Early Administration of the Lutein/Zeaxanthin in Premature Newborns
NCT ID: NCT03340103
Last Updated: 2020-11-02
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
WITHDRAWN
Clinical Phase
NA
Study Classification
INTERVENTIONAL
Study Start Date
2018-10-11
Study Completion Date
2019-10-11
Brief Summary
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Premature birth is the most common cause of mortality, morbidity and disability. Premature infants have a higher risk of developing damage in the eyes (retinopathy of prematurity ROP), in the central nervous system (intraventricular hemorrhage IVH), in the lungs (bronchial pulmonary dysplasia BPD), in the gut (NEC) and infections. Oxidative stress has been implicated in various capacities, in the etiology of these conditions. Lutein and Zeaxanthin are powerful anti-oxidants and commonly assimilated with different foods. Lutein and Zeaxanthin are present at level of umbilical cord, in the breast milk (particularly in colostrum) and pass the placental barrier. Concerning supplementations, the lutein presents, for its specific characteristics, a high bioavailability after oral administration. In the last few years, there have been more and more studies which have shown that lutein could constitute a valid and important preventive and protective factor against certain diseases related to oxidative stress. The preparations of lutein and zeaxanthin have never pointed out in the human being (included in the term newborn) adverse or toxic effects. This spontaneous / non-commercial pilot study involves the administration of a dietary supplement containing lutein / zeaxanthin, because the healthcare structures need to identify a natural antioxidant product that can reduce the incidence of serious diseases related to oxidative stress in the perinatal period. This study aims to evaluate if the administration of lutein in watery solution will reduce the rate of free radicals in preterm infants.
Detailed Description
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Lutein is the most important carotenoid present selectively in certain tissues of the human body, mainly at the level of the retina, macula (hence the name) and lens. In tissues and serum, lutein is found together with a carotenoid dihydroxide, its isomer, zeaxanthin. Lutein and zeaxanthin are present at the level of the umbilical cord and pass through the placental barrier and are also present in the plasmatic ones, in breast milk and especially in the colostrum. Concerning the way of administrating, the lutein presents, through its specific characteristics, an elevated bioavailability after oral administration. The hematic levels of lutein, after providing nutriments rich in carotenoids, are increased with 67% from the 14% observed at beta-carotene. Through interdisciplinary and coordinated studies, performed both in vitro and in vivo, there were identified different action mechanisms; particularly, investigators have demonstrated a defense mechanism of the tissue function by lutein, which is produced through the neutralization (quench) phenomenon of the singlet oxygen and reactive oxygen species (ROS). This action provides molecules with different activities: an antioxidant function, anti-inflammatory properties, properties which promote anti-tumoral effects, induction of detoxification enzymes and positive effect on proteins promoting the communication between joints (up-regulation). Recently, there have appeared experimental and chemical data proving that the oxidative stress and harmful actions determined by ROS can play an important role in the pathogenesis of many neurological diseases as Alzheimer, Parkinson in adult and ROP and NEC in newborns.
This is due to the fact that the nervous system is characterized by membranes rich in polyunsaturated fats, the first cellular compounds affected by ROS attack through the lipid peroxidation. A similar mechanism can appear to certain ocular tissues (macula, lens, retina) which, containing high amounts of polyunsaturated fat acids, are more vulnerable than other structures with oxidative degradations induced by ROS.
Due to the fact that carotenoids are amongst the most powerful antioxidants existing in nature, there are being developed new researches concerning the functional role of these substances in preventing neurodegenerative diseases in newborns.
Because these polyunsaturated fat acids are very sensitive to oxidation, the modification of their plasmatic levels influences the state of the antioxidant systems on the mother and subsequently to the foetus. Many studies have proved that the increase of the susceptibility to the peroxidation of polyunsaturated fat acids on pregnant women is accompanied by an equivalent increase of the tocopherol plasmatic concentration which, immediately after birth, decrease sharply.
The plasmatic concentrations of the newborns' antioxidants were lower than those of the mothers. In the umbilical cord, the levels of tocopherols and carotenoids are significantly lower than the ones registered in the maternal plasma and the concentration of polyunsaturated fat acids on the newborn is significantly higher and a lot more increased than on the mother.
Furthermore, specific studies showed a growing interest towards the oxidative stress and oxygen reactive species which supposedly accumulate after birth. Many practices usually used in the delivery room (for example the drugs given to pregnant woman to ease her pain, the newborns' extraction methods, the techniques to minimize body temperature decrease, blocking the umbilical cord and especially the use of oxygen to 100 % or a ventilated room for newborns presenting asphyxia signs) do not always prove to be efficient and can also compromise the health of the newborn because of a significant increase of free radicals.
Some specific studies have compared the levels of free radicals, highlighted with markers, in the plasma of the umbilical cord of newborns with asphyxia treated 100% with oxygen or 21% with oxygen, comparative to a control group of children without asphyxia. The levels of free radicals were significantly increased immediately after birth in all three groups and grew in the two groups of newborns with asphyxia. In the group treated 21% with oxygen, these values decreased and have reached the same level of the newborns without asphyxia at 28 days after birth, whereas at the group treated 100% with oxygen the levels of free radicals remained very high.
Thus, a short exposure of the newborn to 100% oxygen is the cause of an extended oxidative stress state and a consistent increase of free radicals, which seem to be involved in different diseases and pathologies during the first months of life, especially in the preterm infant increasing significantly the incidence of ROP, IVH, BPD, NEC and infections.
These results show that the newborn need to increase the level of antioxidant protection to establish the redox balance and to prevent the problems occurred from an extended exposure to high levels of free radicals and oxygen reactive species.
The premature birth is the most frequent cause of mortality, morbidity and disability. Premature babies have an extremely high risk to develop ocular or neurological lesions. The main complication at visual level that may appear is called retinopathy of prematurity, so called ROP. Oxidative stress is involved in the etiology of this disease. In fact, premature babies, because of respiratory issues, are often exposed to potentially damaging oxygen concentrations or to phototherapy with high blue light intensity. These therapeutic practices are sources of free radicals.
The studies performed on the babies showed that the levels of carotenoids in the first four / six months of life are much reduced. This is due to the fact that the baby's diet is based exclusively on milk, without any solid elements (as vegetables or green leaves), sole sources of this nutrient. Nevertheless, breastfed babies, in average, present high plasmatic lutein levels than babies fed with prepared milk. Different milk formulas for newborns found at present time on the market are not enriched with this type of carotenoids, thus their content of lutein and zeaxanthin is very low, except certain formulas which are not traded in Italy and prepared using egg mixes. Breast milk, is thus the only source of lutein for the newborn before weaning, and breast feeding proves to be of considerable importance as primary source of these micronutrients for the newborn, proper development and visual function protection. Taking into consideration the correlation between the lutein in the blood and breast milk and the reduction of its levels, similar to all carotenoids, in milk, after 6 days from birth, there is already an important contribution of nutriments high in lutein during breast feeding. Such diet enriched in lutein is particularly important especially for the mothers of premature babies or babies having a small body weight when born. In fact, premature babies and underweight babies need more nutritive essential substances for a fast grow. These babies have not benefit from the contribution of highly nutritive and energetic substances transferred from their mothers during the last weeks of pregnancy. Also, the gastrointestinal and renal functions which are not completely developed reduce the absorption and withhold of important micronutrients, amongst which important antioxidants that protect the newborn from the exposure to high level of free radicals produced excessively at birth and several times as a result of the resuscitation techniques used. Breast feeding is important for the antioxidant contribution to the protection of the newborn and the nutritional state of the mother has subsequently an essential part because it influences the nutrition of the newborn, especially concerning certain solvable nutritive elements, such as lutein and zeaxanthin.
In the literature are already present researches and results with the use of lutein / zeaxanthin in the newborn.
The recent Gong's work has evaluated the role of lutein / zeaxanthin comparing the data obtained from various studies, including those of Romagnoli, Dani and Manzoni. Furthermore, thanks to RCT analysis of Rubin on the subject, investigators concluded that lutein / zeaxanthin is well tolerated and well absorbed from preterm infants also after oral administration.
The extremely interesting result that has emerged although not statistically significant (probably due to the small sample) is that supplementation with lutein / zeaxanthin reduced the incidence and severity of ROP.
This protocol is born from the idea that given the interesting results of earlier work is considered important to deepen a dosage of at least 1 ml / kg equal to 0,5 mg of lutein and 0.05 mg of zeaxanthin.
The evaluation of the key markers for oxidative stress is necessary along with the study of the biological antioxidant potential (BPT) and total hydroperoxide (TH) during and after treatment.
Already in a previous work, S. Perrone and M. Longini have demonstrated a reduction of the free radicals in term infants, during and after administration of lutein / zeaxanthin by determination of the BTP and TH.
Preparations based on lutein and zeaxanthin have never revealed on humans negative or harmful effects after administration, or to the gastrointestinal or systemic level. In recent studies there were not reported adverse phenomena after administrating 20 mg/day of lutein or zeaxanthin for a period of 6 months, or interactions with other liposoluble nutritive elements.
This is due to the fact that the nervous system is characterized by membranes rich in polyunsaturated fats, the first cellular compounds affected by ROS attack through the lipid peroxidation. A similar mechanism can appear to certain ocular tissues (macula, lens, retina) which, containing high amounts of polyunsaturated fat acids, are more vulnerable than other structures with oxidative degradations induced by ROS.
Due to the fact that carotenoids are amongst the most powerful antioxidants existing in nature, there are being developed new researches concerning the functional role of these substances in preventing neurodegenerative diseases in newborns.
Because these polyunsaturated fat acids are very sensitive to oxidation, the modification of their plasmatic levels influences the state of the antioxidant systems on the mother and subsequently to the foetus. Many studies have proved that the increase of the susceptibility to the peroxidation of polyunsaturated fat acids on pregnant women is accompanied by an equivalent increase of the tocopherol plasmatic concentration which, immediately after birth, decrease sharply.
The plasmatic concentrations of the newborns' antioxidants were lower than those of the mothers. In the umbilical cord, the levels of tocopherols and carotenoids are significantly lower than the ones registered in the maternal plasma and the concentration of polyunsaturated fat acids on the newborn is significantly higher and a lot more increased than on the mother.
Furthermore, specific studies showed a growing interest towards the oxidative stress and oxygen reactive species which supposedly accumulate after birth. Many practices usually used in the delivery room (for example the drugs given to pregnant woman to ease her pain, the newborns' extraction methods, the techniques to minimize body temperature decrease, blocking the umbilical cord and especially the use of oxygen to 100 % or a ventilated room for newborns presenting asphyxia signs) do not always prove to be efficient and can also compromise the health of the newborn because of a significant increase of free radicals.
Some specific studies have compared the levels of free radicals, highlighted with markers, in the plasma of the umbilical cord of newborns with asphyxia treated 100% with oxygen or 21% with oxygen, comparative to a control group of children without asphyxia. The levels of free radicals were significantly increased immediately after birth in all three groups and grew in the two groups of newborns with asphyxia. In the group treated 21% with oxygen, these values decreased and have reached the same level of the newborns without asphyxia at 28 days after birth, whereas at the group treated 100% with oxygen the levels of free radicals remained very high.
Thus, a short exposure of the newborn to 100% oxygen is the cause of an extended oxidative stress state and a consistent increase of free radicals, which seem to be involved in different diseases and pathologies during the first months of life, especially in the preterm infant increasing significantly the incidence of ROP, IVH, BPD, NEC and infections.
These results show that the newborn need to increase the level of antioxidant protection to establish the redox balance and to prevent the problems occurred from an extended exposure to high levels of free radicals and oxygen reactive species.
The premature birth is the most frequent cause of mortality, morbidity and disability. Premature babies have an extremely high risk to develop ocular or neurological lesions. The main complication at visual level that may appear is called retinopathy of prematurity, so called ROP. Oxidative stress is involved in the etiology of this disease. In fact, premature babies, because of respiratory issues, are often exposed to potentially damaging oxygen concentrations or to phototherapy with high blue light intensity. These therapeutic practices are sources of free radicals.
The studies performed on the babies showed that the levels of carotenoids in the first four / six months of life are much reduced. This is due to the fact that the baby's diet is based exclusively on milk, without any solid elements (as vegetables or green leaves), sole sources of this nutrient. Nevertheless, breastfed babies, in average, present high plasmatic lutein levels than babies fed with prepared milk. Different milk formulas for newborns found at present time on the market are not enriched with this type of carotenoids, thus their content of lutein and zeaxanthin is very low, except certain formulas which are not traded in Italy and prepared using egg mixes. Breast milk, is thus the only source of lutein for the newborn before weaning, and breast feeding proves to be of considerable importance as primary source of these micronutrients for the newborn, proper development and visual function protection. Taking into consideration the correlation between the lutein in the blood and breast milk and the reduction of its levels, similar to all carotenoids, in milk, after 6 days from birth, there is already an important contribution of nutriments high in lutein during breast feeding. Such diet enriched in lutein is particularly important especially for the mothers of premature babies or babies having a small body weight when born. In fact, premature babies and underweight babies need more nutritive essential substances for a fast grow. These babies have not benefit from the contribution of highly nutritive and energetic substances transferred from their mothers during the last weeks of pregnancy. Also, the gastrointestinal and renal functions which are not completely developed reduce the absorption and withhold of important micronutrients, amongst which important antioxidants that protect the newborn from the exposure to high level of free radicals produced excessively at birth and several times as a result of the resuscitation techniques used. Breast feeding is important for the antioxidant contribution to the protection of the newborn and the nutritional state of the mother has subsequently an essential part because it influences the nutrition of the newborn, especially concerning certain solvable nutritive elements, such as lutein and zeaxanthin.
In the literature are already present researches and results with the use of lutein / zeaxanthin in the newborn.
The recent Gong's work has evaluated the role of lutein / zeaxanthin comparing the data obtained from various studies, including those of Romagnoli, Dani and Manzoni. Furthermore, thanks to RCT analysis of Rubin on the subject, investigators concluded that lutein / zeaxanthin is well tolerated and well absorbed from preterm infants also after oral administration.
The extremely interesting result that has emerged although not statistically significant (probably due to the small sample) is that supplementation with lutein / zeaxanthin reduced the incidence and severity of ROP.
This protocol is born from the idea that given the interesting results of earlier work is considered important to deepen a dosage of at least 1 ml / kg equal to 0,5 mg of lutein and 0.05 mg of zeaxanthin.
The evaluation of the key markers for oxidative stress is necessary along with the study of the biological antioxidant potential (BPT) and total hydroperoxide (TH) during and after treatment.
Already in a previous work, S. Perrone and M. Longini have demonstrated a reduction of the free radicals in term infants, during and after administration of lutein / zeaxanthin by determination of the BTP and TH.
Preparations based on lutein and zeaxanthin have never revealed on humans negative or harmful effects after administration, or to the gastrointestinal or systemic level. In recent studies there were not reported adverse phenomena after administrating 20 mg/day of lutein or zeaxanthin for a period of 6 months, or interactions with other liposoluble nutritive elements.
Conditions
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Antioxidant Role of the Lutein in Preterm Newborn
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Since birth, premature newborns, that are comply with the inclusion parameters, will be introduced and separated in two random groups (A and B).
All newborns, during the observation period, will be submitted to the blood collection (1 ml) from the umbilical cord and peripheral site (at the same time with the routine collections) on which there will be performed blood gas analysis and oxidative stress markers (TH and BAP)
All newborns, during the observation period, will be submitted to the blood collection (1 ml) from the umbilical cord and peripheral site (at the same time with the routine collections) on which there will be performed blood gas analysis and oxidative stress markers (TH and BAP)
Primary Study Purpose
PREVENTION
Blinding Strategy
TRIPLE
Participants
Caregivers
Investigators
Pilot study, non-commercial, with food supplement, treated vs. control with a ratio 1: 1 double-blind. The identical vials, corresponding to placebo and active product, have an alphanumeric code without meaning for the operator, but that identifies the treaties from controls, in an anonymous document kept by the Statistical. The document will be placed in a sealed and anonymous envelope and it will be kept open by the statistician at the time of data analysis.
Study Groups
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Experimental group A
Group A (18 newborns) will be treated with LUTEIN ofta 0,5 drops, (1 ml per Kg equal to 0,5 mg of lutein and 0,05 of zeaxantin) additionaly to the standard hospital treatment foreseen. The first dose will be given within 36 hours of life, the least to 30th day of life.
Group Type
EXPERIMENTAL
LUTEIN ofta 0,5 gocce
Intervention Type
DIETARY_SUPPLEMENT
LUTEIN ofta 0,5 gocce, containing a solution of 5% Lutein and 2,5% Zeaxanthin with excipients (Corn starch, glucose, potassium sorbate, xanthan gum, citric acid)
Control group B
Group B (18 newborns) treated with Placebo solution additionaly to the standard hospital treatment foreseen. The first dose will be given within 36 hours of life, the least to 30th day of life.
Group Type
PLACEBO_COMPARATOR
Placebo
Intervention Type
DRUG
Placebo solution with unique excipients (Demineralised water, potassium sorbate, xanthan gum, citric acid)
Interventions
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LUTEIN ofta 0,5 gocce
LUTEIN ofta 0,5 gocce, containing a solution of 5% Lutein and 2,5% Zeaxanthin with excipients (Corn starch, glucose, potassium sorbate, xanthan gum, citric acid)
Intervention Type
DIETARY_SUPPLEMENT
Placebo
Placebo solution with unique excipients (Demineralised water, potassium sorbate, xanthan gum, citric acid)
Intervention Type
DRUG
Eligibility Criteria
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Inclusion Criteria
* Newborns with a body weight at birth ≤ 1.500 grams and/or gestational age ≤ 32 weeks
* Male and female newborns
* Newborns whose parents want to sign the informed consent
* Informed consent
* Male and female newborns
* Newborns whose parents want to sign the informed consent
* Informed consent
Exclusion Criteria
* Informed consent is not signed
* Infants with a body weight at birth ≥ 1.500 gramms and/or gestational age \> 32 weeks
* Infants hospitalized after 36 hours of life
* Infants with Ophthalmologic diseases
* Infants with severe malformations
* Infants with a body weight at birth ≥ 1.500 gramms and/or gestational age \> 32 weeks
* Infants hospitalized after 36 hours of life
* Infants with Ophthalmologic diseases
* Infants with severe malformations
Minimum Eligible Age
24 Weeks
Maximum Eligible Age
32 Weeks
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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Fondazione Poliambulanza Istituto Ospedaliero
OTHER
Sponsor Role
collaborator
University of Siena
OTHER
Sponsor Role
collaborator
University Hospital Padova
OTHER
Sponsor Role
collaborator
University Hospital Perugia
UNKNOWN
Sponsor Role
collaborator
Sooft Italia
INDUSTRY
Sponsor Role
lead
Responsible Party
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Responsibility Role
SPONSOR
Principal Investigators
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Sara Magnanelli, M.D.
Role: STUDY_CHAIR
Sooft Italia
Giuseppe De Bernardo, M.D.
Role: PRINCIPAL_INVESTIGATOR
Sooft Italia
Locations
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Azienda Ospedaliera Universitaria Padova
Padua, Italia, Italy
Site Status
Azienda Ospedaliera Le Scotte Siena
Siena, Italia, Italy
Site Status
Fondazione Poliambulanza Istituto Ospedaliero
Brescia, , Italy
Site Status
University Hospital Perugia
Perugia, , Italy
Site Status
Countries
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Italy
References
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RESULT
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RESULT
Khachik F, de Moura FF, Chew EY, Douglass LW, Ferris FL 3rd, Kim J, Thompson DJ. The effect of lutein and zeaxanthin supplementation on metabolites of these carotenoids in the serum of persons aged 60 or older. Invest Ophthalmol Vis Sci. 2006 Dec;47(12):5234-42. doi: 10.1167/iovs.06-0504.
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RESULT
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RESULT
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RESULT
Giuseppe Buonocore, Monica Tei, Serafina Perrone. Lutein as protective agent against neonatal oxidative stress. Journal of Pediatric and Neonatal Individualized Medicine 2014;3(2):e030244.
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RESULT
Perrone S, Tei M, Longini M, Santacroce A, Turrisi G, Proietti F, Felici C, Picardi A, Bazzini F, Vasarri P, Buonocore G. Lipid and protein oxidation in newborn infants after lutein administration. Oxid Med Cell Longev. 2014;2014:781454. doi: 10.1155/2014/781454. Epub 2014 Apr 30.
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RESULT
Perrone S, Longini M, Marzocchi B, Picardi A, Bellieni CV, Proietti F, Rodriguez A, Turrisi G, Buonocore G. Effects of lutein on oxidative stress in the term newborn: a pilot study. Neonatology. 2010;97(1):36-40. doi: 10.1159/000227291. Epub 2009 Jul 7.
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RESULT
Fanaris, Bel BO, Guidettic E et al. Ruolo della Luteina nella prevenzione delle patologie oculari nel neonato. Rivista Italiana di Medicina Pediatrica 2006;numero speciale:51-53
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RESULT
Kvansakul J, Rodriguez-Carmona M, Edgar DF, Barker FM, Kopcke W, Schalch W, Barbur JL. Supplementation with the carotenoids lutein or zeaxanthin improves human visual performance. Ophthalmic Physiol Opt. 2006 Jul;26(4):362-71. doi: 10.1111/j.1475-1313.2006.00387.x.
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RESULT
Rodriguez-Carmona M, Kvansakul J, Harlow JA, Kopcke W, Schalch W, Barbur JL. The effects of supplementation with lutein and/or zeaxanthin on human macular pigment density and colour vision. Ophthalmic Physiol Opt. 2006 Mar;26(2):137-47. doi: 10.1111/j.1475-1313.2006.00386.x.
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RESULT
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Provided Documents
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Document Type: Informed Consent Form
Document Type: Study Protocol and Statistical Analysis Plan
Other Identifiers
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3172 10/10/2018
Identifier Type: -
Identifier Source: org_study_id