Effects of Early Vitamin A Supplementation on the Risk for Retinopathy of Prematurity in Extremely Preterm Infants
Condition: Retinopathy of Prematurity
MeSH terms: Retinal Diseases; Retinopathy of Prematurity; Premature Birth
Study type: Interventional

Summary: 
      Retinopathy of prematurity (ROP) is a common retinal neovascular disorder and major cause of
      vision impairment or blindness, despite current treatment of late stage ROP. Because the
      visual disorders after treatment are often poor, preventive therapy for ROP is still lacking.
      Although ROP is a multifactorial disease, the altered regulation of vascular endothelial
      growth factor (VEGF) and insulin-like growth factor (IGF-1) have been implicated in the
      pathogenesis of ROP. Vitamin A is one of the most important micronutrients affecting the
      health of children. Supplementing newborn infants with vitamin A within the first 2 days of
      life reduced infant mortality by almost 25%, with the greatest benefit to those of low birth
      weight. Vitamin A has been used in this population prophylactically for chronic lung disease
      with the large doses and no reported significant adverse effect exists. It is suggested that
      vitamin A-retinoids and their active metabolite, retinoic acid (RA) have highly potent
      antiangiogenic activity by inhibiting VEGF expression. Vitamin A (retinol) is converted into
      retinoic acid in cells. However, the significance of Vitamin A administration has not been
      investigated to our knowledge in an experimental ROP infant. The aim of this study was to
      perform prospective, multicenter, randomized design to demonstrate the preventive effect of
      Vitamin A on ROP.
    

Detailed description: 
      Retinopathy of prematurity (ROP) is a common retinal neovascular disorder and major cause of
      vision impairment or blindness, despite current treatment of late stage ROP. Because the
      visual disorders after treatment are often poor, preventive therapy for ROP is still lacking.
      Although ROP is a multifactorial disease, the altered regulation of vascular endothelial
      growth factor (VEGF) and insulin-like growth factor (IGF-1) have been implicated in the
      pathogenesis of ROP. The vascular endothelial growth factor (VEGF) is a hypoxia-inducible
      cytokine and a vascular endothelial cell mitogen. If VEGF is suppressed, normal vessel growth
      is inhibited, but if in excess, retinal neovascularization is precipitated. This indicates
      that VEGF is a critical factor in retinal neovascularization. Inhibition of VEGF at the
      neovascular phase might prevent destructive neovascularization. However, the choice of any
      intervention for the inhibition of VEGF should be taken into account very carefully, because
      VEGF also promotes normal physiological development of blood vessels in many tissues. In
      addition, this intervention can be applied to all preterm infants when potential side effects
      are almost minimal.

      Vitamin A is one of the most important micronutrients affecting the health of children.
      Supplementing newborn infants with vitamin A within the first 2 days of life reduced infant
      mortality by almost 25%, with the greatest benefit to those of low birth weight. Vitamin A
      has been used in this population prophylactically for chronic lung disease with the large
      doses and no reported significant adverse effect exists. It is suggested that vitamin
      A-retinoids and their active metabolite, retinoic acid (RA) have highly potent antiangiogenic
      activity by inhibiting VEGF expression. Vitamin A (retinol) is converted into retinoic acid
      in cells. However, the significance of Vitamin A administration has not been investigated to
      our knowledge in an experimental ROP infant. The aim of this study was to demonstrate the
      preventive effect of Vitamin A on ROP.

      Methods

      This prospective, multicenter, randomized study was performed from August 2015 to March 2017
      in neonatal intensive care units in China. This study was approved by the Life Science Ethics
      Committee of Zhengzhou University and the local research ethics committees at the
      participating centers. Written informed consent was obtained from both parents when an infant
      was admitted to the NICU.

      Patient Population

      Patients eligible for the study were extremely preterm infants admitted to the NICU with
      gestational age <28 weeks, <72 h of age, receiving mechanical ventilation, noninvasive
      respiratory support or supplemental oxygen (FiO2>0.21) at 24h of age. Infants with genetic
      metabolic diseases, congenital abnormalities, congenital nonbacterial infection with overt
      signs at birth, terminal illness as evidenced by PH<7.0 for >2h or persistent bradycardia
      (heart rate <100 bpm) associated with hypoxia for >2h, or grade III or IV intracranial
      hemorrhage before randomization were excluded, as were infants for whom parental consent
      could not be obtained.

      Randomization

      Subjects were assigned to the oral vitamin A group or the placebo group based on a
      computer-generated randomization plan. The allocation ratio was 1:1, using variable block
      sizes. Randomization to the oral vitamin A group or the placebo group was carried out by
      random number allocation sequence, upon securing the order of admission to the NICU, and
      within 30 min after written informed consent was obtained.

      Vitamin A administration

      Subjects will be given the daily dose 1500 IU/day in drop form added to their enteral feeds
      as soon as minimal feeding is introduced. All extremely preterm infants will be provided with
      basic administration of an intravenous multivitamin (1ml/kg/day, containing vitamin A 230
      IU/kg/day) preparation whilst on parenteral nutrition until fully enterally fed.

      Data Collection

      All vital signs, including blood pressure, heart rate, oxygen saturation, ventilator
      settings, and arterial blood gases, were monitored both before and during mechanical
      ventilation. The primary outcomes were mortality and incidence of BPD, as determined by an
      oxygen reduction test at 36 weeks of postmenstrual age, and further graded by severity, using
      criteria adapted from the National Institute of Child Health and Human Development. Mild BPD
      was defined as the need for supplemental oxygen for <28 days. Moderate BPD was defined as the
      need for supplemental oxygen at postmenstrual age of 36 weeks without positive pressure
      support. Severe BPD was defined as the need for mechanical ventilation.

      Secondary outcomes were days on mechanical ventilation, hospital stay, surfactant
      requirement, and the occurrence of retinopathy of prematurity stage 2 or higher, pulmonary
      hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, or pneumothorax. Doctors
      were blind as to group allocation during the whole study.

      Statistical Analyses

      The minimum sample size of 127 in each group (total 254) was estimated based on an expected
      incidence of ROP (including mild, type 1 and type 2 ROP) in the control group of 62%, a
      2-sided significance level of 0.05, and an 80% chance of detecting a relative 30% decrease
      infrequency. Analyses were performed according to the intention-to-treat principle, and all
      who could be evaluated were included.

      All analyses were performed with statistics software (SPSS 17.0, SPSS Chicago, Illinois).
      Quantitative data are expressed as mean ± SD. Entry data and outcome differences were
      compared with the t test and Fisher exact test. Subgroup interaction analyses were performed
      on the basis of sex, birth weight, single or multiple births, antenatal steroid or postnatal
      surfactant treatment, and intubation time for mechanical ventilation. All subgroup
      statistical analyses were evaluated with the Breslow-Day test for interaction. The kappa test
      was used to examine whether the results were consistent between the 2 centers. The level of
      statistical significance was set at P <0 .05.
    

Intervention name(s): Vitamin A
Intervention type(s): Drug
Intervention description(s): Vitamin A daily dose 1500IU/day will be added to infant's enteral feeds in drop form as soon as minimal feeding is introduced. The vitamin A supplementation was last for 28 days.
Other intervention name(s): Retinoic acid
Intervention MeSH terms: Vitamin A
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Prevention