Neurodevelopment from the fetus to childhood in individuals with congenital heart disease

Importance
Congenital heart disease (CHD) describes heart problems that develop before birth, affecting almost 1 in 100 babies in the UK. Survival of infants with CHD has improved greatly over the past 50 years, due to advances in diagnostics and heart surgery. Despite this, children with CHD do worse at school, with up to half of children experiencing problems with movement, cognition, memory, hyperactivity, attention, speech and language skills. This presents a large and growing public health problem, whilst the underlying cause remains largely unknown.

Our study
The placenta is an organ that develops in the womb during pregnancy. It is the interface between mother and fetus and provides the fetus with oxygen and nutrients. We will compare the function of the placenta in CHD cases to healthy controls. We will also use ground-breaking MRI scans to examine their brains in unprecedented detail and will compare brain development in babies with CHD to healthy babies in the womb and after birth. We will undertake assessments in these children at 18 months so we can link our findings of placental function, brain development and outcome. We expect to find differences in placental function that help explain why some babies with CHD are more vulnerable to brain damage.

We will also study 7-year old children who have CHD and healthy control children. The children will have a brain MRI and we will test their ability to perform a number of different tasks, which will highlight any problems they may have with cognition, attention, behaviour and how well they can interact with their families and other people. We undertook brain MRI scans when these children were babies and we will see how their brain development just after they were born is related to how well they perform on these tasks.

We will also investigate how parental stress and parenting styles are related to the children's outcome at 18 months and 7 years as it may be possible to modify these factors to help to improve the children's outcome.

This study will improve our understanding of why brain development is altered in some children with CHD, explain why these children experience difficulties at school, and will enable us to identify those children who could benefit from interventions to improve outcome. Provision of effective interventions to protect brain health in these children at an early stage will help place vulnerable children onto healthy developmental trajectories, hence avoiding severe distress to children and their families and expense to society at large.

Congenital heart disease (CHD) is the most frequent congenital malformation. While most infants with CHD now survive, children and adults with CHD who required cardiopulmonary bypass surgery in infancy are at increased risk of adverse neurodevelopmental outcome. The underlying mechanisms leading to these impairments are likely to begin in utero when critical processes of brain development are taking place and may be related to impaired placental function. However, to date, the ability to assess placental function in vivo has been limited and little is known about the role of the placenta in brain development and subsequent neurodevelopmental outcome in children with CHD. In addition, while abnormal brain development has been observed in infants with CHD, information on how specific patterns of brain maturation, and how brain developmental trajectories relate to childhood outcome in this group is lacking.

We will undertake placental MR imaging in CHD cases and controls to test the hypothesis, "placental function is abnormal in fetuses with transposition of the great arteries (TGA) and left ventricular outflow tract obstruction (LVOTO)". We will use state-of-the-art fetal, neonatal and childhood neuroimaging to detail patterns of structural and functional brain development from the fetus to childhood that are related to placental function and childhood outcome. We will also determine the relationship between potentially modifiable factors including parental mental health and parenting styles on neurodevelopment in children with CHD.

These longitudinal studies will provide information about mechanisms underpinning impaired brain health in survivors of CHD which are essential to guide the development of new treatments; will improve our ability to identify at-risk fetuses and infants at an early stage, when intervention with appropriate therapies may be possible; and will provide imaging tools to test efficacy in future trials of neuroprotective therapies.

Academic impact
1. Our study will define for the first time the relationship between placental function and brain development in fetuses with congenital heart disease.
2. Our work will study specific neurodevelopmental trajectories from fetal life to childhood that can help identify those children who are most vulnerable to cognitive and behavioural impairment, in order to develop preventative interventions.
3. By using longitudinal multimodal neuroimaging to predict cognitive and behavioural impairments in childhood we will validate imaging modalities as potential biomarkers of impaired neurodevelopment in children with CHD.
4. Training. We will recruit new research associates and provide them with comprehensive training in multidisciplinary neurodevelopmental research.

Societal impact
Cognitive and behavioural disorders associated with CHD now affect a large number of children and represent a tremendous human, emotional, social, and economic burden for their families and society. The proposed study has the potential to improve the quality of life and health of children with CHD as the causes underlying these cognitive and behavioural difficulties remain unclear. At present there are no established preventative strategies to address the neurodevelopmental problems of children with CHD and to provide necessary family support. As early interventions appear to diminish the adverse long-term consequences of some neurodevelopmental conditions [1], the establishment of neuroimaging criteria to identify target groups for intervention will be important in the medium term for shaping and enhancing the effectiveness of health strategies aimed at improving the long-term outcome of children with CHD.

Our research could inform the work of associated carers and therapists, centres that provide facilities and services, charities /associations that support, advise and campaign for those with neurodevelopmental and cognitive impairments. We envisage the results of the study will be highlighted in the media, contributing to increasing public awareness of the long-term consequences of CHD.

Economic impact
Survivors of CHD are more likely to require special education services. The economic cost of childhood cognitive and behavioural problems has been estimated as ranging from £11,030 to £59,130 per child per annum [2]. Provision of preventative interventions at an early stage has the potential to place infants at high risk of neurodevelopmental impairments onto healthy developmental trajectories, thereby avoiding significant later distress and expense to both the individual, their families and society. This project has the potential to reduce the economic burden related to impaired brain development to the NHS and to education providers.

Potential beneficiaries in the commercial sector include pharmaceutical companies developing targeted therapies for neonatal brain injury. This project has the potential to deliver qualified biomarkers by the end of the 5-year period, which can then be employed in studies assessing neuroprotective treatments, enabling sample sizes in treatment trials to be reduced.

Summary
In summary, our work will have important implications for children with CHD and their families, developmental paediatricians, cardiologists, educators and society at large.
Our work is aligned with the MRC health focus theme of "Prevention and Early detection" enabling earlier diagnosis and action, and our normative modelling approach fits with the MRC health focus theme of "Precision Medicine" enabling individual deviations from the normal developmental trajectory to be assessed. Our work is also aligned with the MRC Priority Challenge "Lifelong mental health - with special emphasis on the young where many lifelong conditions emerge."

References
1. Halperin et al. 2012;9:531-541.
2. Suhrcke et al. WHO Regional Office for Europe; 2008