EPICure 1995

Professor Kate Costeloe (Homerton Hospital, London) and Dr Alan Gibson (Jessop Hospital for Women Sheffield) carried out the first phase of the study in 1995, helped by Sally Carne and Fiona Stacey. They were responsible for the original data collection and collating all the returns at one year of age. Joan Morris and Enid Hennessy were the study statisticians. Serono Laboratories UK Ltd funded this part of the study.

The first phase of the study involved every maternity unit in the UK and the Republic of Ireland – all 276 of them.  All deliveries between 20 and 25 weeks 6 days of gestation were recorded.  Once a baby was admitted for neonatal care a full record was completed so we had information on what happened after birth.

In the 10 months of 1995 from March 1 to Dec 31, 4004 births were registered.  Of these 811 were admitted for neonatal care and 314 were discharged home.  Survival ranged from 2 babies (9% of admissions) at 22 weeks, 26 babies (20%) at 23 week, 100 babies (34%) at 24 weeks, to 186 babies (52%) at 25 weeks.

We identified the proportions of babies who had evidence of injury on brain scan, bronchopulmonary dysplasia (BPD) (sometimes called chronic lung disease), treated eye problems from retinopathy of prematurity and the factors associated with them.

All of the details are written up in a scientific article referenced here.  The findings are not described in any great detail here as we now have newer information from births in 2006 – EPICure2.

Survival rates have continued to improve since 1995 and we show this in the overview section.

The second part of this study, compromising the assessments at 2.5 years, was co-ordinated by Professor Neil Marlow (University of Nottingham) in liaison with Professor Kate Costeloe and Dr Alan Gibson. Dr Nick Wood and Mrs Heather Palmer co-ordinated the study. 

Dr Clare Lawson performed all the training in developmental assessment and Ms Enid Hennessy advised on the statistics. This part of the study was funded by Serono Laboratories UK Ltd and Bliss.

This phase of the study was supervised by a steering group:

Each child was examined by an independent paediatrician to determine health status in terms of presence of disability, medical and neurological morbidity, developmental performance and behaviour. In addition, hospital admissions and community support needed were recorded to facilitate an assessment of the burden of morbidity to the child and family after an extremely preterm birth.

Ten paediatricians performed the assessments:

Prior to starting assessments, a training course was arranged to provide a standardised approach to neurological examination and developmental assessment.

Each child had a formal medical and neurological examination, together with a developmental assessment. All parents were asked to complete a questionnaire concerning their home life and their perceptions of their child's behaviour. During the 10 months of the study the examiners provided random video assessments of the developmental testing which were scored by an independent psychologist to ensure each doctor was consistent in their testing.

A formal report detailing the neurological and developmental assessment was passed to the local lead paediatricians for each child, and a summary was sent to the parents.

Assessments

We traced all the babies when they were 2.5 years old and found that 6 of the 314 babies had died since discharge from intensive care leaving a cohort of 308 children. Some had moved abroad with their families (our funds did not stretch to trips to these locations unfortunately!), which left 302 children available for follow up. 283 families accepted our invitation to an assessment (92%).

Everyone was asked to come to a clinic / hospital for an assessment by one of the EPICure assessment team. For a few who could not get to clinic we visited the child at home.

We tried to see everyone as close to 2.5 years after they were supposed to be born as possible. We also had information from local paediatricians about how well each child was doing at one year of age so where we couldn't see children at 2.5 we at least knew how well they were doing at one year. 

Results

We used the information to work out the proportion of children who survived with disability and so were able to provide information that doctors could use on both survival and the chances of a severely disability as the child grew up. We were able to show that those who had no disability tended to be females, whose mothers had received steroid injection before birth and had a normal newborn scan.  These data were then used to inform national discussions about when we should provide care and the risks associated with it organised by the Nuffield Council on Bioethics (2006). These were published in a very valuable document that remains relevant today (www.nuffieldbioethics.org) and were used to develop a framework for the care of women in labour at extremely low gestational ages (Wilkinson et al 2009; see publications list for references to both documents). These have now been updated {Mactier 2019} using data from our study combined with other national or large population studies so parents and doctors can see how we use these important data in practice.

Publications from EPICure are found here.

Thanks

We have to thank all the parents and their children for allowing us to carry out this study as it was extra work for all of them and without it we couldn’t be confident we had the correct information to guide our care.

The third study involved children being assessed at school between 5.5 and 7 years of age. The principal researchers for the third study were Professor Neil Marlow and Professor Dieter Wolke and Enid Hennessy provided statistical advice. Funding was provided by Bliss and PPP Healthcare (now the Healthcare Foundation). The study was co-ordinated in Nottingham by Mrs Heather Palmer with Dr Melanie Bracewell and Catherine Bamford as research fellows.  We recruited paediatricians and psychologists who worked in pairs to carry out the assessment:

Assessment Team

For this phase of the project it was decided to try to see children in their school environment to see how they were settling in and to see if being at school had identified any new problems that were not apparent at 2.5 years

We attempted to trace all the children at 6 years of age: 15 were living abroad and we were unable to contact a further 29 families. 241 (78%) families allowed us to contact their child's school to arrange an assessment.

Some schools were unable to accommodate us and for these we saw the child in an outpatient clinic. A few parents asked in advance for us to see their child outside of school and these happened either in an outpatient clinic or at home.

Each assessment involved the child being seen by a paediatrician and a psychologist who also assessed another, non prematurely born child, on the same day. The other child was often a classmate. The two children were not compared as individuals but the results of the assessments of each group were compared.

Paediatric Assessment We used an up to date test called the NEPSY to assess fine motor, visual and attention skills. The Movement Assessment Battery for Children was used to assess performance and gross motor skills. (Where more appropriate, some children had a Griffiths developmental test instead to assess the same set of skills). The children also performed a number of simple tasks to determine their hand preference. A full medical was undertaken, including looking at how well the arms and legs moved, eyesight, hearing, breathing, blood pressure and growth (height, weight, arm and head size).

Psychological Assessment We used a test that gives us an overall idea of intelligence, a bit like an IQ score (the Kaufman ABC), as well as tests to assess reasoning, verbal skills and memory (the Pre School Language Scales and the Phonological Abilities Test).  

Following the assessment, the parents of each child who had been assessed were sent a report detailing the findings of both paediatrician and psychologist. Parents were sent two copies of the report in case they wished to pass one onto the school or their GP. Parents and teachers also contributed to the picture of how well the children were doing. All parents were asked to complete two questionnaires, one about their child's health and behaviour and another about their family life. We also asked the child's teacher to complete a questionnaire to give us information of how they thought the child was settling at school. 

Once we had completed all this we had to score up all the tests and start the analysis. These results are published in medical journals (see here) and have been reported in the news and on television for example the BBC's panorama programme. 

A summary of the results can be found here.

Overall, we saw 241 of the EPICure group which was just over 80% of those who were in the UK and Ireland at the time of the assessments. The age range was 62-87 months with an average of 6 years 4 months. This is a very high follow up rate - what a fantastic response by our families - but we hope we could see nearer to all of the children next time.

Firstly, we looked at what we termed disability in a similar way to how we had done at 2.5 years. Using conventional ways of classifying this, compared to our findings at 2.5 years we found that a similar number of children were free of disability (just under half) and that just under a quarter had moderate or severe problems.

Over 86% of those who had the worst problems at 2.5 years still had major problems at 6 years. We also found a similar number of children with cerebral palsy but in only half of these was the disability interfering badly with their day-to-day activity. The results are summarised in the graph below:

One of the problems of trying to evaluate results such as these is that most of the problems faced by extremely premature children as they grow up relate to learning and their ability in the classroom. The better comparison to do is with their classmates. This is how BBC Panorama reported the results and is considered by Professor Dieter Wolke, the psychologist working on the study, to be the correct way of looking at these results. When we do this, however, the classmates scored better than average in tests, which often happens with tests that were drawn up 20 years ago.

When we re-do the classification using these better scores as reference, just over 4-in-10 EPICure children are doing significantly worse than classmates (see Figure 2) compared to 2-in-20 using the conventional test results (as in Figure 1).

Once again boys seemed to fare much worse than girls, being more prone to disability and having lower scores than girls. We cannot explain this difference, but it has been found throughout the study from its first results in the period after birth.

We only saw small differences between the children born at 25 weeks and those born at 24 or 23 weeks that were not really clinically significant. When we looked at the detailed results of the intelligence test, we did the children were achieving slightly less well than we would have predicted. It appears that being born extremely early seems to make a difference to children's ability to process a lot of information together. Doing tests in sequence they did better than expected but trying to do things at the same time as other tasks (simultaneously) revealed problems. Boys and girls had the same profiles here.

We also did a lot of tests to look at the fine detail of children's hand-eye skills and of their attention (the NEPSY tests). These were, as we would have predicted, lower in the EPICure children and were responsible for some of the extra difficulties that children were having.

We have looked at some of the growth outcomes as we were concerned about the height and weight of the children at 2.5 years. The children haven't shown much sign of catching up with their peers, but their growth has been at a normal rate for the past 3-4 years.

But...despite all these negative comments, it is important to stress that most of the children were doing reasonably well at school, keeping up in the classroom and had normal behaviour patterns.

This is something the recent press interest doesn't really bring out. Many parents have written to us or e-mailed us to point this out and it is something that is very important for parents and professionals to keep in mind.

We were really excited by the results we have, and they helped us to think again about the aspects of our care that we need to target to help improve the outcome for children in the future. We looked hard at the information that we collected in the neonatal period, at things that happened both before and after birth. We saw that some patterns of problems, particularly cerebral palsy and motor problems, may reduce if we can alter some aspects of our care, for example ensuring that all mothers receive antenatal treatment with steroids to help mature and prepare the baby to be born.

Thanks Again!

Once again, we could not have obtained this information without the help of all the children and their parents – and this time their teachers! – and we must thank them for their continued involvement in the study. The strength of our study is that we have included all babies born in Britain and Ireland and thus it really shows the true picture for all extremely premature babies across both countries.

The BBC Panorama programme helped highlight our findings and the full transcript of the programme can be seen at their website.  

We decided to re-examine the EPICure children again as we were aware that several of the assessments were just after starting school and we wanted to have a more complete picture of their educational attainment and their physical development. This collaboration of the EPICure families, their friends at school, and teachers was really helpful and gave us much new information. 

A further group of about 50 EPICure children travelled down to the UCL Institute of Child Health to act as a focus group from whom we collected information about the function of their lungs and sensory system.  In addition, they wore an activity monitor so we could work out whether EPICure children were more or less active than their classmates!

The principal researchers for this study were Professor Neil Marlow and Professor Dieter Wolke, who were joined by Professor Janet Stocks, Dr Linda Frank (now professor) and Dr Suellen Walker from The Institute of Child Heath, London, and Professor Chris Hollis from Nottingham, with Dr Enid Hennessy again providing statistical support.  The Medical Research Council funded this study and EPICure was adopted as an MRC Cohort! We were also joined by other specialists from Prof Stocks team to help with the lung function testing.

Assessment Team

We put together a team of doctors and psychologists for this new study – Sam Johnson first joined the study for this phase and she has continued since!

Once again, the team travelled out to make their assessments at school where possible and we tried to fit everything in over one school day. We expanded our assessments to include lung function tests – using a spirometer – and used a new approach to working out blood pressures and flow – the Sphygmacor. Children whose families volunteered for our Focus Study had more complex respiratory and exercise testing and contributed to a unique study to see if their sensation had been altered by all the challenges they had as babies!

Following our study at 6 years, we wanted to find out how the children were getting on at the end of primary school and whether the problems we identified earlier were still present when the children were 11 years of age. We contacted all the EPICure families and asked if we could go and see the children at school again, just as we did at 6 years. We made the 11-year assessment very similar to the previous one so that the children would feel comfortable and would know what to expect.  Once again, we are delighted to report that we have a great response from the families and 219 of the children took part together with 153 of their classmates from mainstream schools so that we could compare the results between the groups of children.

This is what we found . . .

Disability

Just as we did at 6 years, we classified ‘disability’ into 4 groups – severe, moderate, mild and none:

We found that moderate or severe disabilities in mobility, vision and hearing were rare (10% or less), but learning problems such as problem solving, thinking and reasoning were much more common: the EPICure children had lower IQ scores in general and 40% had scores that were moderate or severely impaired compared with 1.3% of their classmates. Overall, we found that 45% of the EPICure children had a moderate or severe disability. We were pleased to find that this was almost exactly the same as at 6 years of age, so these kinds of problems do not appear to have worsened over time.

Eye checks

One thing that had increased was the number of EPICure children who needed glasses or who had one eye that squinted.  This tells us it is important to get your eyes checked by an orthoptist if you have been born extremely premature.

School and learning

As we know that extremely preterm children often have difficulties with learning, we were very interested in finding out how the EPICure children were getting on in their last year of primary school.

Just as at 6 years, we found that the majority of EPICure children were in mainstream school and seemed to be coping well.  Again, we found that the EPICure children tended to be better with things presented in order (sequential) compared to being asked to do several things together (simultaneous) and were less attentive when carrying out tasks.

We also carried out detailed reading and mathematics tests and found that the EPICure children had lower scores that their classmates and more often had learning difficulties in these areas. In particular, we found that the EPICure children had greatest difficulties in mathematics.

As mathematics seems to be especially difficult for preterm children, Professor Samantha Johnson and other members of the EPICure team are carrying out further studies in this area to try and find ways of helping children with this at school (the PRISM study). We also found that about 2/3 of the EPICure children needed some support in school, either from the teachers or from classroom assistants, psychologists or other health workers.  These findings were extremely useful because they help health workers and teachers in targeting areas where they may be able to help extremely preterm children at school. To help them out we have also produced an on-line learning tool for teachers and parents to learn more about the effects of being born very early which can be found here https://www.nottingham.ac.uk/helm/dev/prism/index.html. Sam talks about the project in a recent podcast for the Times Educational Supplement.

Behaviour and emotions

We asked parents and teachers of all the children to tell us about their feelings and emotions and about their behaviour. We found that the EPICure children tended to have more problems in these areas than their classmates. These kinds of problems tended to be fears and worries and problems sustaining attention and focusing on tasks. We also found that some of the EPICure children had more difficulties interacting with other children and adults and that a very small number might have difficulties that are like autism. This is a new finding and we are carrying out more studies in this area before we can make any definite conclusions about this. We were very interested to find that the EPICure children were not more aggressive, delinquent or disruptive in school and most often did not have any problems that impacted on their daily life. 

Lungs

As you might imagine having had breathing problems as babies, when we measured the lung function either in the focus group or in the main study, the breathing capacity was reduced overall.  However, most EPICure children had results within the normal range.  We also noted that for many children the results improved when they had been given a medicine to open the airways (called a bronchodilator).  The improvement was greatest for children who had had the most severe lung problems as babies.

These findings have some important implications for extremely preterm children –

Exercise

Although some EPICure children said they had more difficulty than their friends with physical activity, there were few other differences and the activity meter showed similar activity levels to their classmates.

Blood pressure

We noted no real differences in blood pressure between the EPICure children and their classmates but in the group who had special testing of their blood flow we noticed that measures of blood vessel stiffness were a little higher than classmates.  What this means is difficult to establish but we can look again at 19 years and see if this has continued.  This might have importance for later health monitoring.

Sensation

We were interested to see if the EPICure children reacted in the same way to hot and cold as their classmates as the experience of the neonatal period might have led to changes in how EPICure children sense pain and temperature (which use the same nerves).  In fact the EPICure children were less sensitive to hot and cold and not more as we might have expected.  There was also no change in the way they behave to painful things or ask for help when they experience pain.

What does all this mean?

Extremely preterm children need

to be careful, to keep fit, to take prescribed medicine if their chest feels tight, they wheeze or cough excessively and to keep away from smoky places and NOT TO START SMOKING themselves, as this is likely to be more harmful to them than their classmates in the long term

When young people turn 16 we have to ask them for permission to contact them and ask about research studies without asking their parents.  Sixteen is also an important time at school with exam results and decisions about what to do next.

We decided therefore to ask all of the EPICure children for permission to contact them personally for the next studies.  We had to do this through their parents initially.

Of course, we couldn’t resist asking for a little information about how they were getting on at school and themselves generally.  We are still waiting for permission to use the school results centrally but we can extend the information when we do have it.

EPICure@19 is the next phase of our story.  Entering young adult life is a time a great change for families and we want to know how the EPICure young people are getting on as the next adventure begins. This assessment was the fourth in our study so far – following on from the first one at 2½ years, the second at 6 years and the last big assessment at 11.

This was a much more difficult assessment as we had so much to think about having analysed all the results from the previous studies. We needed to repeat what we had done before to see how our early assessments predicted those at 19 years and there were new questions that we wanted to find the answers to.

Once again, the study was led by Professor Neil Marlow – now at University College London. Because of the range of tests that we wanted to carry out we had a much larger set of advisors and collaborators:

Dieter Wolke and Samantha Johnson (psychology), John Hurst (respiratory), John Cockcroft (Cardiff – cardiovascular), Sebastian Ourselin (imaging) Joan Morris (Statistics as Enid Hennessy had retired).  The Medical Research Council continued its funding for this study. The researchers were Jo Beckmann (Paediatrician) Helen O’Reilly (Psychology), Suellen Walker (Sensation) and Andrew Melbourne (Imaging). These were supported by Carmel McEniery (Cambridge CVS), Charlotte Boulton (Nottingham, respiratory), Xavier Golay and Isaac Huen (imaging)

Instead of the team travelling out to see participants close to their home, this time we invited everyone to London for 2 days of assessments unless travelling was difficult. This allowed us to use the great facilities in UCLH (Clinical Research Facility and MRI scanner) and also ask our young adults to do some overnight studies.

Findings

We were delighted that 129 EPICure participants and 65 of the comparison group were evaluated as part of this study.  This was a big request to make for young adults many of whom were at university or college.  The data are really important because they tell us not just how well everyone is doing but also how accurate predictions are from our assessments made during childhood.  So far we have published information about long term psychological outcomes such as IQ and mental health, growth, blood pressure and other cardiovascular markers and respiratory outcomes. The data show that the findings from earlier studies are by and large very accurate in predicting what happens in early adult life. There was concern that some aspects of development may be worsened by adolescence but that has not happened. Although opportunity was less for the EPICure group most were highly content with their lives and still in full time education. These publications are still not yet finished and we have several articles and analyses to complete – we will post the references in the publication section in due course.