Thyroxine Treatment in Premature Infants With Intraventricular Hemorrhage

Intraventricular hemorrhage (IVH) remains a major complication of prematurity. IVH leads to
white matter injury. Indeed, survivors with IVH suffer from cerebral palsy (CP), cognitive
deficits and a constellation of neurobehavioral disorders. Despite this, there is no existing
therapy to minimize WM injury in premature infants of IVH. The occurrence of IVH reduces
proliferation and maturation of oligodendrocyte progenitors cells (OPCs), causing myelination
failure of the WM. IVH reduces deiodinase 2 and elevates deiodinase 3 enzyme levels in brain
region adjacent to the ventricle in both rabbits and humans, thereby decreasing T3 content in
the neural cells. Accordingly, T4 treatment in preterm rabbits enhances proliferation and
maturation of OPCs, and promotes myelination and neurological recovery. Therefore,
investigators hypothesize: T4 treatment in infants with grade III-IV IVH a) will increase
fractional anisotropy and reduce diffusivity in the corpus callosum of preterm infants with
grade III-IV IVH on MRI/DTI evaluation at 36 weeks of postmenstrual age (PMA, Primary
outcome) and b) will reduce the composite outcome of death or NDI (cognitive, language or
motor score < 1 SD below the mean on BSID III or CP with GMFCS level ≥1) from 80% to 50% at
22-26 months of corrected PMA (Secondary Outcome).

Investigators will perform a double-masked, placebo-controlled, and randomized controlled
trial to determine the effect of T4 treatment on preterm infants (230/7—276/7) with grade
III-IV IVH on: a) Primary outcomes: (i) DTI metrics, including fractional anisotropy, radial
and axial diffusivity, and apparent diffusion coefficient, of the white matter (WM)
regions—corpus callous, corona radiata, internal capsule, external capsule and others, (ii)
regional volumes for WM, cortical grey matter, cerebrospinal fluid, hippocampus, and
cerebellum, and (iii) conventional brain MRI abnormalities using Kidokoro/Inder scoring
system at 36 weeks PMA; b) Secondary outcomes: a) death or NDI rate, and b) survival with NDI
at 22-26 months of corrected PMA. NDI has been defined as cognitive, language or motor score
< 85 on BSID III or CP with GMFCS level ≥1. In addition, investigators will assess clinical
outcomes related to the safety of T4 treatment in infants with IVH. Investigators will enroll
100 premature infants (23 0/7--27 6/7 week) of 2-5 days postnatal age with unilateral or
bilateral grade III-IV IVH in 4 NICUs over a period of 3 years. The treatment will consist of
T4 administration (8 µg/kg divided into two doses, IV every 12 hours) up to 34 weeks of
corrected PMA. The proposed clinical trial might improve the neurodevelopmental outcome of
premature infants with moderate-to-severe IVH.

Inclusion Criteria

- NICU inpatients born between 23-0/7 and 27-6/7 weeks of gestation

- Postnatal age 2-5days (≥2 d ≤ 5 d)

- Unilateral or bilateral Grade 3 or 4 IVH

- Parental consent

Exclusion criteria:

- Major malformations, including surgical, cardiac, cerebral, chromosomal, or genetic
syndromes, identifiable at or before birth;

- Congenital bacterial infection proven by culture at birth or viral syndrome known
prior to delivery (e.g. chicken pox, rubella, etc.)