Light/Dark Cycle Promotes Weight Gain in Preterm Infants
Condition: Preterm Infants
MeSH terms: Premature Birth
Study type: Interventional

Summary: 
      The study focuses on the use of light/dark alternation as chronotherapy to prevent
      deterioration and reduce morbidity and mortality in premature patients, as well as favoring
      circadian alteration after birth, which should lead premature infants to a better evolution
      in life. NICU.

      With the hypothesis that exposure to light/dark cycles during hospitalization of preterm
      infants will decrease hospital stay. In addition, the light/dark cycle will allow a circadian
      organization of physiological variables such as salivary levels of cortisol and melatonin.

      To identify the benefits of the light/dark cycle in the clinical maturation of preterm
      newborn patients and early hospital discharge in preterm newborns.
    

Detailed description: 
      Introduction Worldwide, Neonatal Intensive Care Units (NICU) are often maintained under
      24-hour constant bright light (CBL) conditions, without significant variations in light
      intensity. As such, infants under these conditions are exposed to chaotic temporal signals,
      as opposed to predictable temporal signals, without cyclic variations in terms of sounds and
      light. Interestingly, the level of light to which premature infants are exposed represents an
      accessible environmental variable that can be easily controlled. Premature infants are
      generally maintained under CBL conditions for prolonged intervals, thus hampering their
      growth and development. CBL conditions can generate harmful effects to newborn eyes, and
      experimental studies have shown that newborn rats exposed to a CBL environment from the first
      day of birth develop damage in the cellular organization of the retina.

      Previous studies have shown that a 12:12 hour light/darkness cycle (LDC) can promote an
      increase in infant sleep time, decrease feeding time and improve weight gain, compared with
      infants maintained in constant light or constant dark conditions. Further, evidence shows
      that infants exposed to a LDC since birth acquire circadian rhythmicity of activity/rest
      patterns as early as week 34 of life.

      This study presents the results from a multicentric trial which sought to determine the
      benefits of implementing a LDC in the NICU of three different hospitals in Mexico. The
      primary endpoint was weight gain; secondary endpoints included early hospital discharge,
      salivary melatonin levels and the effect of reducing the intensity of nocturnal light in
      development of premature infants.

      Methods Study Design and Participants This prospective, open-label, randomized multicentric
      clinical trial recruited patients in three different public-setting hospitals in Mexico
      between 2016 and 2020. Eligible patients were premature infants (gestational age <37 weeks)
      who were hospitalized in the low risk and high-risk neonatal units of participating
      institution, with a non-severe diagnosis for hospitalization, without concomitant illness,
      and classified as stable. Exclusion criteria included infants hospitalized with severe
      illness, congenital malformations, or important neurological diseases, while elimination
      criteria included infants initially classified as having a non-severe illness who progress to
      severe illness, infants who received intensive treatment for over a week due to medical
      complications (i.e. bacterial infections), as well as infants whose parents requested
      withdrawal from participating in the study. The parents or legal guardians of all included
      patients provided written informed consent to participate in this study. Participating
      institutions included Centro Medico Nacional "La Raza", Mexico City; Hospital General de Zona
      No.1 "Dr. Demetrio Mayoral Pardo" Oaxaca City, Oaxaca, Mexico (both hospitals from the public
      healthcare system "Mexican Institute for Social Security IMSS"), and General Hospital "Dr.
      Aurelio Valdivieso", Oaxaca City, Oaxaca, Mexico (from the public healthcare system of the
      Health Secretariat [SSA]). The study was approved by the scientific and bioethical committees
      of each participating institution (CMNR-No. 3504-35, HGZ 1 IMSS Oaxaca R-2001-2015-8, SSO-R.
      023/2018 y UNAM-094/2014). The study was performed in accord with the declaration of Helsinki
      and the principles of good clinical practice. This study followed the Consolidated Standards
      of Reporting Trials (CONSORT) reporting guidelines.

      Sample Size The sample size was calculated for a two-sample comparison, given an 80%
      sensitivity and a 60% specificity and with a confidence interval of 90%. A total of 150
      patients per group was estimated, for a total sample size of 300 subjects.

      Procedures All study procedures were performed following a predefined study protocol and a
      uniform sample processing plan. Data was registered using a unified registry form in all
      participating sites, and all analyses were centrally performed at the main investigation
      site. All included patients provided information regarding family and perinatal history.

      Each NICU from the participating institutions was evaluated in order to measure the
      illumination level using a luxmeter (HER-410-Steren), in 4 specific areas during 6 different
      times of day to ascertain homogeneous lighting conditions throughout the centers. Subjects
      randomized to the experimental group were allocated to alternating light/darkness conditions
      as follows: from 07:00 to 19:00 hours the subjects were kept under normal room light
      conditions; from 19:00 to 07:00 of the following day the conditions were modified by placing
      the patient under an acrylic cephalic helmet (length: 27 cm; width: 27 cm; height: 17.5 cm;
      opening: 17x12 cm). The helmet was covered with surgical cloth (green or blue) folded to
      50x60cm rectangles, leaving the frontal part open in order to maintain an adequate air flow.
      This intervention exposed infants in the experimental group to light at 25 lux for 12 hours
      every day, while during daytime the cloth was removed in order for study subjects to be
      exposed to regular room lighting. The control group was kept under normal room light
      conditions (CBL) 24 hours a day (level of illumination was 275.82±14 lux during the day and
      145.28±14 lux at night). All included subjects were under 24-hour surveillance for the period
      spanning the length of their hospital stay by the NICU personnel at each participating
      institution. Infants were kept in individual incubators regulated to maintain a body
      temperature ranging from 36.5 °C -37 °C.

      Both study groups were offered feeding every 3 hours (as per NICU guidelines and vital signs
      were recorded every 3 hours (cardiac and respiratory rate, temperature). Every infant
      underwent an 8-12 hour fast after birth for intestinal resting, thereafter enteral feeding
      began at a dose of 12.5 ml/kg of breast milk, which was increased every 12 hours until
      reaching a maximum of 200 ml/kg/day. Every included infant was orally fed, in case of
      abdominal distension or absence of peristalsis underwent a 24-hour maximum fast. Once the
      infants reached 1600 g body weight, breast feeding was indicated in order to prepare for
      discharge. The total caloric content among different hospitals was not standardized in this
      present study.

      Among 20 randomly selected infants (10 randomized to BCL and 10 randomized to LDC) saliva
      samples were collected two times a day (08:00, 23:00) every day during the first 20 days of
      NICU stay in order to determine biomarkers. The salivary concentration of melatonin was
      determined using a standardized ELISA kit, following instructions by the manufacturer (IBL
      International GmbH Flughafenstr. Hamburg, Germany).

      Other procedures performed included capillary blood glucose, administration of medication as
      prescribed by their primary care physician, and sample acquisition for laboratory testing
      pertaining each condition presented by infants included in this trial. All included patients
      were monitored four weeks post hospital discharge to evaluate development and growth at home,
      as well as their circadian activity/rest patterns.

      Healthy premature infants were considered for discharge when participants presented an
      adequate growth curve and met established growth criteria, including the ability to maintain
      a stable body temperature in an open crib, ability to perform all feedings without
      respiratory distress, and a constant weight gain >2000g.

      Statistical Analysis Continuous variables were summarized as arithmetic means with standard
      deviations or medians and ranges according to the data distribution assessed with the
      Kolmogorov-Smirnov test. For descriptive purposes, categorical variables were summarized as
      frequencies and percentages. Data pertaining to body weight gain, feeding and melatonin
      concentration were classified per study group and evaluated as repeated measures according to
      post-natal days. Comparisons among study groups were performed using a two-way ANOVA,
      followed by a TUKEY post-test analysis. A p-value <0.5 was considered statistically
      significant. The initial body weight, gestational week, and length of hospital stay were
      compared using a one-way ANOVA, a p-value <0.5 was considered statistically significant. All
      analyses were performed using the STATISTICA program (V10; StatSoft, Inc. 1993), while
      figures were constructed using the program Sigma Plot (V14; Systat Software, San Jose, CA).
    

Intervention name(s): Cephalic helmet
Intervention type(s): Other
Intervention description(s): An acrylic headgear (length: 27 cm; width: 27 cm; height: 17.5 cm; opening: 17x12 cm) was placed on the patient's head. The helmet was covered with surgical cloth (green or blue) folded into 50x60cm rectangles, leaving the front part open to maintain adequate airflow.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects randomized to the experimental group were allocated to alternating light/darkness conditions as follows: from 07:00 to 19:00 hours the subjects were kept under normal room light conditions; from 19:00 to 07:00 of the following day the conditions were modified by placing the patient under an acrylic cephalic helmet which exposed them to light at 25 lux for 12 hours every day. The control group was kept under normal room light conditions (CBL) 24 hours a day.
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Circadian rhythms; Chronotherapy; Melatonin; Neonatology; Weight gain