We take a look at the pioneering work of the Cerebra Foetal Research Project at the University of Barcelona.
The human brain undergoes a long phase of development that starts in foetal life and ends much later in life. The most critical steps take place in the mother’s womb and during the first two years of life. Millions of neurons are being generated every day and start establishing connections, determining how our brain is going to work for the rest of our lives. This extremely complex process is governed by information contained in our genes, but also by the environment. Any disturbance may have a critical influence in the delicate sequence of events regulated in the genetic blueprint.
One in ten children has neurodevelopmental problems. It is estimated that about two thirds of these are of prenatal origin and in most instances, the problem occurred during foetal life, long before labour started. Severe forms of brain damage affect about 2/1000 of all new-borns and are expressed by serious complications including cerebral palsy and/or intellectual disability.
The vast majority of brain problems however, are manifested as subtle developmental disturbances. These cases are not associated with overt brain injury, but with brain reorganisation and are expressed mainly as alterations in cognition, thus affecting behaviour, social relations, neuromuscular regulation, learning and memory. The impact of these ‘milder’ neurological alterations in the quality of life cannot be overemphasized. Because they are of milder nature, they mostly go unnoticed in early months and even years of life.
Identification of foetal brain injury/reorganisation as early as possible is a major opportunity for public health. The problem involves thousands of families yearly. For the first two years of life, the growing brain has enough plasticity (the brain’s ability to respond and remodel itself) to bring back to normal deviations that occurred during intrauterine life. This has been defined as the ‘window of opportunity’ to revert the effects of in utero diseases on foetal programming.
Unfortunately, early diagnosis is still not possible in a substantial majority of cases. Much is still unknown about how a developing foetal brain adapts to and eventually deteriorates under adverse conditions. We need to improve the understanding and current diagnostic means of perinatal brain injury if we hope to start early interventions.
The list of foetal problems potentially leading to brain injury is large, but the majority of cases are caused by prematurity and intrauterine growth restriction (IUGR). Over the last 10 years the team in Barcelona has worked on both, but have focused more on IUGR as there was much less known about this disease and the opportunities for public health were greater.
Intrauterine Growth Restriction & Prematurity
IUGR is normally the consequence of placental insufficiency. The placenta is the organ that the foetus uses to obtain nutrients and oxygen from the mother. In a proportion of pregnancies, for a variety of reasons, the placenta does not grow properly and is not able to satisfy the enormous requirements of the foetus. In these circumstances, the ‘genetic program’ can not build the brain in the way it was supposed to, so that reprogramming, and consequently reorganization, must occur.
In prematurity, which is typically characterised by intrauterine infection, the baby is exposed to the ‘outer world’ when its brain is still in the critical construction phase. Changes in temperature, feeding, sound and light have, as of yet, unknown effects on the developing brain.
Cerebra Foetal Research Programme
The Cerebra Foetal Research Programme incorporates a variety of projects that aim to diagnose abnormal brain development in foetuses and new-borns, and implement specific interventions to prevent, or reduce its impact. The main interrelated research lines cover problems of maternal, foetal and neonatal health, and are summarised below.
The main objective of this research line is to develop a quantitative imaging biomarker for early diagnosis of neurodevelopmental disorders based on the imaging of the brain connectivity (the way neurons connect the different brain areas). To accomplish that, different techniques of Magnetic Resonance Imaging (MRI) are being used, including diffusion, functional and anatomical MRI.
Neurological Programming (Microstructure and Metabolomics)
In this research line, the group focuses on identifying the structural (the way neurons and other cells are organised within the brain microscopically) and metabolic differences in the brain of foetuses and children that are diagnosed with growth restriction and are at risk of developing neurodevelopmental problems. This requires the development of new mathematical algorithms that will allow the interpretation of subtle brain changes that could be used as new biomarkers.
Diagnosis and Therapy in IUGR
This line of research aims to identify before birth, which babies with growth problems will have abnormal neurodevelopment. The majority of babies considered small in utero are naturally smaller and will face no future problems. However, a proportion of babies are born small due to problems with the placenta. These babies face neurobehavioral problems at birth that persist into childhood.
The Foetal Medicine Research Centre has developed non-invasive methods to measure how much blood reaches the brain, and have described that this is a strong marker of increased risk for neurodevelopmental problems. The prenatal identification of babies at risk is especially important because it would allow us to take preventive measures during pregnancy and early childhood.
The main objective of this line of research on prematurity is to advance our knowledge of the causes of preterm birth. Despite improvements in managing pregnancy, prematurity is still a common outcome and is the leading cause of perinatal morbidity and mortality. It is crucial to understand what triggers premature delivery so that we can prevent it and improve perinatal outcomes.
The Foetal Medicine Research Centre is trying to refine detection of patients at risk of preterm delivery as well as optimise the management and care of neonatal patients in the clinical level. The group hopes that the development of this research line will minimise needless intervention and over-treatment, streamline patient management and achieve the best possible results.
The main objective of the research centre is to reduce the number of instances of adverse neurodevelopment in children and adults and make a difference in their lives. An important contribution of the team to that extent is the implementation of their research findings into clinical practice through their involvement in the writing of clinical national and international guidelines.
The group is also committed to sharing and spreading their knowledge in maternal-foetal medicine with the general public. They have launched Inatal, the first social website directly related to a medical referral centre. Inatal is aimed to pregnant women with no pathologies but doubts and concerns, and provides objective, useful information about health issues while encouraging the active participation of its users.
In the Cerebra research programme 2008-2013, a multidisciplinary research programme for the evaluation of diagnostic techniques and intervention measures for prenatal brain damage using growth restriction as a model, the Foetal Medicine Research Centre has achieved significant advances in our understanding of brain injury of prenatal origin. They demonstrated that even milder forms of foetal growth restriction are associated with a high risk of neurological damage, improved current understanding and changed clinical management of one of the major cause of neurodevelopmental problems in children. However, as usual in research, discoveries have led to new questions, challenges and ideas for better ways to improve even further towards a real reduction in the number and magnitude of neurodevelopmental problems of foetal origin.
The next six years
Cerebra are delighted to be in a position to provide funding for the Foetal Medicine Research Centre at the University of Barcelona for a further 6 years (between 2014 and 2019) to continue the innovative and influential work in the area of perinatal brain damage.