Melatonin Levels in Preterm and Term Newborn Infants
Condition: Pregnancy Preterm
MeSH terms: Premature Birth
Study type: Interventional

Summary: 
      The general goal of the present study is to examine the developmental changes caused by
      melatonin in preterm and term newborns.

      The major brain lesions associated with cerebral palsy and cognitive impairment in preterm
      infants are periventricular white matter damage (WMD). At the present time, despite major
      improvements in neonatal care, there are no established therapeutic regimens for the
      treatment of brain lesions in preterms. Melatonin is secreted by the pineal gland;
      melatonin's neuroprotective action has been well documented in animal experimental models.
      Neuroprotection is believed to stem from its direct free radical scavenging, indirect
      antioxidant activities.

      Originality Several reports have described melatonin secretion in older children, but only a
      few have observed melatonin concentrations during the first year of life. Very little is
      known about the fetal pineal melatonin synthesis and nothing at what prenatal age melatonin
      synthesis starts. Premature infants have a 3 months delay in the development of melatonin
      rhythmicity compared to full-term infants. One study found discordant data with decreasing
      melatonin value around term. The absence of longitudinal study and the low number of children
      included make the interpretation difficult of the secretion of melatonin at the newborn.

      Hypothesis: Infants born before 28 weeks gestation have melatonin deficiency (50pg/ml),
      compared to newborns at term (100pg/ml).

      Study design: prospective, longitudinal, multicenter trial in 3 Neonatal Intensive Care Units
      in Ile de France. Specific aim is to compare the developmental changes of melatonin in
      preterm and term newborns (200 infants and their mothers: 4 groups of 50 infants: 24-27GA +6d
      ; 28-32 GA +6d ; 33-36 GA +6d ; 37-41 GA +6d). Secondary aims are the following:

        -  determine Melatonin creatinin excretion in preterm infants

        -  correlate between serum melatonin secretion and urinary melatonin and
           6-sulfatoxymelatonin excretion

        -  determine endogenous melatonin production in the human pineal

        -  correlate genetic variations between different levels of melatonin in premature infants

        -  assess clinical and neurological outcomes at term Clinical impact The present clinical
           project is part of a translational approach, expected data for infants born before 28
           weeks gestation is melatonin deficiency which should participate in determining the
           potential use of melatonin as a neuroprotectant in human preterm neonates.
    

Detailed description: 
      The general goal of the present study is to examine the developmental changes caused by
      melatonin in preterm compared to term newborns. This secretion is studied in child and
      mother's blood, child's urine, the mother's milk for the women who breastfeed (200 infants
      and their mothers: 4 groups of 50 infants: 24-27 gestational age (GA) +6d ; 28-32 GA +6d ;
      33-36 GA +6d ; 37-41 GA +6d). Secondary aims are the following: determine Melatonin creatinin
      excretion in preterm infants, correlate between serum melatonin secretion and urinary
      melatonin and 6-sulfatoxymelatonin excretion, determine endogenous melatonin production in
      the human pineal, correlate genetic variations between different levels of melatonin in
      premature infants, assess clinical and neurological outcomes at term.

      Study duration for each patient Study duration is one year (inclusion time: 9 months)
      Duration of mother's inclusion:3 days if delivery between 34 and 41+6d weeks of gestation
      (two blood samples in maternal vein and umbilical vein after delivery and one mother's milk
      sample on the third day after delivery, D3) 15 days to 3 months if delivery between 24 and
      33+6d weeks of gestation (two blood samples in maternal vein and umbilical vein after
      delivery and mother's milk sample on the third day after delivery,D10-D15, D30, D60 until
      term age

      Duration of infant's inclusion:

        -  3 days if delivery between 34 and 41+6d weeks of gestation (1 blood sample on the third
           day (D3) after delivery and 4 urinary samples at birth and on D3)

        -  15 days to 3 months if delivery between 24 and 33+6d weeks of gestation (blood and
           urinary samples on the third day after delivery,D10-D15, D30, D60 until term (37-42
           weeks gestational age)

      Population study All the preterm and term newborns in 3 participating centers, will be
      evaluated in term of eligibility. Their clinical characteristics will be compared to the
      criteria of inclusion and exclusion before entering into the study. The inclusion of the
      preterm from 24 GA is justified by the assumption of responsibility of more in earlier of
      this population in 2009 (limit of viability from 24 GA and/or birth weight > 500g).

      The group of the term infants (37-41 GA +6d) will correspond to the inclusion of new-born
      babies in good health in maternity.

      Descriptive analysis The quantitative variables will be described in the form of average
      (standard deviation) or median (quartiles) according to their Gaussian nature or not. The
      qualitative variables will be described by their manpower and frequency.

      Analyzes of criteria of judgment The principal analysis will compare the rate of children
      deprived of melatonin between the 4 groups. This comparison will be carried out by a test of
      the chi-2 or Fisher if suitable. Nevertheless this analysis will be refined by modeling the
      plasmatic secretion according to the gestational age and of the hour of melatonin
      measurement. This modeling will use either a mixed model, or a nonlinear model like the
      models used into pharmacokinetic. In the same way will be modeled the urinary levels of
      melatonin and in the mother's milk by taking of account the same parameters as previously and
      the repetition of the measurements. Some parameters will be used like variables of adjustment
      like the luminous environment, the preeclampsia, the sex, the intrauterine growth restricted
      infants, multiple pregnancies, the way of childbirth.

      The plan of statistical analysis will be finalized at the end of the study and before data
      management and will be the subject of Master into biostatistics.

      The measurement of cortisol, parameters of the ionogram, urea, creatinin, serotonin will be
      compared between the 4 groups by using parametric tests (ANOVA) or not parametric
      (KRUSKALL-Wallis) according to the Gaussian nature or not of the variables. The other
      measurements (blood, urines) will be described in the course of time according to gestational
      age.

      The analyzes will be carried out with software SAS 9.02 .

      Clinical impact:

      The present clinical project is part of a translational approach, expected data for infants
      born before 28 weeks gestation is melatonin deficiency which should participate, in addition
      with existing data and other ongoing studies in an animal model, in determining the potential
      use of melatonin as a neuroprotectant in human preterm neonates.

      It's important to underline that this study must be considered as an interventional study.
      Indeed, in this study patients have many takings modality while in common practice patients
      haven't those takings:

        -  measurements of melatonin levels in urine, blood, milk

        -  measurements of Serum Cortisol concentrations and urinary excretion

        -  measurements of Serum Serotonin level
    

Intervention name(s): Measurements of melatonin levels in urine, blood, milk.
Intervention type(s): Other
Intervention description(s): Measurements of melatonin levels in urine, blood, milk.
Intervention MeSH terms: Melatonin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Screening
Keywords: melatonin; preterm; deficiency; neuroprotection