal structures, namely the photoreceptors inducing
      a photochemical damage, the quencing effect that determines the neutralization of singlet
      oxygen and of other free radicals.

      There are many evidences that suggest a protective effect of lutein against photo-oxidation
      damage in adult (Leeuwen 2006, AREDS 1, AREDS 2).

      Lutein and zeaxanthin are present in the umbilical cord and several studies have shown that
      there is a direct correlation between mother and newborn plasma levels of lutein. Lutein is
      also present in breast milk in concentrations three times higher than other carotenoids with
      the same plasma concentrations. There is also a correlation between plasma levels of lutein
      in the mother and levels in the breastfed infant. Studies on infants have shown that
      carotenoids levels in the first four/six months of life are very low. This is probably due to
      the fact that the infants diet is entirely made of milk without solid foods (such as green
      leafy vegetables) sources of this nutrient. Children breastfed have higher lutein plasma
      levels than children fed with formula milk. The different types of formula milks are
      currently not enriched with these carotenoids and their content of both lutein and zeaxanthin
      is very low, except for some formulations which are prepared using egg homogenate but they
      are not sold in Italy. Breast milk is therefore the only source of lutein for infants before
      the weaning, and the breastfeeding is very important as a primary source of these nutrients
      for the proper development and protection of the vision. Considering the correlation between
      lutein content in plasma and in breast milk and the lowering of lutein levels in milk already
      six days after birth, it is really important to take foods rich in lutein during lactation. A
      diet enriched with lutein is especially important for mothers of premature or low birth
      weight newborns. Indeed the premature and underweight children need many nutrients essential
      for a rapid growth because they did not receive highly nutritious elements and energy
      transferred from the mother during the last weeks of gestation. Moreover, their
      gastrointestinal and renal functions are not fully developed and this could reduce the
      absorption and retention of some micronutrients including important antioxidants that protect
      the infant from exposure to high levels of free radicals produced in excess at birth and
      often as a result of the resuscitation technics used. Breastfeeding is important for the
      intake of antioxidant defenses in the newborn and the nutritional status of the mother plays
      certainly a key role because it affects the nutritional status of the infant, and especially
      the status of some soluble nutrients such as lutein and zeaxanthin. The preparations of
      lutein and zeaxanthin have never had gastrointestinal or systemic toxic effects in humans
      after supplementation. In recent studies, no adverse effects after administration of 20
      mg/day of lutein or zeaxanthin administered for 6 months or interactions with other
      fat-soluble nutrients were reported.
    

Intervention name(s): Lutein drops; Glucose drops
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): After randomisation, the infant received orally a total dose of 0.28 mg of lutein in two doses: within 6 hours after birth and at 36 hours of life; After randomization, newborns received 0.5 mL of 5% glucose solution in two doses: within 6 hours (hrs) after birth and at 36 hrs of life.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention