In premature children the causes are often a combination of several risk factors; whereas in infants born at full term, it could be the child’s inherent abilities to withstand unfortunate events at birth that cause some children to develop CP and others not.

In addition there seems to be a correlation between high prevalence of CP and low neonatal death rates in some Norwegian counties.

“There could be several explanations for this,” says PhD candidate Magne Stoknes at the Department of Laboratory Medicine, Children’s and Women’s Health (LBK), NTNU. One explanation could be that more children that already have a brain injury before birth are saved that otherwise would not have survived.

“Survival rates were higher in smaller counties, but these counties also had a higher prevalence of CP, which could suggest that the distance to hospital may be of some relevance. But we cannot say for certain whether the correlation is due to differences in quality or external factors.”

Individual factors.

When looking at the risk factors present during pregnancy and around birth in children with CP, there are no clear factors that can be singled out, and often there are different combinations of risk factors. It is also not clear when in the pregnancy CP occurs:

“The background for a child developing brain injury leading to cerebral palsy is complex. There are probably several risk factors that independently or combined contribute to a process that leads to brain injury, and these risk factors operate together in a certain order of events (so-called causal pathways).

“In addition some children seem to be more vulnerable to the various combinations of risk factors, so that there are different combinations of risk factors leading to CP in individual children,” Stoknes explains.

Still a puzzle

The research nevertheless offers a new piece to a larger puzzle, but there are still many pieces left to be found before we with certainty can say something about why some children develop CP and how this could be prevented.

Stoknes says the research team now wishes to continue with larger studies that look even closer at how different risk factors come together to contribute to brain injury which again causes CP.

The studies

Stoknes’ research is based on three studies. The first study which looked at low birth weight at full term included 400,488 Norwegian children born in the period 1996-2003, where 36,604 had low birth weight. Of these 104 did not live and 69 developed CP.

The second study, which looked at how risk factors were combined, included 176,979 children born in the period 1996-98, where 241 developed CP.

In the last study where the share of neonatal deaths was compared with the prevalence of CP in surviving children, the researchers used data from 468,443 children born in the period 1996-2003, where 1020 were diagnosed with CP.

Viva

Magne Stoknes will defend his thesis “Novel Approaches to the Study of Risk Factors for Cerebral Palsy” on 8. April 2013 at 12.15 in ØHA11 at NTNU.

The trial lecture will take place at 10.15.

Publications

• Cerebral palsy and neonatal death in term singletons born small for gestational age. Stoknes M et.al.
• The effects of multiple pre- and perinatal risk factors on the occurrence of cerebral palsy. A Norwegian register based study. Stoknes M et.al.

“There is a lot about the brain, and especially brain injury among newborns, that we don’t know about. Over the last 30 years, we have increased our knowledge significantly, but there are still many unanswered questions.”

When injury occurs among newborn children, it happens at a stage when the brain is still not fully developed. This means that hypoxic-ischemic brain injury, in addition to damaging the brain’s structure, also impacts the development of the brain. At the same time, however, it gives rise to the possibility of the brain repairing itself and finding alternative methods for solving various tasks.

Using MRI

In his thesis, “Magnetic Resonance Imaging of Hypoxic-Ischemic Brain Injury Development in the Newborn Rat – Manganese and Diffusion Contrast,” Widerøe finds that the hypoxic-ischemic brain injury process continues for a prolonged period of time after the initial incident, but that anti-inflammatories such as the antibiotic doxycycline can limit the damage.

To map the injury process and treatment effect, Widerøe has developed and adopted new techniques for magnetic resonance imaging (MRI) in newborn animals. The use of MRI means that repeated examinations can be performed without biopsies, and researchers can follow the development in individual animals over a longer period.

The research group he belongs to also uses MRI to assess how too much or too little oxygen affects normal brain development.

It is in connection with this that the researchers have concluded that treatment with an anti-inflammatory gives a more normal brain development after a hypoxic-ischemic brain injury, compared with those who did not receive the same treatment.

The results also confirm previous research which shows that administering pure oxygen can cause further damage and delay maturing-processes in the brain further after an incident of lack of oxygen.

The research using rats will continue, and one of the PhD students in the group will look further into the harmful effects of oxygen in connection with hypoxic-ischemic brain injury. Other PhD students will look at treatments using stem-cells. Using MRI, the researchers can look at the movements of stem-cells in the brain after they have been implanted, and how these can affect inflammation-reactions and the brain’s ability to repair itself. As part of this, the group will continue to study the brain’s development using MRI.

While Widerøe’s part of the group primarily has focused on animal testing, another part of the group, directed by professors Ann-Mari Brubakk and Jon Skranes, has followed children with low birth weight and premature children using MRI and mapped their brain activity into adulthood. Many of these children have had small and/or large brain injury during pregnancy or birth, and the goal has been to follow their brain development and map the long-term effects of impacts around birth.

Viva

Marius Widerøe will defend his thesis on 29 May. A lecture will be given at 09.00 in the Auditorium at Medisinsk teknisk forskningssenter at NTNU. The viva will take place at 11.00.

Hypoxic-ischemic brain injury

Hypoxic-ischemia is a combination of reduced oxygen and limited blood supply to the brain. It is one of the most common causes of brain injury among newborn children and increases mortality, as well as psychological and physiological problems later in life.

Publications:

• Doxycycline treatment in a neonatal rat model of hypoxia-ischemia reduces cerebral tissue and white matter injury: a longitudinal magnetic resonance imaging study. Widerøe M, et.al.
• Longitudinal manganese-enhanced magnetic resonance imaging of delayed brain damage after hypoxic-ischemic injury in the neonatal rat. Widerøe M, et.al.
• Manganese-enhanced magnetic resonance imaging of hypoxic-ischemic brain injury in the neonatal rat. Widerøe M, et.al.