Exploring Metabolic Maturation in the Extremely Preterm Brain at Term Equivalent Age: EMMA study.

Advances in obstetric and neonatal intensive care have led to a significant
improvement of survival in infants born extremely preterm (<28 weeks of
gestation). However, injury to the developing brain is still a very common
finding in preterm infants and is an important risk factor for long-term
neurodevelopmental deficits. Intriguingly, many preterm infants without
apparent lesions on 3 Tesla MRI, tend to also experience neurodevelopmental
delay in later childhood. Conceivably, because lesions might be too subtle to
capture with 3 Tesla MRI, or conventional imaging is unable to show factors of
brain maturation that dictate neurodevelopmental outcome. In depth in-vivo
investigation of maturation of the preterm brain, is the crux in understanding
the link between prematurity and outcome, but we need advanced imaging to
accomplish this. Ultra-high field MRI (i.e. 7 Tesla MRI) especially improves
the use of advanced imaging. With 7 Tesla MRI, we expect to be able to
visualize the developing (micro-)vascular anatomy, perfusion, metabolic
condition and myelination of the brain. We hypothesize that these combined
modalities will provide unique information on the vascular and metabolic
maturation and myelination of the preterm brain, improving neurodevelopmental
prognosis, even in preterm infants without apparent brain damage.

We will combine four 7 Tesla MRI markers in extremely preterm infants (MRSI;
SWI; PC-MRI; ihMT) to assess (1) if they can predict outcome until 2 years of
age; (2) if they are of added value to 3 Tesla prematurity (Kidokoro et al.,
2013) and (3) if they differ from healthy controls.

Forty extremely preterm infants (<28 weeks of gestation) and five healthy
controls will be recruited to undergo a 7 Tesla MRI scan at term equivalent age
(40-42 weeks post-menstrual age). In extremely preterm infants, 7 Tesla MRI
scans will be performed directly after their routine clinical 3 Tesla MRI scan
and will be executed without (additional) sedation. In healthy controls, 7
Tesla MRI will be executed on the day after birth via a planned C-section. For
both groups, the 7 Tesla MRI protocol will consist of magnetic resonance
spectroscopy imaging (MRSI; to investigate metabolism), susceptibility weighted
imaging (SWI; to investigate vessel architecture), inhomogenous magnetization
transfer imaging (ihMT; to investigate myelination), and 4D phase contrast MR
imaging (PC-MRI; to quantify blood flow, velocity and blood vessel
pulsatility).

We expect this study to be beneficial to future patients as we hypothesize that
7 Tesla MRI is of additional predictive neurodevelopmental value in extremely
preterm infants. 7 Tesla MRI is expected to offer a more accurate technique to
assess the extent of injury and the maturation of the developing brain on a
microstructural level, even without apparent injury. This is of importance to
provide parents adequate information about the future perspectives of their
child.
Since the anatomy, water content, injury and development of the brain in
infants are not comparable to adults or older children, this study can only be
performed in infants.
The burden for the (preterm born) infants will be the subjection to 1
(additional) MRI scan. Infants will receive extra feeding before the 7T MRI
scans, but will not receive (a second dose of) sedation, e.g. chloral hydrate.
The parents of the control group can choose to receive some of the images
(after they are checked by the neonatologist) from the 7 Tesla MRI scan as a
gift for their participation. All parents will be asked to fill in the Ages and
Stages questionnaire fourth edition (ASQ-4) at ±12 months of (corrected) age.
This questionnaire can be answered at home in approximately 12 minutes. The
parents of the control group will also be asked to make a one minute movie of
their infants at ±4.5 months of age.
Prior to this study we completed a safety and feasibility study for 7T MRI of
infants (METC 18-598). This showed no changes in vital signs, temperature
(rectal, body and brain), COMFORT scale scores or adverse events (Annink et
al., 2020; abstract appendix 1), suggesting 7 Tesla MRI to be safe and not
different from 3 Tesla MRI in infants. However, in cases of observation of
adverse events or discomfort the scan will be stopped, just like during 3 Tesla
MRI. Also, we use hearing protection and an acoustic hood, similar to what is
used at the 3 Tesla MRI.