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A multidisciplinary research programme for the development of new diagnostic approaches and intervention measures to reduce prenatal brain damage using growth restriction as a model

Introduction and background

In the majority of children with neurodevelopmental problems, brain injury occurred during prenatal life. The possibility of diagnosing brain abnormal development in fetuses and newborns, and to implement specific interventions to prevent or reduce its impact, would represent a major breakthrough in public health.

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  1. Human brain development in fetal and post-natal life

The human brain undergoes a long phase of development that starts in fetal life and ends much later in life. The most critical steps take place in the mother’s womb and during the two first years of age. If we take a look at a fetal brain at 20 weeks (mid-gestation), millions of neurons are being generated ever day in the center (an area called the germinal matrix). From there, they migrate to the brain surface to form the grey matter, the external layer where most thinking processes will occur later in life. The grey matter receives so many new neurons that it has not enough space, and the brain surface starts to fold, adopting its typical wrinkled appearance. These millions of neurons soon start establishing the connections with other areas that will be used later in life. Thus, even if the fetus is using the brain in a non-conscious, primitive, fashion, the way this very particular biological computer is constructed will determine how it works for the rest of our life.

This extremely complex process is governed by the information contained in our genes, of course, but also by the environment. Any disturbance may have a critical influence in the delicate sequence of events regulated in the genetic blueprint. For a variety of reasons, the fetus may be exposed to an adverse environment. This will lead to a suboptimal working of the brain. The good news is that brain development is still very dynamic during, at least, the two first years of life. Thus, even if there was a problem during fetal life, we could start measures that would revert or substantially improve the damage caused during fetal life.

  1. Role of fetal problems in neurodevelopmental disorders

One in ten children have neurodevelopmental problems. It is estimated that about two thirds of these are of prenatal origin and in most instances, the problem occurred during fetal life, long before labor started. Severe forms of perinatal brain damage are the best known by the public. They affect about 2/1000 of all newborns, and are expressed by serious complications including cerebral palsy and/or mental retardation.

However, the vast majority of brain problems are manifested as subtle developmental disturbances. These cases are not associated with overt brain injury, but with brain reorganization. This is a broad term used also for adults suffering brain injury, but in this context of fetal and early postnatal life we use it to reflect that the brain was not constructed properly. This may happen for a variety of causes, which we discuss more in detail later. Milder neurodevelopmental problems are expressed mainly as alterations in cognition, thus affecting behaviour, social relations, neuromuscular regulation, learning and memory.

The impact of these “milder” neurological sequelae 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. Parents and even doctors are not aware of the delays in the child’s neurological development. They have often accepted these as part of his/her personality, until neurological dysfunctions manifest overtly in late childhood or adolescence.

  1. Why early (perinatal) identification is so critical?

Identification of fetal brain injury/reorganization as early as possible in life is a major opportunity for public health. The problem involves thousands of families yearly. The “window of opportunity” to revert changes occurring during fetal life is greatest during the first two years of life. Postnatal early stimulation has shown to substantially improve neurological outcome in other conditions. This occurs because brain reorganization continues during the first two years of life. Thus, the growing brain has enough plasticity 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 fetal programming. Therefore, the Unfortunately, early diagnosis is still not possible in a substantial majority of cases. Much is still unknown about how a developing fetal brain adapts to and eventually deteriorates under adverse conditions. In addition, current clinical tests were designed to detect the risk of fetal death, but they are useless to identify subtle changes such as those present in children with abnormal neurodevelopment. Therefore, we need to improve the understanding and current diagnostic means of perinatal brain injury. The two needs go hand by hand, since understanding leads to better biomarkers and vice versa. It is the only way to detect early enough and allowing an opportunity to start early interventions.

  1. Most relevant causes: prematurity and intrauterine growth restriction

As mentioned above, in the majority of instances, children with abnormal neurodevelopment do not have overt brain injury, they suffered brain reorganization. The brain was constructed differently because the environment was different. The list of fetal problems potentially leading to brain injury is really large, but let’s focus in two of the main causes. Indeed, in most instances prematurity and/or intrauterine growth restriction (IUGR) are behind cases of suboptimal neurodevelopment.

  • In prematurity, the baby is exposed to the “outer world” in a moment in which its brain is still in the critical construction phase. Changes in temperature, feeding, exposure to sound and light... have as yet unknown effects on this developing brain.
  • In growth restriction, the brain is not receiving enough nutrients, so the blueprint has to be executed with less pieces. This will lead to a different construction where some areas are prioritized in favor of others.

Over the last 10 years our group has worked on both, but we have focused more on IUGR because there was much less known about this disease, the challenges for research were greater, and so were the opportunities for public health.

  1. Intrauterine growth restriction: a recently discovered cause of brain problems

IUGR is normally the consequence of placental insufficiency. The placenta is the organ that the fetus 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 fetus. In these circumstances, the “genetic program” can not build the brain in the way it is defined in the genes, so that reprogramming -and consequently reorganization- must occur. Although we are still defining exactly the mechanistic steps, our most plausible explanation of what happens is that this reorganization will bring the building of the brain to an earlier stage in human evolution. Consequently, superior functions, i.e. cognition and fine motor regulation, which were the latest to be acquired during evolution, are the first to be affected by this process so that more basic functions are preserved.

Some statistics about IUGR:

  • Approximately 5-6 % of newborns, about 65,000 yearly in the U.K. and 600,000 in Europe, are born small for gestational age.
  • We believe now that more than two thirds will present features of abnormal neurodevelopment, up to 40,000 children yearly in the UK and 400,000 in Europe.

For a long time it was thought that growth restriction was, in a majority of cases, a benign condition. We know now that this is not the case.

  1. Previous Cerebra Research Programme

In the first research project, we demonstrated the value of assessing fetal brain perfusion with novel techniques in order to improve the prediction of brain injury and advance in the understanding of fetal growth restriction.

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, we achieved significant advances in our understanding of brain injury of prenatal origin. We demonstrated that even milder forms of fetal 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.

Main scientific goals

The main aim of this research programme, and the main expected impact, is to reduce the prevalence and severity of neurodevelopmental problems of fetal origin. The research will be conducted using intrauterine growth restriction (IUGR) as a disease model, although the findings will be applicable to other conditions, particularly the results on new biomarkers.

This general goal is to be achieved by means of three specific objectives, which are corresponding to the three research workpackages of this programme.

If successful, this research will have an important impact in clinical practice, in the form of new clinical protocols, diagnostic tools and interventions.

WORKPACKAGE 1: To develop a new set of diagnostic criteria to increase substantially the detection of fetuses suffering “restriction” in utero, demonstrating this notion in large clinical studies.

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Refining the understanding and the identification of fetuses at risk.

It is critical to be able to define as best as possible the population at risk. By identifying “mild” growth restriction as one of the main contributors we have taken a huge step forward. This works very well at the level of a population, but from the point of view of families we do not have answer to the question “what will happen in our case?” We still need to improve the selection of individual patients at risk. We can do that partly with brain imaging biomarkers, but these will be always expensive and should be used only in selected cases. A more efficient and realistic way is to improve the selection of cases with measures that we can apply in the majority of patients. With that we will be able to pick up cases that we are now missing, and will avoid dedicating our (limited) resources to patients who do not need them.

  • Challenges: While we have improved, we have discovered that our definitions of “growth restriction” are far from perfect. While not all “small” babies have abnormal neurodevelopment, there are on the other hand instances of mild neurodevelopmental problems occurring in “normally grown” babies. In other words, there might be cases of growth restriction that we are not detecting. In fact, we have good evidence to believe so. Therefore, we need better means of detecting when a fetus is not growing properly because it is suffering placental insufficiency.
  • Opportunities:We have preliminary evidence suggesting that if we change the current definitions we select much better and, importantly, we could pick up a far greater proportion of cases that now are missed. Here are important opportunities to detect brain damage in a larger proportion of cases. If we design proper research and investigate the use of new ultrasound and blood markers, we could substantially improve the definition of “growth restriction”.

In Workpackage 1, we will create a better and more refined identification of intrauterine growth restriction. We are now using only the fetal weight. However, we have developed strong biomarkers that can very subtlety detect initial stages of brain adaptation to an adverse or sub-optimal environment. This goal is ambitious but we believe that it is based on sound preliminary evidence. It might represent a radical change in current practices and an invaluable opportunity for public health to advance in the goal of improving health from the beginning of life. Our vision is that we can have combined algorithms which include the weight percentile and some markers of brain and uterine blood perfusion, which will radically increase the detection rate of thousands of fetuses that are now considered to be normal, because their weight is above the 10th centile.

What we will do: We will conduct a number of ambitious research projects in a very large number of pregnancies that will be recruited and followed up post-natally. We will assess the isolated and combined value of ultrasound and maternal blood biomakers in order to identify the instances of true growth restriction, and consequently of high risk for impaired neurodevelopment.

WORKPACKAGE 2: To develop new biomarkers of abnormal neurodevelopment using cutting edge technologies to study brain development.

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Identifying new imaging biomarkers of brain reorganization.

Once we select patients at risk, we still need imaging biomarkers. These can inform us in a quantitative fashion about subtle aspects of the development of the brain, long before neurodevelopment becomes overtly abnormal. Imaging biomarkers will be particularly important in fetuses, by definition we can not evaluate neurodevelopment, but also in infants, because neurodevelopmental tests are very limited on an individual level due to the immaturity of the brain. Once developed, in clinical practice we will obviously not be using these biomarkers in all patients. They entail the use of expensive equipment. However, in selected cases of high risk of fetal brain injury (not only in IUGR but also in other prenatal conditions) they will provide extremely useful information. In addition, they are an indispensable tool to allow advancing in research. For instance, thanks to biomarkers we can obtain information about neurodevelopment very early in life and we can know whether an intervention is effective in improving neurodevelopment in a more accurate fashion and earlier than using neurodevelopmental tests.

  • Challenge: In the beginning we were looking for brain injury, but now we know that in reality there is virtually never “brain injury” but brain reorganization. This makes the goals of early detection even more challenging. How identifying by medical imaging of a “different” complex tridimensional structure such as the brain, when, in addition, part of the changes occur at a microscopic level?
  • Opportunities: During these years we have demonstrated that new technologies based on ultrasound and MRI can detect and quantify subtle changes in brain microstructure. With these techniques we could predict more accurately the presence of brain injury or reorganizationrisks, we could monitor very early whether there is need for interventions and whether there is a benefit of these interventions. Importantly, we would offer this information for families who suffered problems in pregnancy not only more accurately, but without having to wait for years.

In Workpackage 2, we will advance in current imaging biomarkers and will create new ones. We are now closer and we will continue investigating in quantitative ultrasound and connectomics beyond the programme. We are now starting a fascinating new research line: brain metabolism. Indeed, the use of MRI spectroscopy allows to detect brain metabolites. So far, this type of imaging has been little exploited for the investigation of brain reorganization. We have preliminary evidence supporting that it could work, so we will consolidate a new line of investigation in order to identify metabolites that can be measured non-invasively. We envisage a future in which we have a range of imaging techniques (quantitative imaging, connectomics, brain spectroscopy-metabolism, and possibly others now not imagined) making possible to detect brain injury from very early. Aside from the important field of IUGR, the potential applications of these technologies for the large list of conditions that can result in brain injury during perinatal life (prematurity, infections, rare diseases, exposure to environmental factors…) are uncountable. We have now made substantial progress and have directions to follow: brain microstructure, brain connectivity and brain metabolism. All these three features of the brain become abnormal and all three are potentially detectable by imaging techniques.

What we will do: We will complete some of our started projects in texture analysis and brain connectivity. We will consolidate a new highly promising line, the study of brain metabolites.

WORKPACKAGE 3: If the research would progress sufficiently, to conduct studies assessing whether changes in pregnancy management could prevent or reduce the rate of adverse outcomes.

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Evaluating the impact of interventions in clinical studies.

Once we can select the populations at risk, it is time to start evaluating what can we do to reduce the burden of these problems. Thanks to our and others’ research in recent years, and if we can make advances in the two points above, we should be able to start relevant clinical trials.

  • Challenges: In spite of having described the mechanisms, there is today no effective intervention for preventing or improving neurodevelopment in children who suffered IUGR. There have been a lack of clinical studies on IUGR because the importance of late-onset IUGR was not properly understood. The lack of biomarkers for identifying the risk and monitoring the neurodevelopmental evolution in the first years of life has also made unrealistic any attempt to demonstrate the impact of interventions to improve outcome. Finally, clinical studies require large sample sizes and can only be undertaken in a large institutions and with adequate funding ensuring a well-conducted research leading to the generation of real answers with relevance and a translation into improved clinical practice.
  • Opportunities: Over the last years, we have advanced in the understanding of the disease. Thanks to the research conducted in previous years we think we can select much better which newborns and infants will be at highest risk. Aside from early stimulation of infants at risk, which by itself could be the best intervention, several evidences from human and experimental research provide evidence that certain supplements could improve neurodevelopment. Once we solve challenges 1 and 2, we will be able (1) to select much better target populations of infants suffering IUGR with the highest risk of poorer neurodevelopment, and (2) to implement neurostructural biomarkers which, from very early in life, will be able to inform us about the impact of the tested interventions.

In Workpackage 3 we will implement clinical trials, some that are almost ready and might start during the last year of the ongoing Cerebra program. Some others that will start later. Involvement of other groups in new multinational trials is very likely. These trials should evaluate important notions to clarify the best management strategies (including prenatal and postnatal) to reduce the instances of revert adverse fetal neurological programming due to intrauterine growth restriction.

What we will do: We will conduct clinical studies to ascertain whether we can improve early neurodevelopment changing obstetrical management. In addition, we will conduct clinical trials in children who suffered IUGR with supplements during pregnancy and post-natally to evaluate the effect on neurodevelopment.