Understanding the link between child growth and development

Understanding the link between child growth and development

Understanding the link between child growth and development: Dr Joe Freer, NIHR In-Practice Fellow, Barts and The London School of Medicine, Queen Mary University of London (QMUL)

Children’s growth and development are closely connected, but the links between them are complex. Over the past three decades, there has been mounting evidence from low and middle income countries that children growing up in poverty are not meeting their potential for growth and development, including cognitive, speech and language, motor and social-emotional abilities.

Unearthing new insights with the Millenium Cohort study

There has been little recent research in this area in high-income countries such as the United Kingdom. As part of our research into associations between growth and development (see our other article in this newsletter), we recently looked at data from children participating in the Millennium Cohort Study (MCS). The MCS, also known as ‘Child of the New Century,’ has been following around 19,000 children from birth at the turn of the century, through school and into adulthood. We have published our findings in the journal BMC Medicine.

Association between short stature and language development

We found that children in this cohort who had short stature at age three years had poorer performance in language testing from ages three to 11 years. Because shorter stature can be a marker of deprivation and other factors, we used statistical tests to remove the effect of these factors, but found that short stature was still – independently – associated with poorer language development.

Some children who have short stature in early life grow faster at a later point in childhood. We looked at children who had experienced this ‘catch-up’ growth in height, and found that they had better language test scores than children who still had short stature at age five years, but had lower language attainment compared to children who never had short stature.

These results form a useful part of the body of research looking at associations between growth and development.

However, it is possible that factors that were not included in the original dataset, and which we therefore could not examine in our analysis, truly explain the link we found between short stature and poorer language development. For this reason, growth may just be a ‘marker’ of these factors and of poorer language development, rather than the ‘cause.’

Implications and future directions

This research suggests that short stature at age three years or younger could potentially be used to predict future risk of cognitive or educational problems and be used to identify children who would benefit from further assessment and early intervention. Further research is required to investigate this further.

If you would like to get in touch about this study or would like to input into our work, please contact Joe at [email protected] or Helen at [email protected] by email.

Child growth and development in East London study: an update

Child growth and development in East London study: an update

Child growth and development in East London study: an update

Dr Joanna Orr, Postdoctoral researcher, Queen Mary University London (QMUL)

The Child Growth and Development in East London (CGEL) study is currently being rolled out in Tower Hamlets.

The study, conducted by our team at QMUL, is assessing the feasibility and acceptability of the use of growth screening in pre-school aged children. Early results show that screening children at age two as part of the Healthy Child Programme run by health visitors would be possible and likely beneficial to the child population.

The study has been running since May 2022 and has so far recruited over 450 children. Study participation involves the child having their standard two-to-two-and-a-half-year review with the study health visitor. The health visitor then collects some extra information about the child, their health, their circumstances, and the heights of the parents.

The child’s and the parents’ heights are then used to calculate a standardised height score for the child, and a measure of how close each child is to their expected height based on their parental heights.

Children who are below expected levels on either of these measures are flagged for referral to a specialist growth clinic. A follow-up visit will also allow us to look at children’s growth over time. Several children who have been identified by this screening have already been seen at Professor Helen Storr’s growth clinic. Our early experience is that this could have a positive impact on children living with growth-affecting conditions who have yet to receive a diagnosis.

To implement such a screening programme nationwide would require both healthcare providers and families to be on board. Because of this, the study has also collected qualitative focus group data on parents and health visitors’ views on growth screening. We found that parents would like more formal screening programmes for their children and would appreciate more clarity in the roles and what can be expected from the various healthcare professionals involved in their child’s care.

Health visitors were interested in new tools to help assess and refer children. Both parents and health visitors stressed the importance of properly resourcing any screening programme, so that children and families who were found to need support could access it.

Finally, we are also interested in the link between growth and early child development. We are collecting data from the standard developmental test used to assess children at this age (Ages and Stages Questionnaire – ASQ).

We are also conducting more detailed developmental assessments on a subsection of our participants. This data will help us understand the association between growth and development. We have explored this question before, as detailed here

Growth in childhood is becoming increasingly recognised as a marker for a child’s health and environment. Recent reports of the UK’s declining position in the global height rankings for five year olds (NCD Risk Factors Collaboration) have raised questions on what the causes of this decline is, and whether austerity could be to blame.

Our group previously found that short stature in children was highly associated with deprivation, and that the most deprived areas of the country had higher rates of short stature (including East London). Whether these inequalities are also linked to poorer access to healthcare, diagnosis and treatment of growth-affecting conditions is an important future question.

If you would like to get in touch about this study or would like to input into our work, please contact Joanna at [email protected] or Helen at [email protected] by email.

Somatrogon (Ngenla) – Weekly Growth Hormone Therapy

Somatrogon (Ngenla) – Weekly Growth Hormone Therapy

Somatrogon (Ngenla) – Weekly Growth Hormone Therapy: An update from Peter Laing – Advanced Nurse Practitioner, Endocrinology, Alder Hey Children’s Hospital

Background

Treatment with daily GH injections has been a mainstay in the management of GHD for close to 40 years.

Since 2022, the options for management have changed in that there is now the availability of a Long-Acting Growth Hormone (LAGH) formulation that is given once weekly.

Somatrogon is recommended, within its marketing authorisation, as an option for treating growth disturbance that is caused by growth hormone deficiency in children and young people aged 3 years and over.

Following recent marketing authorisation by NICE – www.nice.org.uk/guidance/ta863 – clinicians can consider Somatrogon from one of a range of suitable treatments that are available (including any preparation of somatropin) and discuss the advantages and disadvantages of GH products/devices with parents, carers, children and young people.

The decrease in frequency of injection provided by LAGH has the potential to improve adherence and has the potential for better patient engagement and concordance with treatment, potentially maximise efficacy related to improved treatment outcomes and offer increase flexibility for children and young people.

Evidence from clinical trials has demonstrated that Ngenla (LAGH) is as effective as one preparation of somatropin (Genotropin) with non-inferior annual height velocity achieved.

Weekly administration of LAGH was generally well tolerated in paediatric patients with GHD and the most commonly reported treatment related adverse event was injection site reactions.

Injection site reactions included an increase in injection site pain and erythema.

About Somatrogon (Ngenla)

Ngenla is available in a pen-device with two strengths of formula available – 24mg pen and 60mg pen. The device is pre-loaded with the GH medicine and premixed and is disposable following use.

The 24mg pen can administer doses in increments of 0.2mg that range from 0.2mg to a maximum dose of 12mg per dose actuation.

The 60mg pen can administer doses in increments of 0.5mg that range from 0.5mg to a maximum dose of 30mg per dose actuation.

Both formulations contain 1.2mls of solution per pen device. The recommended dose is 0.66 mg/kg body weight administered once weekly by subcutaneous injection.

Each pre-filled pen is capable of setting and delivering the dose prescribed by the clinician. The dose may be rounded up or down based on the clinician’s expert knowledge of the individual patient needs.

When doses higher than 30 mg are needed (i.e. bodyweight > 45 kg), two injections have to be administered on the same day.

Ngenla dose may be adjusted as necessary, based on growth velocity, adverse reactions, body weight and serum insulin-like growth factor 1 (IGF-1) concentrations, which should be checked 4 days after the prior dose of Ngenla.

Both the 24mg and 60mg Ngenla device use a standard 5mm needle for administration (4mm-8mm needles can be used with 31-32G) and the pen devices do not have a needle cover/guard.

Ngenla is stored in a refrigerator between 2 and 8 degrees and can be taken out of the fridge before use and held at room temperature for up to 4 hours. The pen can be used for up to 28 days after the first use (first injection) before it needs to be discarded.

The weekly dose of Ngenla can be changed if needed and it is recommended that there are at least 3 days since the last dose. Ngenla can therefore be given up to 3 days past the normal dosing day.

Alder Hey experience of Somatrogon (Ngenla)

Since autumn 2022 we have been prescribing Ngenla for some patients with a diagnosis of GHD. The decision to prescribe Ngenla has been based on clinical diagnosis and within the licensed indication > 3years.

Key factors have included both the eligibility of patients who may be considered for a LAGH formulation and following a discussion concerning choice and the preference of the child, young person and their family.

Selecting the most appropriate pen size is important to ensure adequate weekly dosing and to minimize potential wastage of medicine where possible. The recommended dose is 0.66mg/kg body weight and to ensure adequate dosing the dose is rounded up when needed. For patients with a body weight >45kg patients are counselled that they will need two injections given on the same day once weekly as the maximum dose actuation with the 60mg pen is 30mg per injection.

The use of the pen is relatively simple. Training and education of children, young people and their families usually takes a similar amount of time as to the standard daily GH formulations.

Needle covers/guards are not available, for some patients switching from a daily GH formulation this has been a feature that they have on occasion noticed and provided comment.

The volume of medicine per injection is more than with the standard daily GH formulations. This can result in a slightly longer period of injection following administration.

Some patients have complained of minor discomfort but not significantly more than with the standard daily GH formulation.

We have also been arranging for patients to have a blood sample collected for IGF-1 measurement approximately 6 weeks following initiation of treatment, 4 days following their last injection of Ngenla.

Overall, patients have reacted positively to this new GH formulation, reduced burden associated with frequency of injection has been welcome.

In terms of response to treatment we do not have any patients that have been on Ngenla longer than 6 months and we will continue to evaluate the efficacy and safety at approximately 6 to 12 month intervals and assessed by evaluating auxological parameters, biochemistry (IGF-1, hormones, glucose levels) and pubertal status.

Manchester BabyGRO study update

Manchester BabyGRO study update

Foreword: by Chloe Lane

 

We are pleased to see the final report from the Manchester BabyGRO study which has some important implications for early identification of children born small who may be at risk of developing health problems in later life and who would therefore benefit from closer follow-up. We hope that the findings from this research will have a positive impact for many families.

 

The Manchester BabyGRO Study: by Reena Perchard

 

IUGR and preventable disease risks

Intrauterine growth restriction (IUGR) is a condition where growth slows down during pregnancy. This happens in about 3 in every 100 pregnancies and can result in babies being born very small, who are then seen by Paediatricians to check their growth and general health. However, other babies are born small but not severe enough to be called IUGR. They would not see a doctor, but they may be at risk of later health problems.  The Manchester BabyGRO Study has focussed on both groups of babies.

 

There are specific risk factors that we focus on to try and reduce risks of later life illness such as diabetes, heart disease and stroke. As an example, IUGR is related to higher blood pressure; for each 1kg lower birthweight, blood pressure is higher by 1.7mmHg in adolescence. Putting this into context, in adulthood, a lowering of blood pressure by 2mmHg is associated with an 8% reduction in stroke risk.

 

Identifying individuals at greater risk and stepping in early may be key to starting these children on the right path towards a healthy adult life.

 

The Manchester BabyGRO Study

 

The Manchester BabyGRO Study examined which factors in pregnancy impact on risks of later-life illness that begin to present in childhood.

 

The important questions that we addressed were:

 

  1. What factors in the womb are linked to greater disease risks in later life, that begin to show in childhood?
  2. What are the patterns of growth in the first year of life, that are worst in terms of risk development in childhood? Can we link these to specific factors in the womb?
  3. What are the processes and mechanisms that lead to development of these risks in childhood?

 

The study had two arms:

 

  1. One examining the rate of growth in babies whose mothers were at risk of delivering a small baby and
  2. Another investigating the levels of risk of later life illness, in children aged 3-6 years.

 

Findings from the study

 

Thanks to all the willing participants and their families, we met all our recruitment targets for the study. We have now completed analyses of the data and we have made links that may help early identification of children who might benefit from closer follow-up.

 

1. The BabyGRO Babies

 

We recruited 80 mother and baby pairs for this arm of the study. All women were identified as being at risk of delivering a small baby, based on their blood tests during pregnancy. Not only did we look at patterns of weight gain, but we specifically examined measures that indicated adiposity (fat) gain. These included skinfold thicknesses (a measure of fat underneath the skin) and body mass index (BMI).

 

By studying patterns of growth in these babies in relation to their growth patterns before birth, we have made interesting links between the two. Those babies who had the severest growth restriction whilst in the womb, put on the greatest skinfold thicknesses between birth and six months. Their gain in BMI was the greatest, showing the potential helpfulness of introducing these measurements in the first few months of life.

 

2. The BabyGRO Children

 

81 children attended the Clinical Research Facility for measurements, which helped us to assess later-life disease risk. These included height, weight, abdominal, arm and thigh circumferences and skinfold thicknesses.  Children particularly enjoyed going in the BODPOD (Cosmed, USA), a specialised piece of equipment that let us accurately measure fat percentage in the body. We measured blood pressure and the rate at which blood flows through vessels.

 

We have studied these data carefully, and have made links between particular childhood measurements, and growth rates of these children before they were born. These growth rates are, in turn, linked to specific measurements of how much blood is getting to the placenta, the organ which supplies the unborn baby with oxygen and nutrients.

 

A main finding was that of a potential triad of associations between growth rates before birth, rates after birth and blood pressure in childhood. Therefore, our evidence supports that those babies who go on to develop blood pressures towards the higher end of the normal range in childhood could be identified in very early life.

 

Half of the children attending for measurements also agreed to a fasted blood test. Therefore, we have measured levels of fat and sugar in the blood, as well as gene activity levels (“transcriptomics”) and the end points of processes that these genes govern (“metabolomics”). In combination, these have led us to identify a key pathway involved in the development of higher blood pressure in children; the arginine-nitric oxide pathway.

 

This could be the key to understanding how we can identify, follow up, and prevent the onset of diseases such as diabetes, heart disease and stroke in later life.

Investigating Behaviour in Silver-Russell Syndrome

Investigating Behaviour in Silver-Russell Syndrome

Investigating Behaviour in Silver-Russell Syndrome: Research Summary

by Chloe Lane, Louisa Robinson, Megan Freeth

Megan Freeth, Chloe Lane & Louisa Robinson

 For the past year, we have been conducting a study to investigate behavioural characteristics observed in SRS. The study involved a play session/semi-structured interview which was used to observe how children play with different toys, their ability to tell stories and how they communicated with the researcher. For older children and adults, this was an informal conversation to find out about things such as friendships, hobbies and school/work. The study also involved completing a few different activities to assess skills such as language, memory and problem solving. We finished visiting families in October 2018 and in total, we saw 15 individuals with an mUPD7 diagnosis and 18 individuals with an 11p15 diagnosis. This was slightly more than our original target so we are extremely grateful to all of the families who took part in the study and made it possible. The findings from the study have been written for publication in a scientific journal and as soon as the article is published, we will share this with the CGF. Below is a summary of the main findings from the study.

Autistic behaviours are broadly defined as having difficulty with social interaction and social communication, as well as displaying restricted interests and repetitive behaviours. Previous research has indicated that autistic traits may be more common in SRS than in the general population. In particular, it has been suggested that individuals with an mUPD7 diagnosis are more likely to display autistic traits, with some also having a diagnosis of an autism spectrum disorder (ASD). Although this research has indicated that autistic traits are common in SRS, the nature of these behaviours has not been assessed in a systematic way, using standardised measures. Therefore, the aim of our research was to use both a gold-standard behavioural assessment and a questionnaire, completed by a parent/caregiver, to identify autistic traits associated with SRS 11p15 and SRS mUPD7. A further aim of the study was to assess cognitive abilities associated with SRS 11p15 and SRS mUPD7. Autistic traits were assessed using the Social Responsiveness Scale, second edition (SRS-2) and the Autism Diagnostic Observation Schedule, second edition (ADOS-2). Cognitive abilities were assessed using the British Ability Scales, third edition (BAS3). Participants in the 11p15 group ranged in age from 4 – 15 years and in the mUPD7 group, participants ranged in age from 8 – 28 years.

In relation to autistic traits, the findings from the questionnaire (SRS-2) indicated that 53% of the mUPD7 participants and 45% of the 11p15 participants were reported by their family member as having some difficulty with social skills and restricted interests/repetitive behaviours in daily contexts. The level of difficulty with these behaviours varied between the groups, with 38% of the mUPD7 participants reported as having significant difficulty with these behaviours, compared with 11% of the 11p15 participants. Furthermore, the level of difficulty with social skills did not differ between the groups but the mUPD7 group were reported as displaying more difficulty with restricted interests/repetitive behaviours. Overall, this suggests that autistic traits are more common in both SRS mUPD7 and SRS 11p15 than in the general population but that these traits seems to be more pronounced in SRS mUPD7. In particular, these individuals may struggle with restricted interests and repetitive behaviours.

Autistic traits were also assessed using an in-person assessment (ADOS-2). The ADOS-2 provides an opportunity to observe whether an individual displays difficulty with social skills and restricted interests/repetitive behaviours in a semi-structured context. The findings from this assessment supported the findings from the SRS-2, with 33% of the mUPD7 group and 11% of the 11p15 group displaying autistic behaviours during the assessment. Once again, this indicates that individuals with an mUPD7 diagnosis are more likely to have difficulty with autistic behaviours. It is important to note that in both groups, a number of individuals did not display these behaviours. Therefore, clinicians should be aware of this increased likelihood of ASD in SRS but consider on an individual basis, whether a full assessment for ASD would be appropriate.

Cognitive abilities were also assessed in order to identify the overall ability of individuals with SRS and whether individuals show consistent strengths and difficulties with specific aspects of learning. Each participant completed several different activities which provided a general conceptual ability (GCA) score. This is equivalent to an IQ score and in the general population, a score of 100 is average. In the 11p15 group, the average GCA score was 99, with scores ranging from 62 (below average) to 140 (above average). This distribution of scores is typical of the general population, indicating that learning is not affected in individuals with SRS 11p15. In the mUPD7 group, the average GCA score was 80, with scores ranging from 57 (below average) to 91 (average). The average score for this group is lower than the general population and the majority of participants had scores in the borderline range. This means that although they do not have intellectual disability, their scores tended to be slightly below average. This indicates that individuals with mUPD7 may have more difficulty with learning than their peers and that additional support in school may be beneficial. Once again, this should be considered on an individual basis. In both groups, there was no evidence of consistent strengths and difficulties between individuals, in relation to the cognitive abilities that were assessed. 

Conclusions

In summary, the findings from this study indicate that some individuals with SRS have difficulty with autistic traits and these tend to be more common in individuals with SRS mUPD7. It is important for families and clinicians to be aware of this increased likelihood of ASD as, in some cases, a full assessment for ASD may be appropriate. In addition, individuals with SRS mUPD7 may be more likely to have difficulty with learning, compared to their peers so it is important to consider whether additional support with learning and development may be useful. It is important to note that there was variability within each group, indicating that some individuals may have more difficulty with autistic traits or learning than others. Therefore, a referral for additional support or services may be beneficial for some individuals with SRS but not required for others.

Communication Abilities of Children with Sotos Syndrome

Communication Abilities of Children with Sotos Syndrome

Communication Abilities of Children with Sotos Syndrome: Research Summary

by Chloe Lane, Megan Freeth, Louisa Robinson

Megan Freeth, Chloe Lane & Louisa Robinson

Sotos syndrome is a congenital overgrowth syndrome associated with intellectual disability. Previous research has reported that individuals with Sotos syndrome often have communication impairments and delayed language development. However, the nature of these difficulties has not been explored in detail. Language and communication skills are fundamental for human interaction. Effective communication can facilitate learning and enable individuals to share information and ideas so it is important to identify the extent to which children with Sotos syndrome struggle with language and communication, as difficulties may impact upon learning and social development.

Two important communicative abilities are language structure and pragmatic language. Language structure refers to understanding the rules governing language, such as the ability to construct coherent sentences in which words are used in the correct order. Pragmatic language involves understanding how to use language appropriately, such as using language that is appropriate to the context. Some individuals may have better language structure skills or pragmatic language skills, so difficulty with one does not necessarily mean that an individual will also struggle with the other. To date, these communication skills have not been investigated in individuals with Sotos syndrome. So, the aim of our research was to establish whether children with Sotos syndrome have difficulty with these skills and if so, whether particular aspects of language and communication are more problematic than others.

Our study included 31 children with a diagnosis of Sotos syndrome, ranging in age from 4 – 16 years. Communication abilities were assessed using a questionnaire (The Children’s Communication Checklist, second edition (CCC-2)), which was completed by the parent or caregiver of each child. The CCC-2 has 70 questions which are designed to assess a range of communication abilities, including both language structure skills and pragmatic language skills, as well as social relations and restricted interests.

In terms of overall communication skills, we found that the majority of children with Sotos syndrome were reported by their parent or caregiver as having difficulties with language and communication. This was defined as having greater difficulty with language and communication than typically developing peers of the same age (children the same age with no diagnosed conditions). There was no difference between overall language structure skills and overall pragmatic language skills, indicating that children with Sotos syndrome have similar difficulty with both of these aspects of language and communication. Furthermore, the findings identified that language structure skills predict pragmatic language skills, meaning that better language structure skills result in better pragmatic language skills for children with Sotos syndrome.

Four specific language structure skills (speech, syntax, semantics and coherence) were compared in order to see whether children with Sotos syndrome had particular difficulty with any of these specific skills. The findings indicated that the participants were reported as having a similar degree of difficulty with all of the skills. Comparisons were also made between the four specific pragmatic language skills (inappropriate initiation, stereotyped language, use of context and nonverbal communication). The findings identified that children with Sotos syndrome were reported as having greater difficulty with use of context and nonverbal communication, compared with inappropriate initiation and stereotyped language. Furthermore, participants were reported as having particular difficulty with social relations.

Conclusions

Overall, the findings from this research demonstrate that the majority of children with Sotos syndrome struggle with language and communication skills and will therefore require support with the development of these skills. In particular, children with Sotos syndrome have difficulty with the consistency of communication across different situations, with understanding and using nonverbal communication, such as eye contact, gestures and facial expressions and with forming and maintaining relationships with peers.

For the full paper, please see: Lane, C., Van Herwegen, J. & Freeth, M. (in press). Parent-reported communication abilities of children with Sotos syndrome: Evidence from the Children’s Communication Checklist-2. Journal of autism and developmental disorders, doi.org/10.1007/s10803-018-3842-0

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