Based Practice Project: Diabetes Intervention Presentation

Managing diabetes in preschool children

ISPAD Clinical Practice Consensus Guidelines

Sundberg Frida, MD, PhD, The Queen Silvia Children’s Hospital/Sahlgrenska University

Hospital and Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

Barnard Katharine Health Psychologist, PhD CPsychol AFBPsS, Faculty of Health and

Social Sciences, Bournemouth University, UK

Cato Allison, Neuropsychologist, PhD, Neurology Division, Nemours Children’s Health

System, Jacksonville, FL USA

de Beaufort Carine, MD, PhD Clinique Pediatrique/CHL, Luxembourg, Luxembourg and

Department of Pediatrics, UZ Brussels, Belgium

DiMeglio Linda A, MD, MPH Department of Pediatrics, Section of Pediatric

Endocrinology/Diabetology, Indiana University School of Medicine, Indianapolis, USA

Dooley Greg, parent of a child with type 1 diabetes diagnosed at age 2, co-founder of the type

1 diabetes blog Inspired by Isabella (www.inspiredbyisabella.com)

Hershey Tamara, Ph D, Psychiatry, Neurology and Radiology Departments Washington

University School of Medicine, Washington, USA

Hitchcock Jeff, parent of a child with diabetes diagnosed at age 2, founder and president of

Children with Diabetes (www.childrenwithdiabetes.com)

Jain Vandana, MD, Pediatric Endocrinology Division, Department of Pediatrics, All India

Institute of Medical Sciences, New Delhi, India

Weissberg-Benchell Jill, Psychologist, PhD Northwestern University´s Feinberg School of

Medicine, Ann and Robert H. Lurie Children´s Hospital of Chicago, Chicago, USA

Rami-Merhar Birgit, MD, PhD, MB, Department of Pediatric and Adolescent Medicine,

Medical University of Vienna, Austria

Smart Carmel E, RD, PhD, Department of Endocrinology, John Hunter Children’s Hospital

and University of Newcastle, Newcastle, Australia

Hanas Ragnar, MD, PhD, Department of Pediatrics, NU Hospital Group, Uddevalla and

Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

This article is a new chapter in the ISPAD Clinical Practice Consensus Guidelines

Compendium. The complete set of guidelines can be found for free download at

www.ispad.org. The evidence grading system used in the ISPAD Guidelines is the same as

that used by the American Diabetes Association. See page 3 in ISPAD Clinical Practice

Consensus Guidelines 2014 Compendium: Pediatric Diabetes 2014; 15 (Suppl. 20):1-3)

Recommendations

• The target HbA1c for all children with type 1 diabetes, including preschool children, is

recommended to be <7.5% (<58 mmol/mol) (B).

___________________________________________________________________

This is the author's manuscript of the article published in final edited form as: Sundberg, F., Barnard, K., Cato, A., Beaufort, C. de, DiMeglio, L. A., Dooley, G., … Hanas, R. (2017). Managing diabetes in preschool children. Pediatric Diabetes, 18(7), 499–517. https://doi.org/10.1111/pedi.12554

2

• This target is chosen with the aim of minimizing hyperglycemia, severe hypoglycaemia, hypoglycemic unawareness and reducing the likelihood of

development of long-term complications (B).

• Intensive insulin therapy, i.e. as close to physiological insulin replacement as possible with preprandial insulin doses and basal insulin, should be used, with frequent glucose

monitoring and meal-adjusted insulin regimens. (C).

❖ Insulin pump therapy is the preferred method of insulin administration for young children (aged < 7 years) with type 1 diabetes (E). If pump therapy is not available,

multiple daily injections (MDI), with consideration of use of an injection port, should

be used from the onset of diabetes (E).

❖ For preschool children using intensive insulin therapy, preprandial administration of bolus insulin given for correction if blood glucose is high and for at least part of the

meal is preferable to giving the whole dose during or after the meal (C).

❖ Carbohydrate counting is best introduced at onset of diabetes (E). ❖ The small insulin doses of preschool children may necessitate diluting insulin for

precise dosing (E).

❖ Syringes with ½ unit marking and pens with at least ½ unit dosing increments should be used to facilitate more accurate insulin dosing if a pump is not used (or as a back-

up to pump use) (E).

❖ Continuous glucose monitoring (CGM) can be helpful as an approach to adjusting insulin doses (E). Some CGM devices are approved for this use. If CGM is not

available, 7-10 plasma glucose tests/day are usually needed for satisfactory glucose

control (E).

❖ Injection, infusion, and CGM sites should be properly prepared and regularly rotated in order to reduce the likelihood of lipohypertrophy, scarring, infection, rashes, skin

reaction and dry skin (E).

❖ Injection, infusion and CGM sites should be inspected by diabetes team members at every clinic visit to detect and treat any skin problems, such as skin reactions,

lipohypertrophy or lipohypotrophy (E).

❖ The use of pumps and CGM are often limited by skin reactions to the adhesive. A skin moistener that preserves water can be used to prepare the site a few days prior to

insertion. Topical cortisone (group I or II) can be used to treat skin reactions and to

manage itching after removal (E).

❖ Life style interventions designed to reduce the risk of subsequent cardiovascular disease in children with type 1 diabetes are needed, and should be directed towards the

entire family and not just the individual child with type 1 diabetes (C).

• Family-centred meal routines with restrictions on continuous eating habits (grazing) are important to ensure dietary quality and optimize glycemic control in preschool

children (C).

• Diabetes education should be provided to staff at preschools and schools where children with type 1 diabetes are enrolled, in order to ensure that equal participation in

all preschool/school activities occurs and is safely managed (E).

• Optimal glycemic control, involving the minimising of both hypo- and hyperglycemia will give the child the best opportunity to concentrate, participate and learn whilst at

preschool and school (C).

• Weight, height (or length if < 18 months) and BMI SDS (or percentiles) should be monitored on growth charts in all children with type 1 diabetes (E).

Introduction

3

This chapter focuses on components of care unique to toddlers and preschool-aged children

with type 1 diabetes. These guidelines are written in particular for children with type 1

diabetes aged 6 months to 6 years. Children <6 months of age at diagnosis should be

suspected of having diabetes other than type 1 diabetes, including monogenic diabetes, and

their management is discussed in the ISPAD guideline on “The diagnosis and management of

monogenic diabetes in children and adolescents” (1).

Preschool children are dependent on others for all aspects of their care. For the families

(primarily parents) of preschool children with type 1 diabetes, their diabetes teams, and other

caregivers, including school and day care staff members and babysitters, treatment is a

constant challenge. Yet, despite this hurdle, it is important to strive for normoglycemia, as

current knowledge about the implications of dysglycemia makes reducing the likelihood of

acute and chronic complications imperative from the time of diabetes onset. Optimizing

glycemic control for children in this age group often requires treatment using strategies that

differ from those employed for older children and adolescents with type 1 diabetes. These

strategies need to take into consideration the cognitive, motor and social immaturity of

preschool children as well as their small body size and growth pattern.

In addition to their dependence on others for insulin administration and glucose monitoring,

preschool children are also dependent on others for aspects of their lifestyle related to healthy

eating and engagement in physical activity. Lifestyle choices and preferences established

during early childhood provide a window of opportunity for ingraining healthy habits that will

be perpetuated throughout the child’s life. The early establishment of positive behaviours is

necessary to ameliorate the high risk of cardiovascular disease that is associated with diabetes.

Providing adequate education and support of lifestyle changes requires that the multi-

disciplinary diabetes team uses a family-based approach to ensure that the whole family is

appropriately supported.

Supporting the family is necessary for promoting health in the preschool child with type 1

diabetes. Early childhood is important for establishing the “salutogenic” (health promoting)

capacity needed for a long life with type 1 diabetes (2). The core aspect of a person’s

salutogenic capacity is a good “sense of coherence”, consisting of an everyday perception of

comprehensibility, manageability and meaningfulness of health promoting actions taken in

everyday life. The main sources of the child’s salutogenic capabilities are the parents.

Supporting the parents to endure the burden of intensified insulin treatment, including their

need for counselling and sleep, is essential to promote and maintain the health and well-being

of the child. It is also important to support the parents to involve the child in diabetes-related

tasks such as helping to select finger for monitoring, site for injection/infusion, and to

encourage age-appropriate positive problem solving strategies when diabetes-related

problems occur.

Screening and promotion of optimal health related quality of life should be regularly

undertaken in preschool children with type 1 diabetes as in any child with type 1 diabetes. It is

important to use validated parent and parent-proxy screening questionnaires to capture factors

important to the quality of life of children and their parents as both are important and

impactful on diabetes management.

Children younger than seven years of age with type 1 diabetes constitute a minority of the

population of all pediatric patients with type 1 diabetes. In small centres this will make the

4

number of very young patients small and the time needed to gain experience in care of this

patient group will be longer. Close collaboration between centres is necessary in order to

optimize quality of care for preschool children with type 1 diabetes.

Growth and development in the first years of life

Growth and development in the first years of life are characterized by an intricate interplay

between genetic, metabolic, hormonal and environmental factors. “Growth” is an increase in

size of the body and its constituent organs. “Development” is the differentiation of the form

and function of the organs, and refers to not only somatic development but also neuro-

cognitive, and psychosocial development. Rapid changes in growth and development occur in

the first years of life.

In the first year of life children grow 25-30 cm, in the second year approximately 12 cm,

(comparable to the growth spurt in puberty) and in years 3-6 around 6-8 cm per year. Weight

triples in the first year of life, increases by approximately 2.5 kg in the second year, followed

by an increase of around 2kg per year in the next 3-4 years. A peak in subcutaneous tissue

mass is observed around 9 months of age, which subsequently decreases until 6 years of age.

In order for preschool children to experience normal growth and development, it is essential

that they maintain near normoglycemia, aiming to increase glucose time in range, and are

provided with sufficient nutrients (3-6). Restrictive diets or lack of food make it difficult to

provide essential nutrients for growth and development, and should be avoided. It is essential

to monitor weight, height (or length if <18 months) and BMI-SDS (or percentiles) on growth

charts in all children with type 1 diabetes at every clinic visit.

This requirement of sufficient nutrition is in part due to the brain’s high metabolic

expenditure in infancy and childhood (three times higher than in adults). Body proportion at

birth is characterized by a large head and prominent abdomen. After birth the brain and the

cranium continue to grow and reach 4/5 of the adult size by the end of the second year,

growing much faster than many other body parts including the extremities (7).

The brain and cognitive development in children with early onset type 1 diabetes

The brain is metabolically highly demanding, accounting for 20% of the total energy

requirement in adults (8). In the adult, the brain depends on a continuous supply of glucose as

fuel. In the neonate, glucose is essential for different intracerebral pathways (9). Brain

development requires different nutrients to support the five key processes: 1) neuron

proliferation, 2) axon and dendritic growth, 3) synapse formation, pruning and function, 4)

myelination, 5) neuron apoptosis. Regional and temporal variation in glucose utilization

suggests that glucose is essential not only for energy production in the brain, but potentially

for cellular proliferation and synaptogenesis as well (10). In the neonatal and infant brain,

alternative energy sources may be identified such as ketone bodies, which are transported

over the blood brain barrier in times of glucose shortage. The ketone bodies are a substrate for

lipid synthesis, although not essential (11).

In addition to somatic growth, preschool children experience rapid cognitive development.

Children start by investigating objects in their immediate environment, eventually expanding

to exploring anything within reach. Mobility and thus physical activity increases with age.

5

Multiple risk factors have been associated with potential suboptimal cognitive and fine motor

development in children and adolescents with type 1 diabetes. These factors include early

onset of disease (typically defined as < 5 years of age) (12), disease duration, history of

moderate to severe ketoacidosis (including those at diagnosis) (13, 14), severe hypoglycemia

(including seizures or unconsciousness) (15), cumulative exposure to hyperglycemia, and

possibly, the sex of child (16). A meta-analysis showed that the risk of cognitive disruption is

largest for children with early-onset diabetes and that the effect is detectable after a mean

diabetes duration of six years (17). The mean effect size is moderate but might not be large

enough to affect school performance. Clinicians should be concerned about DKA, severe

hypo- and hyperglycemia, all being detrimental for the health of the preschool child.

When reviewing these findings, it is important to distinguish between statistically significant

group differences versus clinically significant findings. Statistically significant group

differences may or may not translate into a functional impact on the daily life of a child,

which has not been fully explored in children with type 1 diabetes. However, we know that

early brain and cognitive development are important for later success in school and beyond.

Glucose uptake by the brain is insulin-independent and mainly driven by the concentration of

glucose. This directly exposes the neuronal cells of the brain to oxidative stress and

glucotoxicity in hyperglycemia, and to lack of fuel in hypoglycemia.

The maturation of grey matter in the brain is intense throughout the toddler and preschool

years. Grey matter development slowly curtails over time beginning around puberty. In

contrast, white matter maturation (that is necessary for processing speed and coordinated,

fluid movements) continues until early adulthood (18, 19).

During toddler and preschool years, the brain is highly sensitive to metabolic disturbances,

and potential abnormalities have repeatedly been identified in MRI studies of young brains

exposed to glycemic extremes, as in type 1 diabetes (20-23). The mechanisms by which early

brain development is affected by type 1 diabetes are not clearly understood. Long-term

exposure to hyperglycemia as well as hypoglycemia (especially with seizures) and oxidative

stress caused by glycemic variability have been suggested as contributing factors. The main

effects seem to occur in the early phase of the disease. It has been suggested that metabolic

conditions such as hyperglycemia and ketoacidosis at diagnosis can be predisposing events

that makes the brain more vulnerable to subsequent metabolic insults (13, 16).

Some, but not all, studies investigating cognition in childhood onset type 1 diabetes, report

decrements in the domains of IQ (Verbal IQ in particular), executive functions (attention,

working memory, response inhibition), delayed memory (episodic recall), and processing

speed (paper-pencil); however, these differences are generally not reported until the children

are studied later in childhood (24, 25). One possibility is that chronic exposure to different

aspects of dysglycemia is additive, and that brain and cognitive changes only become

apparent over time.

Studies that specifically target the youngest children with type 1 diabetes have found only

modest differences in cognitive function compared to peers. Among a large group (n=144) of

children aged 4 to 7 yrs, small differences in the following areas were reported: IQ, especially

verbal, executive functions and internalizing mood disorders (26). The cognitive differences

remained when controlled for parental IQ and level of internalizing mood disorders.

Longitudinal follow up of these children is ongoing and may reveal how these differences

6

change with time, further exposure to diabetes (including hypo- and hyperglycemia), and

brain development (27).

A young child who has executive functioning difficulties, language/literacy deficits, slowed

processing speed, or fine motor coordination difficulties will likely require professional

attention at some point in their youth. Typically, these children are referred to a

neuropsychologist or other learning specialist during the early elementary years. These

children can require specialized tutoring, small group instruction, support in the classroom or

other assistance. For all children with cognitive development issues, early identification and

remediation are crucial to avoid poor outcomes. Optimal glycemic control will give young

children with type 1 diabetes the best opportunity to concentrate, participate and learn whilst

at preschool and school. By achieving good glycemic control, including mitigating prolonged

exposure to hyperglycemia, and by providing early identification and intervention for

academic, cognitive or motor issues, health care professionals are best able to help children

avoid any negative impact of type 1 diabetes on everyday function.

For further reading, the ISPAD guideline on psychological care of children and adolescents

with type 1 diabetes comprehensively addresses this subject (28). See also the ISPAD

Guideline on hypoglycaemia (29).

Glycemic targets and control in preschool children with type 1 diabetes

Optimizing glycemic control for preschool children with type 1 diabetes is crucial for their

future, both with respect to acute and long-time diabetes complications as well as their neuro-

cognition, brain structure and health-related quality of life (HRQoL).

ISPAD published glycemic targets for HbA1c (<7.5%; <58mmol/mol) and for SMBGs (from

optimal to high risk) in the latest guidelines 2014 (30). See Table 1. The targets are applicable

to all pediatric age groups, including preschool children, and the aim should be to achieve

optimal glycemic control. The American Diabetes Association (31) in 2014 redefined blood

glucose targets for all pediatric age groups to be at the same level as ISPAD (32). In UK,

glycemic targets for all pediatric age groups are recommended in the NICE guidelines,

recently updated to an even lower HbA1c level of ≤6.5% (≤48 mmol/mol) (33). (The numbers

are based on the published guidelines).

ISPAD (30) ADA (31) NICE (33)

Preprandial glucose

target

4.0-8.0 mmol/l

(70-145 mg/dL)

5.0 – 7.2 mmol/l

(90-130 mg/dL)

4.0-7.0 mmol/l

(72-126 mg/dL)

Postprandial glucose

target (two hours

post meal)

5.0-10.0 mmol/l

(90-180 mg/dL)

5.0-9.0 mmol/l

(90-162 mg/dL)

Bedtime

Overnight

6.7-10 mmol/l

(120-180 mg/dL)

4.5-9.0 mmol/l

(80-162 mg/dL)

5.0-8.3 mmol/l

(90-150 mg/dL)

HbA1c target <58 mmol/mol

(<7.5%)

<58 mmol/mol

(<7.5%), a lower

target of <53

≤48 mmol/mol

(≤6.5%)

7

mmol/mol (<7%)

can be set if it can be

achieved without

hypoglycemia

It is important that the diabetes team and family share the same target HbA1c and glucose

ranges. Otherwise there is a high risk of discrepancy that can go both ways. Sometimes

parents strive for lower glucose levels than the diabetes team, who at times may articulate that

the family is too strict and take too many glucose tests, especially at night. At other times, the

parents have their own set of higher glucose targets that they feel fit better with their daily

life, finding the targets set by the health care team unachievable.

When evaluating glycemic targets together with the family, it might be useful to express them

as time spent within target and time below or above target. It is important that both the

diabetes team and the families consequently use a language that tells the child that a glucose

value can be high, low or normal, and that the glucose level is never “bad”. The knowledge of

a glucose value often calls for action, but never for blaming or punishing the child.

❖ Parents express that diabetes management style can make a difference. A positive, nonjudgmental, attitude will likely have a positive influence on the way a young child

views and manages his/her type 1 diabetes as he/she gets older. Parents should be

encouraged to adopt a ‘matter-of-fact’ approach to the routines (injections/ pump site

changes, finger pricks and meal times), treating numbers as just numbers/data points,

and not apologizing for aspects of care such as finger pricks, site changes, injections

that cannot be avoided.

Maximizing the amount of time glucose values are in range needs to be the target for multi-

disciplinary diabetes teams, as well as the family/caregivers. Diabetes education (34, 35) and

a clearly set glycemic target (36) are very important (37, 38). Age specific challenges need to

be considered and age-appropriate actions taken to achieve these.

As discussed above, there are detrimental effects of hyperglycemia; yet it is an existing

practice to allow glucose levels to reach the hyperglycemic range in the youngest age group in

order to avoid hypoglycemia at all costs. This is unsafe and treatment should instead aim to

minimize both hyperglycemia and hypoglycemia in the effort to achieve (near)

normoglycemia. If the diabetes team is inexperienced in treating preschool children with type

1 diabetes, support and advice should be sought from more experienced colleagues.

It might not just be the HbA1c level that is important. Glycemic variability may play a role in

the development of diabetic complications (39, 40), but the long term impact of glycemic

variability remains controversial (41, 42). In adults using CGM, glycemic variability was

significantly lower in those without complications compared to those with complications (SD

3.4 mmol/l versus 4.1 mmol/l) despite comparable HbA1c values (43).

Age-specific, family-centered diabetes education plays a key role in achieving metabolic

targets, together with flexible insulin regimens, glucose monitoring and carbohydrate

counting (30, 34, 44).

Hyperglycemia is a major risk factor for (recurrent) ketoacidosis (45) and microvascular

complications later in life (46, 47).

8

Long-term tracking of glycemic control from childhood until adulthood has been reported

(48-52). There is a correlation between the HbA1c achieved within the first few months after

diabetes diagnosis, the glycemic control later in life and the risk for cardiovascular

complications. A lower HbA1c achieved at an early phase of life with diabetes is associated

with a lower HbA1c later on (48-52).

Long-term studies, e.g. the DCCT-EDIC, describe a prolonged effect of prior glycemic levels

on diabetic complications, called glycemic memory. This effect is independent of more recent

glycemic control. The DCCT showed a significant difference of around 2% in HbA1c

between the intensive and conventional groups, but 1 year after the closeout of the study,

HbA1c levels were approximately the same (around 8%) (46, 47). Nevertheless, the intensive

group showed fewer microvascular complications, with a risk reduction in retinopathy even

18 years after the end of the study (53). The DCCT-EDIC results have led to the

recommendation of early tight glycemic control to reduce the risk for diabetic microvascular

and macrovascular complications (47, 54, 55). The ISPAD guideline on microvascular and

macrovascular complications provides a more detailed discussion (56).

Early onset of diabetes at a very young age will lead to a longer duration, which in itself is

associated with a higher lifelong risk of complications, compared to persons with later onset

type 1 diabetes (57). So far, conflicting data exist to whether the prepubertal years contribute

to the same degree as the pubertal years for the development of microvascular complications

(58). Sub-optimal metabolic control in children with early prepubertal diabetes onset may

further contribute to the risk of complications (59-61). Persons with poor glycemic control

during childhood have a high risk of long-term complications, even if substantial

improvement is achieved as young adults (62), and NICE emphasizes the need to reduce the

risk of long-term complications of type 1 diabetes in a population that will have a long

duration of diabetes because the condition starts before adulthood.

Insulin therapy in preschool children.

Insulin treatment guidelines for preschool children are essentially similar to older children and

adolescents, but age-dependent aspects have to be taken into consideration. See the ISPAD

guidelines for further reading on insulin and insulin analogs in pediatric use (63). Worldwide,

most preschool children with diabetes use insulin injections to manage their diabetes.

Although for many of these children insulin pump use should be considered, injection therapy

is used in many centres in the following instances: early in the course of the disease in their

remission period; children who were using an insulin pump but have experienced pump

failures; and if living in limited resource settings where insulin pumps are unavailable.

Approval of insulin analogs in different age-groups is regulated by authorities. Two examples

are the European Medicines Agency (EMA) (www.ema.europe.eu) approvals and the U.S.

Food and drug administration (FDA) (www.fda.gov) as of January 2016 (Table 2).

Approved by EMA from age Approved by FDA for

(studied from age)

Insulin lispro “adults and children” “adults and children”

(3 years)

Insulin aspart ≥ 2 years “adults and children”

(2 years)

9

Insulin glulisine ≥ 6 years “adults and children”

(4 years)

Insulin detemir ≥ 1 year “adults and children”

(2 years)

Insulin glargine ≥ 2 years “adults and pediatric

patients” (6 years)

Insulin degludec ≥ 1 year ≥ 1 year

When using injections for insulin delivery, pain can be reduced by usage of subcutaneous

catheters changed every third day (Insuflon® or I-port®) (64).

Insulin dosing

Preschool children with optimal glycemic control usually need somewhat less insulin than

older children. The total insulin dose has been reported to be 0.4-0.8 U/kg/day (median 0.6

U/kg/day) in preschool children with well controlled type 1 diabetes after the remission phase

(65). Insulin pumps offer both greater flexibility in insulin dosing and a better means to

deliver very small, precise doses of insulin than when using injections (66), and are thus

considered the preferred method for insulin delivery in infants, toddlers and preschoolers with

diabetes, although earlier randomized studies have failed to show an effect on glycemic

control (63). If pump therapy not is available due to lack of economic resources, multiple

daily injections (MDI), with consideration of use of an injection port, can be used. If the

diabetes team is not experienced enough in pump treatment of preschool children, advice

should be sought from a more experienced center to optimize quality of care.

Basal insulin

When using injections for insulin treatment, the special diurnal pattern of insulin requirements

in preschool children should be taken into consideration in designing an individualized basal

dosing scheme. The low requirement of insulin and tendency toward low glucose levels are

often most obvious during the night and especially between 3-6 am. Preschool children often

need much more insulin late in the evening between 9 pm-12 midnight (67-69). This creates

typical patterns when programming the basal rates of an insulin pump used by a preschool

child. With MDI (multiple daily injections), a basal insulin analog can reduce hypoglycemia,

including night-time hypoglycemia, compared to NPH insulin (70-72).

The combination of the low body weight, and thus low total insulin dose, demands special

consideration when using commercially available insulin pumps. A pump with a very high

precision in delivering very small basal rates should be chosen for a preschool child.

Sometimes further reduction in the dose is needed, necessitating dilution of the current U 100

insulin (65, 73, 74), or an intermittent basal rate of 0 U/h for limited periods i.e. every second

hour during the night. Use of these approaches may help to meet the needs of the young child

and the planning of the child’s insulin treatment has to be carefully discussed (with

advantages and disadvantages) with the parents so they are well aware of the benefits and

risks of the chosen strategy. The given insulin should always be prescribed and documented in

normal units to avoid hazardous misunderstandings regarding insulin dosing, especially if the

10

child is admitted to hospital. A pump containing diluted insulin should be labelled with

information regarding the currently contained concentration of insulin. (See table 3).

Advantages Disadvantages

Diluted insulin (ie 10 U/ml

or 50U/ml) • Fine tuning of basal rates

is possible.

• All technical features of pump can be used, such

as temporary basal rate

changes and bolus

calculations.

• Possible to set extremely low basal rates and make

changes in small

increments.

• Risk of mistakes due to the delivered insulin

dose not being the same

as that displayed on the

screen.

• Pain can occur when large volumes are given

as bolus doses.

• Impractical to prescribe doses with diluted

insulin

• More expensive insulin.

“Empty” hours without

basal rate. • The pump gives exactly

the doses displayed on

the screen, decreased risk

of mistakes in dosing for

instance when insulin is

given temporarily with

pen.

• Use of more stable commercially available

insulins is possible.

• Increased risk of occlusion in tubing due

to low flow rate.

• Increased risk of ketosis due to planned hours

without insulin.

• Some of the pumps’ technical features (as

temporary basal dose

changes) cannot be used.

Table 3. Different strategies for delivering minute basal rates. No pumps that are available

today can adjust the insulin concentration. Thus, if using diluted insulin, recommended doses

from the bolus calculator must be recalculated to the diluted concentration.

A glucose and meal-adjusted basal-bolus insulin regimen (delivered by injections or pump)

requires that the basal rate can be fine-tuned by the parents in accordance with the child’s

current insulin sensitivity. Insulin sensitivity can be increased after very active days, such as a

day at the beach or out in the snow (decreased insulin resistance). The overnight basal might

then be reduced with 10-30% when using a pump or a similar decrease in bedtime long-acting

insulin. Insulin sensitivity can be markedly reduced (increased insulin resistance) for example

during fever when the basal rate might need to be increased by 20-100% according to glucose

levels when using a pump, or a similar increase in dose of long-acting insulin. Under these

circumstances, glucose levels have to be extremely carefully monitored and parents need

constant access to support from the diabetes team.

Bolus dosing

11

Although still often used, twice daily insulin dosing in this age group does not give the

flexibility needed in adapting doses to varying situations in daily life. It is difficult to fine-

tune, and difficult for the family to understand and adjust on their own, which is a necessity

for a successful insulin treatment. A glucose and meal-adjusted basal-bolus insulin regimen

(delivered by injections or pump) can be adapted to the preschool child’s daily activities, and

is the preferred type of insulin treatment.

Preschool children often need proportionally larger bolus doses than older children, often

constituting 60-80 % of the total daily insulin dose (TDD). The often used rule of 500

(500/TDD = how many grams of carbohydrate is covered by one U of insulin) for bolus

calculations, as detailed in the ISPAD guideline on insulin therapy (63) rarely fits the

youngest children as it often underestimates the insulin dose (70, 75, 76). Different strategies

can be used; either use 330 or 250 rule (gives 50-100% more insulin) instead of 500, or,

which is preferable, to observe and calculate the correct proportion between insulin and

carbohydrates from real life meals. To calculate the insulin to carbohydrate ratio from a given

meal, divide the carbohydrate content in the meal (in grams) by the insulin dose in units that

gives an appropriate glucose profile after the meal. The need for insulin at breakfast is often

very high, and one might consider using 150/TDD in the calculation, or calculate from real

life meals as above.

The timing of the prandial bolus is important. As outlined in the review by Bell et al (77),

several studies show that preprandial bolus insulin is preferable to insulin administered during

or after the meal and should thus be routinely advised for all toddlers and pre-schoolers, even

the most unpredictable eaters. However, the dose can be split into one pre-prandial and one

during the meal when eating is erratic or new foods are offered.

The dose given during the meal can be based on what the parent estimates the child will eat of

the remaining meal, taking into consideration the food that has just been eaten and the child’s

remaining appetite. Small inaccuracies in calculation of up to 5-7g carbohydrate will usually

not be problematic (78). Larger inaccuracies may result in possible hypo- or hyperglycemia 2-

3 hours after eating, but not immediately (79). These can be anticipated and treated with

additional carbohydrate or a small correction dose of insulin. With a pump, a combination

bolus (also called combo or dual wave bolus) can be helpful, i.e. part of the bolus is given

before the meal and the remainder over 20-40 minutes. If the child stops eating before the

meal is finished, the remainder of the bolus can be suspended.

When giving these relatively large bolus doses, one must remember that they interact with the

need for basal insulin in the following hours. Thus, the total basal rate can be relatively low,

around 20-40% of TDD. In preschool children, it is often estimated that the effect of a

subcutaneous given bolus of rapid acting insulin analogues (e.g. as lispro, aspart, or glulisine)

lasts for only 2-3 hours (active insulin time in pumps) (75).

At breakfast there is often some degree of insulin resistance, and it is common to experience a

marked glucose peak after breakfast in spite of an adequate insulin dose taken before the

meal. The nutritional content of the breakfast has to be discussed and planned by the dietitian,

together with the parents. Increasing the insulin dose (lower insulin-to-carbohydrate ratio) too

much can risk hypoglycemia before lunch. In this situation, it may be helpful to give the

prandial insulin 10-20 minutes before breakfast. The need for a large bolus dose of insulin to

cover breakfast might necessitate a very low or suspended basal rate during the following 3

hours. For some children, a small amount of fruit (5-10g of carbohydrates) may be given 2

hours after breakfast (without insulin) to avoid hypoglycemia, but it is preferable not to

12

establish a practice that necessitates skipping a bolus as this may continue as the child gets

older.

When using multiple daily injections (MDI) with frequent glucose testing and meal-adjusted

insulin dosing, one possible strategy is to give a rapid-acting insulin analog for all meals, with

the exception of the last meal of the day when short-acting regular insulin can be used to meet

the increase in glucose before midnight. Part of the dose can be given as rapid-acting analog

insulin to avoid needing to give the dose 30 min. before the meal; the insulins can be mixed in

a syringe or given as separate injections (if injection aid is used).

Nutritional needs of the preschool child with type 1 diabetes

Breastfeeding should be encouraged for all infants, including infants with diabetes (WHO

recommendation, www.who.int). Complementary foods, preferably iron-rich, should be

commenced from 4 to around 6 months of age (80). If breastfeeding is not possible, an iron-

fortified infant formula should be given as the main milk drink until 12 months of age.

A routine regarding breast- or formula-feeding is important for infants with diabetes as this

enables appropriate interpretation of glucose levels and basal and bolus insulin adjustments.

This may involve 3-4 hourly feeds (of approximately 150-240ml) during the day with

complementary solids. Continuous or hourly breastfeeding is discouraged as this makes

insulin dosing difficult. Breast milk has approximately 7.4 g carbohydrate (CHO) per 100ml;

so for infants 6 months and older it is possible to bolus before the feed for at least 5-7g CHO

and 15g CHO in older babies (>9 months).

Optimal nutrition is required to provide sufficient energy and nutrients to meet the rapidly

changing needs of children at this stage of life. Dietary recommendations are based on healthy

eating principles suitable for all preschool children, with the aim of establishing family based

meal-time routines that promote glycemic control and reduce cardiovascular risk factors.

Carbohydrate counting is important to permit the matching of insulin dose to carbohydrate

intake on intensive insulin regimens (44), and should be taught to the family at the onset of

diabetes. Nutritional advice must be individualised and adapted to cultural and family

traditions. A pediatric diabetes dietitian should provide education, monitoring and support at

regular intervals throughout the preschool years, as parents of preschool children with

diabetes report meal-times as one of the most difficult components of their child’s care (81).

Preschoolers require more frequent review than older children (44), with a suggestion for

reassessment twice annually until age 6 years.

There is international agreement that carbohydrate should not be restricted in children with

type 1 diabetes as it may result in deleterious effects on growth. Care should be taken when

giving dietary education that methods of quantifying carbohydrate do not increase total fat

and/or saturated fat intake (44). Although caregivers may prefer high-fat snacks to avoid

affecting glucose levels, this should be discouraged as they will provide unnecessary calories,

an unhealthy fat intake and negatively impact dietary quality.

Preschool children with type 1 diabetes should consume a diet that emphasizes fruit,

vegetables, whole grain bread and cereals, dairy foods and appropriate types and amounts of

fats. Low fat diets are not suitable for children under two years of age. Lower glycemic index

(GI) choices, such as wholegrain bread and cereals can be introduced as substitutes for higher

GI food choices from two years of age. Iron deficiency can be a concern in this age group;

13

adequate consumption of lean meat or alternatives is important and should not be over-looked

because of the increased focus on carbohydrate.

A guide to the macronutrient distribution of the total daily energy intake in preschool children

is as below. However, this should be based on an individualized assessment.

• Carbohydrates: 45-55 Energy (E) % (44, 82). Average intakes 150g/day in children aged 1½- 3 years. 200g/day in children 4-10 years (83).

• Protein: 15-20 E % (decreasing with age from approximately 1.5g/kg body weight/day in six month old infants to 1g/kg body weight/day in preschoolers) (84)

• Fat: 30–35 E % (less than10 E% saturated fat, less than 10 E% polyunsaturated fat, and more than 10 E% mono-unsaturated fat). Infants less than 12 months may

consume up to 40% energy from fat.

It is important to encourage all children, including children with type 1 diabetes, to eat plenty

of fruit and vegetables. Examples of recommendations from Australia (85), USA (86) and the

Nordic Countries (87) are expressed in different ways but consistent in content, and state

180g vegetables (2 ½ servings) and 150g fruit (1 serving) daily from 2 years of age (85); or 1

½ serving of fruit and vegetables daily between 1 and 3 years (86). 400g fruit/vegetables are

recommended each day from 4 years of age (87).

Research has shown the dietary quality of preschool children with diabetes is poorer than their

healthy peers (88).Studies have shown that preschool children with type 1 diabetes consume

less fruit and vegetables and have higher saturated fat intakes than peers (89) than

recommendations would advise (90, 91). Poor food intake may increase the risk of

cardiovascular disease. Eating habits in young children can influence food choices later in life

(92), so early intervention with increased attention to an increase in fruit and vegetable intake

and decrease in saturated fat is needed. Just like healthy children, children with diabetes may

require up to 10 exposures to a new food before it is accepted (93).

Several studies show that children with type 1 diabetes are more overweight compared with

children in the general population (91, 94), with the youngest children (<6 years) being the

most overweight (95, 96). It is important to plot the growth chart including assessments of

weight for length or height regularly to identify excessive weight gain, in order to commence

interventions that involve the whole family. Encouraging participation in family meals has

been recommended to promote dietary quality (97) and social interaction.

Age-appropriate finger foods should be encouraged for self-feeding, and the reintroduction of

a bottle as an easy method of carbohydrate intake discouraged. Bottles can lead to

overconsumption of fluids, increasing carbohydrate intake and placing other nutrients at risk.

Establishing positive food behaviours and meal-time routines

Establishing positive food behaviours and meal-time routines are important for preschool

children with type 1 diabetes, as these behaviours impact glycemic control (81, 98) and

encourage life-long nutrition practices (92). Normal early childhood development, including

seeking independence, transient food preferences, variable appetite, food refusal and

behavioural resistance often make meal times challenging for parents and carers. Parents of

14

children with type 1 diabetes report more disruptive meal behaviours, including longer meal

duration and more frequent food refusal compared to controls (99, 100); even for children

using insulin pump therapy (101). Research has demonstrated positive correlations between

suboptimal dietary adherence and higher glucose levels (81, 89, 101, 102). Caregivers’ fear of

hypoglycemia associated with food refusal or unpredictable dietary patterns can result in force

feeding, grazing continually over the day and postprandial insulin administration, causing

prolonged periods of hyperglycemia.

Family-centred meals are important to model eating practices and to encourage new foods.

For small children, meal times should be limited to approximately 20 minutes per meal (103).

Conventional insulin regimens require adherence to a structured plan of carbohydrate intake,

and parents frequently report problems with this approach (81). Intensive insulin management

offers greater flexibility in meal timing and carbohydrate quantities.

To assist the reliable intake of carbohydrate at meal-times and to minimise food refusal, the

following strategies should be advised:

• structured meal-times

• avoidance of continuous eating habits

• small snacks including limits on low carbohydrate foods as these fill the child up

• limits on the time spent at the table

• avoidance of force feeding

• reassurance by all team members regarding the usual non-severity of hypoglycemic episodes related to inadequate carbohydrate consumption.

Parents should be advised that postprandial bolus insulin is problematic as it can become an

established habit and also reinforces anxiety about the child under-eating. Fear of

hypoglycemia can lead to under-bolusing for meals, resulting in inadequate bolus doses given

over the day and subsequent hyperglycemia. Continuous eating (grazing) makes interpretation

of glucose levels and insulin dose adjustments difficult. A regular meal pattern with one small

snacking episode between meals (7 to15g CHO) will assist with preventing food refusal as the

child will be hungrier at main meals. A dietitian should advise regarding age appropriate

carbohydrate amounts as it is necessary to ensure the anticipated carbohydrate intake is

reasonable based on age, growth and the child’s previous intake. Unreasonable expectations

of a child’s intake may result in food refusal and subsequent hypoglycemia. Food refusal

should generally be dealt with effectively and similarly to toddlers without diabetes.

Preschool children becoming increasingly independent can recognise parental stress and

quickly learn to use their diabetes as a way of getting their favourite foods. It is important to

emphasise parental patience and to encourage parents not to use food bribes.

All diabetes team members should provide the family with clear and consistent messages

regarding food and meal-time behaviours. Distractions such as the television and toys should

be removed at mealtimes. Research has demonstrated that disruptive child behaviours can be

reduced by establishing specific rules and consequences for mealtimes and teaching parents

behavioural strategies for meals (104).

There is consensus that continuation of support by a pediatric dietician throughout childhood

and adolescence is essential for optimal care.

15

❖ In parental experience, it can be difficult at times to give pre-prandial bolus doses of insulin due to the fear of food refusal and resultant hypoglycemia. Strategies to handle

this need to be discussed with the parents (as above) and the risk of all aspects of

dysglycemia following postprandial bolus doses need to be explored.

❖ Should a child have a high plasma glucose because of eating something unplanned, a calm explanation of the need to cover food with insulin is necessary.

Lifestyle factors in preschool children

The American Heart Association (AHA) has identified certain childhood conditions

(including type 1 diabetes) associated with extremely high risk of cardiovascular disease,

calling for treatments to minimise this risk (105).

Lifestyle habits, such as nutritional preferences (92), physical activity (106) and time spent

sedentary (107), that are established in childhood have a great propensity to follow into

adulthood. Thus, lifestyle factors in early childhood have a dual impact on later

cardiovascular risk, observable both as early markers of atherosclerosis during adolescence

(108) and also as a set of behaviours that influences the child’s risk of cardiovascular disease

as an adult and even into senescence.

Children tend to follow the lifestyle habits of their parents and entire family regarding

physical activity (109), TV watching (110) and food choices (97, 111, 112), and this has been

found to influence children´s food habits throughout their lives (92). Lifestyle supporting

interventions should thus be directed towards the parents and entire family and not the

individual child with T1DM.

There is no contradiction between population-based interventions to promote increased

physical activity or healthier food choices in all children and interventions that are routinely

part of the diabetes care delivered by the diabetes team. Preschool children with type 1

diabetes could benefit from both efforts, but targeted interventions are necessary to meet the

specific needs of children with type 1 diabetes.

Physical activity

Physical activity confers many health benefits for healthy children. A strong graded inverse

cross-sectional association has been observed between physical activity and insulin resistance

(113, 114) and body fat (115). Spending more time in moderate and vigorous physical activity

is associated with decreased cardiometabolic risk factors in children (116). When designing

physical activity interventions to reduce the risk of cardiovascular disease in children,

including children with type 1 diabetes, it is important to focus on high-intensity physical

activity to be most effective (116). Engaging in regular physical activity is also necessary in

order to acquire and improve gross motor skills (117).

Many countries recommend at least 60 minutes per day of moderate and vigorous physical

activity for all children (118), and WHO recommends this at least from five years of age

(119). Some countries have changed their recommendations for physical activity in preschool

children from 60 minutes of moderate and vigorous physical activity to 180 minutes of any

intensity of physical activity per day (120, 121). This change of recommendation has been

questioned because the reduction in the risk of cardiovascular and metabolic problems might

be too low with lower intensity of physical activity (115, 116).

16

It has been shown that outdoor playing and especially spacious outdoor playing environments

are associated with increased physical activity in preschool children (122). Asking families

about the amount of time spent playing outdoors can be a useful way to quantify the physical

activity of a preschool child with type 1 diabetes.

Physical activity should be promoted in all children with type 1 diabetes. Both having

diabetes and being a girl has been reported to be associated with lower levels of physical

activity in preschool children with type 1 diabetes, indicating that particularly young girls

with type 1 diabetes are at high risk of being too physically inactive (123).

Practical monitoring of glycemic control

In this chapter, “plasma glucose” values refer to glucose values measured by capillary blood

test (“finger prick”, “blood glucose monitoring”).

Plasma glucose (SMBG)

Glycemic control is often evaluated with plasma glucose monitoring (SMBG). All families

with a child with diabetes should be taught how to measure and interpret plasma glucose

values. A high precision glucometer (error less than 10%) should be used in preschool

children, both when relying on SMBG for glycemic monitoring and when using the

glucometer for calibration of CGM. Accuracy in everyday monitoring situations should be

ensured by follow-up with the diabetes team. This shall include education on the importance

of ensuring that the fingertips are clean and dry before monitoring plasma glucose, as sugar

on the fingertips is a common reason for erroneously high glucose levels. The child should be

introduced to glucose monitoring and interpretation according to age appropriate and

individual capabilities, as the development of the mathematical understanding of numbers and

time is gradual.

Most children with type 1 diabetes can by the age of seven years be capable of taking plasma

glucose tests and performing some basic interpretation of glucose levels under supervision.

However, this should always be overseen by a parent or other caregiver, since independent

self-care is not expected from any preschool child with type 1 diabetes.

General advice on SMBG monitoring is available in the ISPAD Guidelines on Assessment

and monitoring of glycemic control (29). In children younger than seven years of age, the

recommended testing frequency of 4-6 times per day is rarely sufficient when striving for

target glucose and HbA1c. Even with a higher testing frequency of 7 or 10 tests per day, the

number of undetected hypo- and hyperglycemic events in insulin treated preschool children

are high (124, 125).

Observational studies from different countries show that a common frequency of SMBG in

preschool children with type 1 diabetes is 7-10 tests per day (125, 126). Nighttime SMBG is

recommend by many diabetes teams, and performed by most families with preschool children

(127). Preschool children with diabetes can spend a long time in the hypoglycemic range

without detection, despite night-time monitoring of SMBG (125).

Many parents are sleep-deprived due to night-time testing of plasma glucose (127, 128). The

normal activities of the child have to be interrupted in order to measure a plasma glucose

value during daytime. Thus, SMBG has several limitations as method of monitoring glycemic

control.

17

❖ Parent experience from Children with diabetes (CWD) conferences: “I have seen many young children in the age group of 5-6 who understand both the numbers and

trend arrows on their CGM”. We also know from personal experience that children

who are diagnosed young sometimes grasp ‘the numbers’ of diabetes very quickly.

Continuous glucose monitoring (CGM)

CGM can provide an effective mode of monitoring for low and high glucose levels,

allowing for efficacious insulin adjustment. When available, CGM with alarms is generally

the preferred method for monitoring of glucose levels in children younger than seven years of

age with type 1 diabetes. CGM should be available and utilized as a tool for adjusting insulin

doses.

• Data on CGM use in preschool children are limited, but suggest low overall rates of use (126, 129), often due to financial constraints.

• Parental satisfaction with CGM use is high, in large part because the technology can decrease the likelihood of severe hypolycemia (130).

• When parents/caregivers share their thoughts and interpretations, real-time CGM information, including a color coded screen with arrows, and alarms can often be

understood by preschool children from around age 5-6 years. Talking with the child in

an age-appropriate way about actual CGM information gradually increases the child´s

understanding and participation in their insulin treatment.

• Even if children can have some understanding of this, interpretetaion and necessary steps of action are always the responsibility of the parent/caregiver.

• Use of CGM devices in preschool children can be hampered by issues of adhesion and skin irritation (131, 132).

• The ability of some CGM devices to remotely transmit glucose values to a phone can be of benefit for parents/caregivers who rely on others for part-time care of their child

with diabetes, for example while at daycare or preschool.

• CGM enables deepened analysis and understanding of glycemic patterns (such as postprandial glycemic excursions), and downloading data from the device is a

pedagogic tool for the team when discussing solutions to various problems with the

parents of a child with diabetes.

• Downloading at home by parents should be encouraged, and can form a basis for self- adjustment of insulin doses for experienced families.

Use of insulin pumps with and without CGM in preschool children

Preschool children are unique consumers of novel insulin delivery and device technologies, as

they are dependent on caregivers for all aspects of device use. Recent technologies, such as

pumps and CGM, can be particularly helpful to parents and caregivers of preschool children

who are extremely dependent on fine-tuning of small insulin doses, both with regard to size

and timing of insulin doses.

An insulin pump system is available that can suspend insulin delivery when glucose levels, as

measured by CGM, are predicted to become low, and thus reduce the risk and duration of

hypoglycemia (133). On the other hand, insulin pumps and CGM are associated with

increased cost and may increase the provider burden; insulin pumps may also carry additional

risks associated with pump and infusion set malfunctions.

18

• Insulin doses in preschool children need to be modified frequently as children of this age are growing rapidly and have changing patterns of eating and sleeping.

• The decrease in size of insulin pumps and CGM devices (including the infusion sets/sensors) over the past few years make these therapies more acceptable for

preschool children.

• The safety of insulin pump and CGM use in this population appears to be similar to that seen in other age groups (130, 134).

• It is essential for the family to have access to blood ketone testing to detect problems with the supply of insulin from the pump. See the section on ketone monitoring below

and the ISPAD guideline on sick days (135).

• Regular downloading of data from the pump (and CGM if used), both at home and in clinic, allows patterns of dosing (136) and glucose levels to be recognizable.

• Always give extra insulin with a pen or syringe in case of suspicion of problems with insulin delivery from the pump.

• If the child is prone to ketosis, replacing part of the overnight basal (30-40%) with a small dose of long-acting insulin (detemir or glargine) may help, but might also reduce

the flexibility in basal insulin administration by temporary basal rates.

• Parents of preschool children who switch from multiple daily injections to insulin pumps report more flexibility and freedom, as well as less stress and anxiety related to

their child’s care (137).

• Data suggest a decrease in HbA1c (129, 134) and reductions in rates of severe hypoglycaemia (95, 134) after implementation of insulin pumps in preschool children.

• Insulin pump features that enable automatic bolus calculations based on insulin sensitivity factors and insulin to carbohydrate ratios can aid caregivers in insulin

administration.

• Insulin pump therapy may be effective in helping to manage toddler-eating behaviors by facilitating split bolus dosing.

• The pump calculates “insulin on board”, i.e. how many units from a previous dose of insulin that still exerts a glucose-lowering effect. A phone app that can calculate

“insulin on board” can be used for calculation of bolus doses of insulin when on

injection therapy.

• Although CGM provides an overwhelming amount of data, it is important to look for daily patterns (for example the “modal day” when downloading data), and adjust

insulin-to-carbohydrate ratios and correction factors only after a repeated pattern has

been found.

• The frequency of insulin pump and CGM use varies between centres. Barriers to the use of these treatment options in preschool children need to be explored.

Skin Care

There are very few data on special considerations regarding skin care in preschool children

with type 1 diabetes but CGM-related skin problems seem to be most common in very young

users (132). CGM-related skin problems are not associated with atopy (138). In general,

recommendations for site use (including site selection, site preparation, site rotation) are

similar as for older children. Many preschool children receive insulin injections and insert

infusion sets and CGM sensors in their buttocks, an area often covered by a diaper. The

abdomen, upper arm, and upper thigh regions are also commonly used. For children under the

19

age of 6 using insulin pumps, data suggest that rates of scarring and lipohypertrophy are high

(50% and 45% respectively) but not different than in older children (139).

• Injection, infusion, and CGM sites should be properly prepared and regularly rotated in order to reduce the likelihood of lipohypertrophy, superficial scarring, infection,

rashes, skin reactions and dry skin.

• Injection, infusion and CGM sites should be inspected by diabetes team members at every visit to the clinic to detect any skin problem or lipo-hyper/hypotrophy early, in

order to treat promptly.

• The use of pumps and CGM are often limited by skin reactions to the adhesive. Prepare the site a few days prior to insertion by the use of a skin moistener that

preserves water. Topical cortisone (group I or II) can be used to treat skin reactions

and break the vicious circle of itching after removal.

Ketone monitoring

Measuring ketone bodies in blood (betahydroxybutyrate, BOHB) should be recommended as

the primary method of detecting and monitoring ketosis in preschool children with type 1

diabetes; see the ISPAD Guidelines on Sick days (135). Measurement of acetoacetate in urine

can be used as an alternative, but gives less precise information. As preschool children do not

urinate on command, especially when sick, results from blood ketone testing will be more

easily available both for the child and parent. Blood ketone testing also gives the healthcare

professional much better information to provide advice over the phone or in the emergency

room.

Ketones should be monitored when there is a suspicion of lack of insulin raised either by high

blood glucose (two values above 14 mmol/l within two hours that does not decline on a

correction insulin dose) or when the child shows symptoms suggestive of ketosis (vomiting,

nausea, stomach pain, fever, “unclear illness”).

Elevated glucose levels and ketone levels suggest lack of insulin and should promptly be

treated with injection of insulin 0.1 U/kg (or 10% of TDD) every second hour until BOHB is

below 0.5 mmol/l. If levels are above 3.0 mmol/L, the family should seek guidance by phone

or in person immediately, possibly in an emergency room, due to the high risk of

ketoacidosis. Slightly elevated BOHB (usually <1.0 mmol/mol) in combination with normal

or low glucose levels indicates combined lack of carbohydrate and insulin, commonly

associated with gastroenteritis in preschool children. This can most often be treated at home

with ingestion of sugary fluids and administration of extra insulin subcutaneously. See the

ISPAD Guidelines on Sick days for further advice (135).

Ketoacidosis is a life-threatening acute complication of diabetes that demands care at a skilled

hospital unit. Six percent of children younger than six years in the US and 4% of children in

Germany/Austria (from data from the Type 1 Diabetes Exchange clinic registry and the

Prospective Diabetes Follow-up Registry: DPV) have suffered from ketoacidosis during the

past year (45). Education of families on prevention of ketoacidosis is an essential part of

diabetes care (140). See the ISPAD Guidelines on Diabetic Ketoacidosis for further advice

(140).

20

Hypoglycemia

Hypoglycemia, including fear of hypoglycemia, is a limitation to striving for normoglycemia.

The risk of hypoglycemia presents a major physiological and psychological barrier to

achieving optimal glycemic control, and may result in significant emotional morbidity for

patients and caregivers (29, 141, 142). Young age is traditionally regarded as a marker of high

risk of severe hypoglycemia during insulin treatment (29).The frequency of severe

hypoglycemia has decreased over time in all children (29, 35, 143, 144). In Germany and

Austria, fewer than 2 % of children younger than six years with type 1 diabetes have

experienced a severe hypoglycemic event with seizures/unconsciousness during the previous

year; in US this figure is less than 3% (126).

The erratic daily life of a preschool child (food intake, activity, sleep, sick days) has been

regarded as the explanation for the historically high risk of severe hypoglycemia in preschool

children with type 1 diabetes. Preschool children are not yet able to identify and articulate

their symptoms and it can be very difficult for caregivers to detect these symptoms. Prolonged

nocturnal hypoglycemia is not uncommon in children younger than seven years with type 1

diabetes as detected in CGM studies (125, 145-147),which is associated with a higher risk of

severe hypoglycemia (146).

The fear of an hypoglycemic event, rather than the frequency of hypoglycemic events, is

associated with higher HbA1c and poorer HRQoL (141). The role of fear of hypoglycemia

cannot be underestimated for parents of children with type 1 diabetes (142). Asking about

frequency and severity of hypoglycemia is typical in a clinic visit, but it may also be helpful

to ask about thoughts and feelings during and after the hypoglycemic event. Fear of nocturnal

hypoglycemia is a particular challenge (142). Fear is not correlated with the numbers of

hypoglycemic episodes, but is related to their severity, especially in mothers of children who

have experienced a hypoglycemic seizure.

The use of insulin pumps and CGM has been reported to decrease the risk of hypoglycemia

(148, 149). Insulin pumps with low glucose suspend features appear to further reduce the time

spent in hypoglycemia (150, 151).

The comparison of data between the United States T1D Exchange and German/Austrian DPV

registries showed that an HbA1c of <7.5% (<58mmol/mol) can frequently be achieved in

children younger than six years with type 1 diabetes without an increased risk of severe

hypoglycemia (126). In many countries, children younger than seven years most frequently

have the lowest HbA1c. In Sweden, 74% of insulin treated children younger than seven years

have HbA1c < 7.4% (< 57mmol/mol), and the overall frequency of severe hypoglycemia

(seizures/unconsciousness) in the pediatric age (0-18 y.) is 2.5% (152).

For definitions and further information see the ISPAD Guidelines on Hypoglycemia (29).

Treatment of mild hypoglycemia in infants and preschool children

Oral glucose as tablets, gel or a drink (0.3 g glucose/kg bodyweight) is the preferred method

of hypoglycemia treatment (29, 153). This dose will raise plasma glucose approximately 2.5-

3.6 mmol/l (45-64 mg/dl) (29). It is important not to give too much carbohydrate when

treating hypoglycemia, in order to avoid subsequent hyperglycemia. Giving something that

contains fat (i.e. milk, chocolate) will slow down the gastric emptying, and cause a slower rise

in plasma glucose (154). Sucrose sweetened confectionary should not be routinely used to

21

treat hypoglycemia, as it can lead to increased risk of dental caries and food refusal if the

child learns that sweets are substituted for unconsumed food. It is important that

hypoglycemia is not over-treated, as 5-7 g carbohydrate is usually adequate in raising the

plasma glucose to normal levels for small children using intensive therapy.

To treat hypoglycemia in breast- or formula-fed infants, carbohydrate gel, diluted juice or a

glucose polymer from a spoon or bottle can be offered. Honey should not be given to infants

younger than 1 year due to risk of botulism.

Screening for associated diseases

Early onset of type 1 diabetes is associated with a higher frequency of celiac disease

compared with older children, which affects the treatment situation of the child (155-157),

and may influence the risk of complications and quality of life. Repeated screening for celiac

disease, thyroid disease and other autoimmune disorders is essential (158).

Living with diabetes in the family

For people living with type 1 diabetes and their families, the management of the condition is

complex and individual. Daily challenges imposed by type 1 diabetes include cognitive and

emotional burdens that can take the form of increased vigilance to dietary intake, symptom

monitoring and frustrations with glucose excursions. For caregivers of preschool children

with type 1 diabetes, additional complexities are encountered, including the necessity to adapt

to developmental changes to ensure adequate psychological adjustments for the child and

themselves, and to facilitate care in the context of other care providers such as preschool staff

(159). Clinicians need to be aware of the overwhelming sense of responsibility and worry

which parents of preschool children with type 1 diabetes can feel. Parents who have access to

a supportive network (relatives and/or friends) have lower risk of diabetes related stress and

burn-out (128). It is important to educate secondary caregivers about type 1 diabetes and

insulin treatment. Attention should be given to the needs of the siblings of a child with type 1

diabetes.

As children grow, they understand more about health and illness. When appropriate, it needs

to be explained that diabetes is not caused by eating too much sugar, and that you cannot

catch diabetes from another person. This needs actively to be taught to friends and relatives as

well to avoid common misconceptions about diabetes.

Parents are an integral part of the diabetes team and have the most important supportive role

to play over the years as their children eventually learn to self-manage their diabetes.

Providing this support can be difficult when parents have their own stressors to deal with, and

struggle with the constant vigilance needed to ensure the safety of their child. Dashiff et al

(160) report that parents of older children with type 1 diabetes experience an ongoing

struggle, worry and frustration about their parenting role. During young childhood, parents

take responsibility for all diabetes-related tasks such as insulin administration, dosing

calculations, blood glucose testing, and so on. It is important that they do this in a way that is

neither threatening nor frightening for their child. Involving the child in aspects of diabetes

management as soon as possible (for example finger pricks and carbohydrate counting) is

recommended, so the child can begin to develop a sense of ownership/management of their

own health. A supportive and emotionally warm parenting style is important for promoting

improved quality of life for children with type 1 diabetes (161).

22

Establishing good habits in the early years will form the basis for optimal diabetes self-

management during adolescence and into adulthood (2, 92, 106, 107). In order to create an

environment in which parents feel confident and comfortable, it is crucial that they are

appropriately supported by all members of their multi-disciplinary team and that they have

adequate access to appropriate support when they need it. The way that parents model

diabetes-related tasks will have a direct impact on the way their children learn. Supporting

parents towards a positive adjustment to living with diabetes will help them to effectively

model those tasks and assignments involved in daily life with diabetes. It is important to

engage both fathers and mothers in diabetes care from the onset, and to keep them both

involved in everyday diabetes care throughout the childhood years.

❖ Parents express that it is important to explain to their child in very simple and clear terms what type 1 diabetes involves. There are certain aspects of diabetes management

that are not negotiable (glucose checking, insulin injections/pump site changes, CGM

use, etc), and the child needs to begin to understand that as early as possible. It is

important to involve the child in diabetes management as soon as possible so they can

begin to develop a sense of ownership/management of their own disease. Reinforcing

such an attitude early on will help to shape the child’s attitude and approach to

diabetes in the future.

❖ Parents report that diabetes will often initially disrupt the normal parent-child relationship, as diabetes frequently comes first in the mind of the parent in response to

a child’s requests. It is important for parents to ask themselves, “If my child didn’t

have type 1 diabetes, would I say no to this request?”, and thus strive to re-establish

the normal parent-child relationship.

Screening children for psychosocial distress

Regular screening of children for psychosocial distress is important to ensure that difficulties

are identified early, and appropriate support and treatment plans established as soon as

possible. Most children are not able to complete questionnaires or report on their own level of

emotional distress in a reliable manner until they are approximately 7-8 years of age.

Therefore, either talking with them directly about how they feel, or asking their parents to

report on their children’s psychosocial well-being is recommended. For children that are

older, there are several paediatric measures of depressive symptoms that are validated and

reliable for use with children as young as 7 years of age, varying in length and depth of detail.

These include the Children’s Depression Inventory (CDI) (162) and the Center for

Epidemiologic Studies – Depression (CES-D) scale (163). Both measures are self-reported

questionnaires containing items on types of symptoms (e.g. sadness, low self-esteem) and

functional areas (e.g. not having friends, schoolwork is not as good as it was before, arguing

with others). Pediatric quality of life can be addressed by specific questionnaires such as the

Pediatric Quality of Life Inventory (PedsQL) generic and Type 1 Diabetes modules (164).

These measures offer a child self-report for youth ages 5-7 and also for youth ages 8-18 years.

There are also PedsQL parent proxy reports for children ages 2-18 years (164). Diabetes-

specific emotional distress can be assessed in children ages 8-11 (PAID-C) and teens (PAID-

T) and parent’s diabetes-specific emotional distress can also be assessed (P-PAID-C and P-

PAID-T) in measures developed by Weissberg-Benchell and colleagues. Similarly, diabetes-

specific emotional distress from age 8 can be assessed by the PAID-Parent (PAID-PR) scale

23

and from age 8 years in youth with the PAID-Peds scale, both developed by Markowitz et al

(165, 166).

Parental anxiety can have a direct and negative effect on diabetes management and health

outcomes. There can often be a co-morbidity of depression; however they are two separate

conditions and should be treated separately. They may act in opposite directions with regard

to diabetes management and control, so we recommend assessing anxiety separately from

depression. The CESD is often used as a measure of depressive symptoms in adults, and the

Beck Depression as well as the Beck Anxiety scales are also often used. Worries about

diabetes impact on glycaemic control in children and should be acknowledged and addressed.

Preschool care

Many preschools provide excellent care for children with type 1 diabetes. Parents and

healthcare professionals should work together to overcome any difficulties and ensure the

safety and well-being of the child with type 1 diabetes when cared for outside the home

setting. It is crucial that every child is supported effectively to achieve their full potential.

Legislation protects children with type 1 diabetes in many countries. One example is the

Equality Act 2010 (England, Scotland and Wales) which dictates that schools must make

reasonable adjustments to ensure that children with disabilities are not put at a substantial

disadvantage compared with their peers. For diabetes this means schools ensuring they have

enough staff trained so that the child with diabetes can take part in all aspects of preschool

and school life. Contingency plans must be in place to train replacement staff quickly. The

Kids and Diabetes in Schools (KiDS) program of the International Diabetes Federation (IDF)

offers education and guidance for families and school staff on ways to help children with type

1 diabetes manage in school. KiDS information is available in eight languages (as of

September 2015) and can be accessed online at http://www.idf.org/education/kids.

In addition to ensuring the rights of the child with diabetes, it is important to create trust and

cooperation between the preschool, the family and the diabetes team. An individually written

diabetes management plan is helpful in this cooperation to help the child with type 1 diabetes

(167), and should include information about and practical training for the use of diabetes-

related technologies (168). Both the parents and the diabetes team need to share the

responsibility for educating the preschool institution, especially when the child is newly

diagnosed with diabetes or when additional diagnosis such as celiac disease occurs. Preschool

staff often find carbohydrate counting helpful as it gives them a tool to assess the dose of

insulin to be given in relation to the food intake and current glucose level. In countries where

there are no regulations to support the child with diabetes, the diabetes team together with the

parent organisations should advocate for improved regulations.

❖ Parents express that while regulations certainly help to ensure documentation and agreements on daily care, maintaining a close relationship with the school (staff,

teachers, etc) is equally if not more important to ensure effective daily management of

their child's diabetes. Parents can be in very close contact with the school, including

offering training sessions, educational materials for other parents etc, which will lead

to better and more effective diabetes management. This helps them to feel more

comfortable/less stressed when sending their child to preschool.

Alternative and complementary therapies

24

At times families try alternative indigenous remedies and even discontinue insulin. This can

be avoided if parents are counselled regarding the absolute necessity of insulin for the child’s

survival. Alternative therapies may be tolerated if important for the family as long as they do

not interfere with the regular diabetes care, including insulin doses, glucose monitoring and

healthy food choices, or impact the child’s growth or development or deplete economic

resources needed for insulin treatment.

Care for the preschool child with type 1 diabetes in limited resources settings

Whenever possible, the guidelines described above in the preceding sections should be

followed.

It is important to remember that building a good rapport with the family and providing

comprehensive diabetes education are inexpensive, and remain the most effective strategies to

improve diabetes management by the family (37). Knowledge about the effects of insulin,

food and physical activity on glucose levels are essential to protect the child from acute and

chronic complications of diabetes under all circumstances. The first few visits of the family

are the most crucial in this regard. Initial approach to diagnosis and treatment is based upon

staffing and facilities at specialized centers for the care of young children with diabetes, with

many centers recommending hospitalization. Parents should be counselled and educated in

detail.

The challenges in managing type 1 diabetes in the preschool child are several-fold higher in

resource limited settings. Awareness, health infrastructure and number of medical

professionals trained in the management of childhood diabetes are inadequate for a significant

proportion of the population in many countries in South East Asia and sub-Saharan Africa.

The diagnosis is often delayed, and may even be missed in some cases, resulting in death

before diagnosis. Common misdiagnoses are gastroenteritis, pneumonia, asthma, urinary tract

infection, genital tract infection (candidiasis), enuresis and malaria. Parents may take longer

to come to terms with the diagnosis and the need for life-long insulin therapy. The financial

implications of the condition add to the psychological distress brought about by the diagnosis.

Risk of acute and chronic complications, as well as mortality is higher in these children due to

sub-optimal management (169). In the US, young people of African descent have increased

risk of short-term complications (ketoacidosis and severe hypoglycemia) when adjusted for

socioeconomic status (170), and higher HbA1c even when adjusted for mean glucose levels

(171). HbA1c was higher even when fasting glucose is < 7 mmol/l in black individuals both

with and without diabetes compared to white, but the prognostic value of HbA1c for

predicting cardiovascular disease, nephro- and retinopathy were similar (172).

The financial issues need to be addressed upfront by the treating team. The challenge of

finding ways to support the families lies chiefly with the care providers. The team should be

familiar with the governmental and non-governmental agencies in the area that may provide

financial assistance for procuring insulin and glucose strips, and ensure that parents have

access to these before the child is discharged home.

Most preschool children in resource-limited settings remain on Regular and NPH insulin

administered by insulin syringes. With only Regular and NPH available (as in the DCCT

study), a multiple injection therapy with regular insulin for meals and NPH insulin at bedtime

can be effective in teaching the family the relationship between insulin dose and carbohydrate

content of the meal. Carbohydrate counting can be used in this situation. The challenge to

overcome will be the lunchtime injection at school. It is very important to motivate and

explain this to the school staff as the alternative of giving a twice daily mixture of Regular

25

and NPH does not result in a physiological insulin profile. In a situation where food

availability is unpredictable, a child on twice daily injections will experience hypoglycemia,

while the child on multiple injections can adjust mealtime doses accordingly.

Few patients are able to afford analog insulin and pen devices. The use of insulin pumps is

affordable by a low percentage of the population. Administration of small doses is therefore a

practical challenge. In young infants, parents may be taught to dilute insulin with normal

saline (available in 10 ml vials). The use of syringes with 30 U in 0.3ml allows an accurate

administration of half units, appropriate for most preschool children. Similarly, use of CGM

remains unavailable for most children with type 1 diabetes in the resource-limited scenario,

and frequent self-monitoring of plasma glucose is the only method for monitoring glycemia.

However, even this may not be feasible for some families due to the high cost of glucose

strips. If possible, the child can be recommended a meal plan with a relatively consistent

carbohydrate intake at meal and snack times during the day to match the insulin regimen. The

family can be taught to have a high index of suspicion for hypoglycemia and treating it on

suspicion, relying mostly on urinary glucose monitoring, and to use SMBG at least on sick

days if available (173). With limited number of strips, the family can, for example, measure

before and 2 hours after lunch one week, and before and after dinner the next to get a more

stringent picture of the day compared to random checks.

Another issue that may compound the challenge in resource-limited settings is that some

parents may have low levels of literacy and health literacy, meaning thereby that they cannot

read the numbers on the insulin syringe and on the glucometer. For example, in India, literacy

rate is 74.04% according to the 15th official census in 2011,

(http://www.census2011.co.in/literacy.php). In such cases, it is helpful to identify a suitably

literate relative, friend or neighbour who can undergo diabetes education along with the

parents and assist them in the domiciliary management. The parents should also be

encouraged to learn the basics of reading and writing. In case of low literacy, a simpler insulin

regime such as twice daily dosing with pre-mixed insulin can be given. Hearing the number of

clicks from an insulin pen can obviate the need to read the number of units. Teaching the

parents to recognise ‘Hi’ and ‘Lo’ on glucometer, to treat hypoglycemia based on symptoms

alone, and to recognize hyperglycemia and ketonuria by urinary strips is also useful to prevent

life-threatening episodes.

Vomiting in a child with diabetes should always be regarded as imminent ketoacidosis, and

appropriate treatment should be sought immediately in the absence of knowledge and

diagnostic measurements. If the child is not feeling well with other symptoms, the first line of

treatment should be something containing sugar to treat impending hypoglycemia. This

should be well known by all the older children and adults that are close to the child with

diabetes, and they should know where to readily find a source of sugar.

To conclude, the goals of management of type 1 diabetes in resource-limited settings must be

situated in the context of the resource limited environment and based on the family’s

educational and financial status. Avoidance of acute life-threatening complications and

continuation of regular treatment and follow-up are the immediate goals.

Future needs of preschool children with type 1 diabetes

26

“Diabetes during early childhood creates a psychosocial challenge to the families of these

children. Successful management of infants and toddlers with diabetes depends on a well

functioning and educated family, the availability of a diabetes health care team experienced

in the treatment of these youngsters, and the involvement of the extended family, child care

personnel and others who play a role in their daily care” (Daneman 1999) (174).

The addition of new tools should enable families living with type 1 diabetes to provide

increasingly effective therapy and support for preschool children with diabetes. The cognitive,

motor and social immaturity, as well as the small body size of preschool children must be

considered when designing new equipment, including sensors, insulin pumps and (semi)

closed-loop solutions for insulin delivery.

It is important to include children younger than seven years in both epidemiological and

clinical studies regarding treatment strategies and tools (both technical equipment and

pharmacological) and outcomes; moreover, when the youngest children with type 1 diabetes

are included in these studies, data regarding children with early-onset diabetes must be

presented separately to enable subgroup analysis. Children younger than seven years with

type 1 diabetes constitute only approximately 10% of the population of all children and

adolescents with type 1 diabetes (126, 152), but in many countries the incidence in this

subgroup is increasing most quickly. Collaboration between centres is thus necessary in order

to conduct studies that are sufficiently powered.

References:

1. Rubio-Cabezas O, Hattersley AT, Njolstad PR, Mlynarski W, Ellard S, White N, et al. ISPAD Clinical Practice Consensus Guidelines 2014. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2014; 15 Suppl 20:47-64. 2. Antonovsky A. Unraveling the mystery of health. Jossery-Bass Inc. Publishers, San Francisco, 1987. 3. Gruszfeld D, Socha P. Early nutrition and health: short- and long-term outcomes. World review of nutrition and dietetics. 2013; 108:32-9. 4. Khadilkar VV, Parthasarathy LS, Mallade BB, Khadilkar AV, Chiplonkar SA, Borade AB. Growth status of children and adolescents with type 1 diabetes mellitus. Indian journal of endocrinology and metabolism. 2013; 17:1057-60. 5. Kim MS, Quintos JB. Mauriac syndrome: growth failure and type 1 diabetes mellitus. Pediatr Endocrinol Rev. 2008; 5 Suppl 4:989-93. 6. Prado EL, Dewey KG. Nutrition and brain development in early life. Nutrition reviews. 2014; 72:267-84. 7. Kuzawa CW, Chugani HT, Grossman LI, Lipovich L, Muzik O, Hof PR, et al. Metabolic costs and evolutionary implications of human brain development. Proceedings of the National Academy of Sciences of the United States of America. 2014; 111:13010-5. 8. Leonard WR, Snodgrass JJ, Robertson ML. Effects of brain evolution on human nutrition and metabolism. Annual review of nutrition. 2007; 27:311-27. 9. Brekke E, Morken TS, Sonnewald U. Glucose metabolism and astrocyte-neuron interactions in the neonatal brain. Neurochemistry international. 2015; 82:33-41.

27

10. Caravas J, Wildman DE. A genetic perspective on glucose consumption in the cerebral cortex during human development. Diabetes Obes Metab. 2014; 16 Suppl 1:21-5. 11. Morris AA. Cerebral ketone body metabolism. Journal of inherited metabolic disease. 2005; 28:109-21. 12. Northam EA, Anderson PJ, Jacobs R, Hughes M, Warne GL, Werther GA. Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset. Diabetes Care. 2001; 24:1541-6. 13. Ryan CM. Why is cognitive dysfunction associated with the development of diabetes early in life? The diathesis hypothesis. Pediatr Diabetes. 2006; 7:289-97. 14. McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet. 2012; 379:2291-9. 15. Asvold BO, Sand T, Hestad K, Bjorgaas MR. Cognitive function in type 1 diabetic adults with early exposure to severe hypoglycemia: a 16-year follow-up study. Diabetes Care. 2010; 33:1945-7. 16. Schoenle EJ, Schoenle D, Molinari L, Largo RH. Impaired intellectual development in children with Type I diabetes: association with HbA(1c), age at diagnosis and sex. Diabetologia. 2002; 45:108-14. 17. Gaudieri PA, Chen R, Greer TF, Holmes CS. Cognitive function in children with type 1 diabetes: a meta-analysis. Diabetes Care. 2008; 31:1892-7. 18. Bullmore E, Sporns O. The economy of brain network organization. Nature reviews Neuroscience. 2012; 13:336-49. 19. Giedd JN, Rapoport JL. Structural MRI of pediatric brain development: what have we learned and where are we going? Neuron. 2010; 67:728-34. 20. Bjorgaas MR. Cerebral effects of severe hypoglycemia in young people with type 1 diabetes. Pediatr Diabetes. 2012; 13:100-7. 21. Perantie DC, Koller JM, Weaver PM, Lugar HM, Black KJ, White NH, et al. Prospectively determined impact of type 1 diabetes on brain volume during development. Diabetes. 2011; 60:3006-14. 22. Ferguson SC, Blane A, Wardlaw J, Frier BM, Perros P, McCrimmon RJ, et al. Influence of an early-onset age of type 1 diabetes on cerebral structure and cognitive function. Diabetes Care. 2005; 28:1431-7. 23. Mauras N, Mazaika P, Buckingham B, Weinzimer S, White NH, Tsalikian E, et al. Longitudinal assessment of neuroanatomical and cognitive differences in young children with type 1 diabetes: association with hyperglycemia. Diabetes. 2015; 64:1770-9. 24. Lin A, Northam EA, Rankins D, Werther GA, Cameron FJ. Neuropsychological profiles of young people with type 1 diabetes 12 yr after disease onset. Pediatr Diabetes. 2010; 11:235-43. 25. Perantie DC, Lim A, Wu J, Weaver P, Warren SL, Sadler M, et al. Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Pediatr Diabetes. 2008; 9:87-95. 26. Cato MA, Mauras N, Ambrosino J, Bondurant A, Conrad AL, Kollman C, et al. Cognitive functioning in young children with type 1 diabetes. Journal of the International Neuropsychological Society : JINS. 2014; 20:238-47. 27. Cato MA, Mauras N, Mazaika P, Kollman C, Cheng P, Aye T, et al. Longitudinal Evaluation of Cognitive Functioning in Young Children with Type 1 Diabetes over 18 Months. Journal of the International Neuropsychological Society : JINS. 2016; 22:293-302. 28. Delamater AM, de Wit M, McDarby V, Malik J, Acerini CL, International Society for P, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Psychological care of children and adolescents with type 1 diabetes. Pediatr Diabetes. 2014; 15 Suppl 20:232-44. 29. Ly TT, Maahs DM, Rewers A, Dunger D, Oduwole A, Jones TW, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2014; 15 Suppl 20:180-92.

28

30. Rewers MJ, Pillay K, de Beaufort C, Craig ME, Hanas R, Acerini CL, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatr Diabetes. 2014; 15 Suppl 20:102-14. 31. American Diabetes A. 11. Children and Adolescents. Diabetes Care. 2016; 39 Suppl 1:S86-93. 32. Chiang JL, Kirkman MS, Laffel LM, Peters AL, Type 1 Diabetes Sourcebook A. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care. 2014; 37:2034-54. 33. NICE (National Institute for Clinical Excellence). Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people and adults. National Institute for Clinical Excellence, 2015 (nice.org.uk/guidance/ng18). 34. Lange K, Swift P, Pankowska E, Danne T, International Society for P, Adolescent D. ISPAD Clinical Practice Consensus Guidelines 2014. Diabetes education in children and adolescents. Pediatr Diabetes. 2014; 15 Suppl 20:77-85. 35. Rosenbauer J, Dost A, Karges B, Hungele A, Stahl A, Bachle C, et al. Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using prospective multicenter data from Germany and Austria. Diabetes Care. 2012; 35:80-6. 36. Swift PG, Skinner TC, de Beaufort CE, Cameron FJ, Aman J, Aanstoot HJ, et al. Target setting in intensive insulin management is associated with metabolic control: the Hvidoere childhood diabetes study group centre differences study 2005. Pediatr Diabetes. 2010; 11:271-8. 37. Cameron FJ, de Beaufort C, Aanstoot HJ, Hoey H, Lange K, Castano L, et al. Lessons from the Hvidoere International Study Group on childhood diabetes: be dogmatic about outcome and flexible in approach. Pediatr Diabetes. 2013; 14:473-80. 38. de Beaufort CE, Lange K, Swift PG, Aman J, Cameron F, Castano L, et al. Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009. Pediatr Diabetes. 2013; 14:422-8. 39. Ceriello A, Ihnat MA. 'Glycaemic variability': a new therapeutic challenge in diabetes and the critical care setting. Diabet Med. 2010; 27:862-7. 40. Virk SA, Donaghue KC, Cho YH, Benitez-Aguirre P, Hing S, Pryke A, et al. Association Between HbA1c Variability and Risk of Microvascular Complications in Adolescents With Type 1 Diabetes. J Clin Endocrinol Metab. 2016; 101:3257-63. 41. McNeilly AD, McCrimmon RJ. The Scylla and Charybdis of glucose control in childhood type 1 diabetes? Pediatr Diabetes. 2015; 16:235-41. 42. Shalitin S, Phillip M. Which factors predict glycemic control in children diagnosed with type 1 diabetes before 6.5 years of age? Acta Diabetol. 2012; 49:355-62. 43. Soupal J, Skrha J, Jr., Fajmon M, Horova E, Mraz M, Skrha J, et al. Glycemic variability is higher in type 1 diabetes patients with microvascular complications irrespective of glycemic control. Diabetes Technol Ther. 2014; 16:198-203. 44. Smart CE, Annan F, Bruno LP, Higgins LA, Acerini CL, International Society for P, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Nutritional management in children and adolescents with diabetes. Pediatr Diabetes. 2014; 15 Suppl 20:135-53. 45. Maahs DM, Hermann JM, Holman N, Foster NC, Kapellen TM, Allgrove J, et al. Rates of diabetic ketoacidosis: international comparison with 49,859 pediatric patients with type 1 diabetes from England, Wales, the U.S., Austria, and Germany. Diabetes Care. 2015; 38:1876-82. 46. DCCT Research Group (Diabetes Control and Complications Trial Research Group). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine. 1993; 329:977–86. 47. Nathan DM, Group DER. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014; 37:9-16. 48. Edge JA, James T, Shine B. Persistent individual tracking within overall improvement in HbA1c in a UK paediatric diabetes clinic over 15 years. Diabet Med. 2010; 27:1284-8.

29

49. Hofer SE, Raile K, Frohlich-Reiterer E, Kapellen T, Dost A, Rosenbauer J, et al. Tracking of metabolic control from childhood to young adulthood in type 1 diabetes. J Pediatr. 2014; 165:956- 61 e1-2. 50. Danne T, Mortensen HB, Hougaard P, Lynggaard H, Aanstoot HJ, Chiarelli F. Persistent differences among centers over 3 years in glycemic control and hypoglycemia in a study of 3,805 children and adolescents with type 1 diabetes from the Hvidore Study Group. Diabetes Care. 2001; 24:1342–7. 51. Lawes T, Franklin V, Farmer G. HbA1c tracking and bio-psychosocial determinants of glycaemic control in children and adolescents with type 1 diabetes: retrospective cohort study and multilevel analysis. Pediatr Diabetes. 2014; 15:372-83. 52. Samuelsson U, Steineck I, Gubbjornsdottir S. A high mean-HbA1c value 3-15 months after diagnosis of type 1 diabetes in childhood is related to metabolic control, macroalbuminuria, and retinopathy in early adulthood--a pilot study using two nation-wide population based quality registries. Pediatr Diabetes. 2014; 15:229-35. 53. Diabetes C, Complications Trial /Epidemiology of Diabetes I, Complications Research G, Lachin JM, White NH, Hainsworth DP, et al. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes. 2015; 64:631-42. 54. Lind M, Oden A, Fahlen M, Eliasson B. The shape of the metabolic memory of HbA1c: re-analysing the DCCT with respect to time-dependent effects. Diabetologia. 2010; 53:1093-8. 55. Bailey C, Day C. Glycaemic memory. Br J Diabetes Vasc Dis. 2008; 8:242–7. 56. Donaghue KC, Wadwa RP, Dimeglio LA, Wong TY, Chiarelli F, Marcovecchio ML, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Microvascular and macrovascular complications in children and adolescents. Pediatr Diabetes. 2014; 15 Suppl 20:257-69. 57. Olsen BS, Sjolie AK, Hougaard P, Johannesen J, Marinelli K, Jacobsen BB, et al. The significance of the prepubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes. J Diabetes Complications. 2004; 18:160-4. 58. Cho YH, Craig ME, Donaghue KC. Puberty as an accelerator for diabetes complications. Pediatr Diabetes. 2014; 15:18-26. 59. Salardi S, Porta M, Maltoni G, Rubbi F, Rovere S, Cerutti F, et al. Infant and toddler type 1 diabetes: complications after 20 years' duration. Diabetes Care. 2012; 35:829-33. 60. Donaghue KC, Fung AT, Hing S, Fairchild J, King J, Chan A, et al. The effect of prepubertal diabetes duration on diabetes. Microvascular complications in early and late adolescence. Diabetes Care. 1997; 20:77-80. 61. Holl RW, Lang GE, Grabert M, Heinze E, Lang GK, Debatin KM. Diabetic retinopathy in pediatric patients with type-1 diabetes: effect of diabetes duration, prepubertal and pubertal onset of diabetes, and metabolic control. J Pediatr. 1998; 132:790-4. 62. Anderzen J, Samuelsson U, Gudbjornsdottir S, Hanberger L, Akesson K. Teenagers with poor metabolic control already have a higher risk of microvascular complications as young adults. J Diabetes Complications. 2016; 30:533-6. 63. Danne T, Bangstad HJ, Deeb L, Jarosz-Chobot P, Mungaie L, Saboo B, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Insulin treatment in children and adolescents with diabetes. Pediatr Diabetes. 2014; 15 Suppl 20:115-34. 64. Hanas R. Reducing injection pain in children and adolescents with diabetes: a review of indwelling catheters. Pediatr Diabetes. 2004; 5:102-11. 65. Danne T, Battelino T, Jarosz-Chobot P, Kordonouri O, Pankowska E, Ludvigsson J, et al. Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries. Diabetologia. 2008; 51:1594-601. 66. Phillip M, Battelino T, Rodriguez H, Danne T, Kaufman F. Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for

30

Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2007; 30:1653-62. 67. DiMeglio LA, Boyd SR, Pottorff TM, Cleveland JL, Fineberg N, Eugster EA. Preschoolers are not miniature adolescents: a comparison of insulin pump doses in two groups of children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab. 2004; 17:865-70. 68. Holterhus PM, Bokelmann J, Riepe F, Heidtmann B, Wagner V, Rami-Merhar B, et al. Predicting the optimal basal insulin infusion pattern in children and adolescents on insulin pumps. Diabetes Care. 2013; 36:1507-11. 69. Nicolajsen T, Samuelsson A, Hanas R. Insulin Doses before and One Year after Pump Start: Children Have a Reversed Dawn Phenomenon. J Diab Sci Tech. 2012; 6:589-94. 70. Alemzadeh R, Hoffmann RG, Dasgupta M, Parton E. Development of optimal kids insulin dosing system formulas for young children with type 1 diabetes mellitus. Diabetes Technol Ther. 2012; 14:418-22. 71. Thalange N, Bereket A, Larsen J, Hiort LC, Peterkova V. Treatment with insulin detemir or NPH insulin in children aged 2-5 yr with type 1 diabetes mellitus. Pediatr Diabetes. 2011; 12:632- 41. 72. Hathout EH, Fujishige L, Geach J, Ischandar M, Maruo S, Mace JW. Effect of therapy with insulin glargine (lantus) on glycemic control in toddlers, children, and adolescents with diabetes. Diabetes Technol Ther. 2003; 5:801-6. 73. Mianowska B, Fendler W, Tomasik B, Mlynarski W, Szadkowska A. Effect of Insulin Dilution on Lowering Glycemic Variability in Pump-Treated Young Children with Inadequately Controlled Type 1 Diabetes. Diabetes Technol Ther. 2015; 17:605-10. 74. Elleri D, Allen JM, Tauschmann M, El-Khairi R, Benitez-Aguirre P, Acerini CL, et al. Feasibility of overnight closed-loop therapy in young children with type 1 diabetes aged 3-6 years: comparison between diluted and standard insulin strength. BMJ open diabetes research & care. 2014; 2:e000040. 75. Hanas R, Adolfsson P. Bolus Calculator Settings in Well-Controlled Prepubertal Children Using Insulin Pumps Are Characterized by Low Insulin to Carbohydrate Ratios and Short Duration of Insulin Action Time. Journal of diabetes science and technology. 2017;11(2)247-252. 76. Andersen AJ, Ostenfeld A, Pipper CB, Olsen BS, Hertz AM, Jorgensen LK, et al. Optimum bolus wizard settings in insulin pumps in children with Type 1 diabetes. Diabet Med. 2016; 33:1360-5. 77. Bell KJ, Smart CE, Steil GM, Brand-Miller JC, King B, Wolpert HA. Impact of fat, protein, and glycemic index on postprandial glucose control in type 1 diabetes: implications for intensive diabetes management in the continuous glucose monitoring era. Diabetes Care. 2015; 38:1008-15. 78. Smart CE, Ross K, Edge JA, Collins CE, Colyvas K, King BR. Children and adolescents on intensive insulin therapy maintain postprandial glycaemic control without precise carbohydrate counting. Diabet Med. 2009; 26:279-85. 79. Smart CE, King BR, McElduff P, Collins CE. In children using intensive insulin therapy, a 20-g variation in carbohydrate amount significantly impacts on postprandial glycaemia. Diabet Med. 2012; 29:e21-4. 80. Infant Feeding Guidelines. Australian Government; National Health and Medical Research Council, Canberra, 2012 (https://www.nhmrc.gov.au/guidelines-publications/n56). 81. Patton SR, Dolan LM, Powers SW. Mealtime interactions relate to dietary adherence and glycemic control in young children with type 1 diabetes. Diabetes Care. 2006; 29:1002-6. 82. Mann J, Cummings JH, Englyst HN, Key T, Liu S, Riccardi G, et al. FAO/WHO scientific update on carbohydrates in human nutrition: conclusions. Eur J Clin Nutr. 2007; 61 Suppl 1:S132-7. 83. Carbohydrates and Health Scientific Advisory Committee on Nutrition, TSO, London 2015 (https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/445503/SACN_Ca rbohydrates_and_Health.pdf).

31

84. Joint FAO/WHO/UNU Expert Consultation on Protein and Amino Acid Requirements in Human Nutrition. WHO technical report series; no. 935, Geneva, 2002 85. Australian Dietary Guidelines Australian Government; National Health and Medical Research Council, Canberra, 2013 (https://www.nhmrc.gov.au/guidelines-publications/n55). 86. 2015–2020 Dietary Guidelines for Americans. 8 Ed. U.S. Department of Health and Human Services and U.S. Department of Agriculture., 2015 (http://health.gov/dietaryguidelines/2015/guidelines/). 87. Integrating nutrition and physical activity. Nordic Nutrition Recommendations 2012. 5 Ed, 2014 (www.livsmedelsverket.se). 88. Sundberg F, Augustsson M, Forsander G, Cederholm U, Axelsen M. Children under the age of seven with diabetes are increasing their cardiovascular risk by their food choices. Acta Paediatr. 2014; 103:404-10. 89. Patton SR, Dolan LM, Chen M, Powers SW. Dietary adherence and mealtime behaviors in young children with type 1 diabetes on intensive insulin therapy. Journal of the Academy of Nutrition and Dietetics. 2013; 113:258-62. 90. Patton SR, Dolan LM, Powers SW. Does eating during television viewing affect mealtimes in young children with type 1 diabetes mellitus? J Pediatr Nurs. 2013; 28:364-8. 91. Mehta SN, Volkening LK, Quinn N, Laffel LM. Intensively managed young children with type 1 diabetes consume high-fat, low-fiber diets similar to age-matched controls. Nutrition research. 2014; 34:428-35. 92. Kaikkonen JE, Mikkila V, Magnussen CG, Juonala M, Viikari JS, Raitakari OT. Does childhood nutrition influence adult cardiovascular disease risk?--insights from the Young Finns Study. Ann Med. 2013; 45:120-8. 93. Cooke L. The importance of exposure for healthy eating in childhood: a review. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2007; 20:294- 301. 94. DuBose SN, Hermann JM, Tamborlane WV, Beck RW, Dost A, DiMeglio LA, et al. Obesity in Youth with Type 1 Diabetes in Germany, Austria, and the United States. J Pediatr. 2015; 167:627-32 e1-4. 95. Kapellen TM, Heidtmann B, Bachmann J, Ziegler R, Grabert M, Holl RW. Indications for insulin pump therapy in different age groups: an analysis of 1,567 children and adolescents. Diabet Med. 2007; 24:836-42. 96. Islam ST, Abraham A, Donaghue KC, Chan AK, Lloyd M, Srinivasan S, et al. Plateau of adiposity in Australian children diagnosed with Type 1 diabetes: a 20-year study. Diabet Med. 2014; 31:686-90. 97. Christian MS, Evans CE, Hancock N, Nykjaer C, Cade JE. Family meals can help children reach their 5 a day: a cross-sectional survey of children's dietary intake from London primary schools. J Epidemiol Community Health. 2013; 67:332-8. 98. Overby NC, Margeirsdottir HD, Brunborg C, Andersen LF, Dahl-Jorgensen K. The influence of dietary intake and meal pattern on blood glucose control in children and adolescents using intensive insulin treatment. Diabetologia. 2007; 50:2044-51. 99. Powers SW, Byars KC, Mitchell MJ, Patton SR, Standiford DA, Dolan LM. Parent report of mealtime behavior and parenting stress in young children with type 1 diabetes and in healthy control subjects. Diabetes Care. 2002; 25:313-8. 100. Patton SR, Dolan LM, Powers SW. Differences in family mealtime interactions between young children with type 1 diabetes and controls: implications for behavioral intervention. J Pediatr Psychol. 2008; 33:885-93. 101. Patton SR, Piazza-Waggoner C, Modi AC, Dolan LM, Powers SW. Family functioning at meals relates to adherence in young children with type 1 diabetes. Journal of paediatrics and child health. 2009; 45:736-41. 102. Patton SR, Dolan LM, Powers SW. Dietary adherence and associated glycemic control in families of young children with type 1 diabetes. J Am Diet Assoc. 2007; 107:46-52.

32

103. Adamson M, Morawska A, Wigginton B. Mealtime duration in problem and non- problem eaters. Appetite. 2015; 84:228-34. 104. Kuhl ES, Clifford LM, Stark LJ. Obesity in preschoolers: behavioral correlates and directions for treatment. Obesity. 2012; 20:3-29. 105. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006; 114:2710-38. 106. Telama R, Yang X, Leskinen E, Kankaanpaa A, Hirvensalo M, Tammelin T, et al. Tracking of physical activity from early childhood through youth into adulthood. Medicine and science in sports and exercise. 2014; 46:955-62. 107. Biddle SJ, Pearson N, Ross GM, Braithwaite R. Tracking of sedentary behaviours of young people: a systematic review. Preventive medicine. 2010; 51:345-51. 108. Trigona B, Aggoun Y, Maggio A, Martin XE, Marchand LM, Beghetti M, et al. Preclinical noninvasive markers of atherosclerosis in children and adolescents with type 1 diabetes are influenced by physical activity. J Pediatr. 2010; 157:533-9. 109. Hesketh KR, Goodfellow L, Ekelund U, McMinn AM, Godfrey KM, Inskip HM, et al. Activity levels in mothers and their preschool children. Pediatrics. 2014; 133:e973-80. 110. Jago R, Sebire SJ, Edwards MJ, Thompson JL. Parental TV viewing, parental self- efficacy, media equipment and TV viewing among preschool children. Eur J Pediatr. 2013; 172:1543- 5. 111. Fisk CM, Crozier SR, Inskip HM, Godfrey KM, Cooper C, Robinson SM, et al. Influences on the quality of young children's diets: the importance of maternal food choices. Br J Nutr. 2011; 105:287-96. 112. Raynor HA, Van Walleghen EL, Osterholt KM, Hart CN, Jelalian E, Wing RR, et al. The relationship between child and parent food hedonics and parent and child food group intake in children with overweight/obesity. J Am Diet Assoc. 2011; 111:425-30. 113. Brage S, Wedderkopp N, Ekelund U, Franks PW, Wareham NJ, Andersen LB, et al. Features of the metabolic syndrome are associated with objectively measured physical activity and fitness in Danish children: the European Youth Heart Study (EYHS). Diabetes Care. 2004; 27:2141-8. 114. Andersen LB, Harro M, Sardinha LB, Froberg K, Ekelund U, Brage S, et al. Physical activity and clustered cardiovascular risk in children: a cross-sectional study (The European Youth Heart Study). Lancet. 2006; 368:299-304. 115. Steele RM, van Sluijs EM, Cassidy A, Griffin SJ, Ekelund U. Targeting sedentary time or moderate- and vigorous-intensity activity: independent relations with adiposity in a population- based sample of 10-y-old British children. Am J Clin Nutr. 2009; 90:1185-92. 116. Ekelund U, Luan J, Sherar LB, Esliger DW, Griew P, Cooper A, et al. Moderate to vigorous physical activity and sedentary time and cardiometabolic risk factors in children and adolescents. JAMA. 2012; 307:704-12. 117. O'Neill JR, Williams HG, Pfeiffer KA, Dowda M, McIver KL, Brown WH, et al. Young children's motor skill performance: relationships with activity types and parent perception of athletic competence. Journal of science and medicine in sport. 2014; 17:607-10. 118. Beets MW, Bornstein D, Dowda M, Pate RR. Compliance with national guidelines for physical activity in U.S. preschoolers: measurement and interpretation. Pediatrics. 2011; 127:658-64. 119. WHO. Global Recommendations on Physical Activity for Health, Geneva, 2010 (http://www.who.int/dietphysicalactivity/factsheet_recommendations/en/). 120. Tremblay MS, Leblanc AG, Carson V, Choquette L, Connor Gorber S, Dillman C, et al. Canadian Physical Activity Guidelines for the Early Years (aged 0-4 years). Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2012; 37:345-69.

33

121. Australian Government, Department of Health. National Physical Activity Recommendations for Children (0-5 years). 2014 (http://www.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act- guidelines#npa05). 122. Boldemann C, Blennow M, Dal H, Martensson F, Raustorp A, Yuen K, et al. Impact of preschool environment upon children's physical activity and sun exposure. Preventive medicine. 2006; 42:301-8. 123. Sundberg F, Forsander G, Fasth A, Ekelund U. Children younger than 7 years with type 1 diabetes are less physically active than healthy controls. Acta Paediatr. 2012; 101:1164-9. 124. Jeha GS, Karaviti LP, Anderson B, Smith EO, Donaldson S, McGirk TS, et al. Continuous glucose monitoring and the reality of metabolic control in preschool children with type 1 diabetes. Diabetes Care. 2004; 27:2881-6. 125. Sundberg F, Forsander G. Detection and treatment efficacy of hypoglycemic events in the everyday life of children younger than 7 yr. Pediatr Diabetes. 2014; 15:34-40. 126. Maahs DM, Hermann JM, DuBose SN, Miller KM, Heidtmann B, DiMeglio LA, et al. Contrasting the clinical care and outcomes of 2,622 children with type 1 diabetes less than 6 years of age in the United States T1D Exchange and German/Austrian DPV registries. Diabetologia. 2014; 57:1578-85. 127. Barnard KD, Oliver N, Adolfsson P, Aldred C, Kerr D. Is iatrogenic sleep disturbance worth the effort in Type 1 diabetes? Diabet Med. 2015; 32:984-6. 128. Lindstrom C, Aman J, Norberg AL. Parental burnout in relation to sociodemographic, psychosocial and personality factors as well as disease duration and glycaemic control in children with Type 1 diabetes mellitus. Acta Paediatr. 2011; 100:1011-7. 129. Blackman SM, Raghinaru D, Adi S, Simmons JH, Ebner-Lyon L, Chase HP, et al. Insulin pump use in young children in the T1D Exchange clinic registry is associated with lower hemoglobin A1c levels than injection therapy. Pediatr Diabetes. 2014; 15:564-72. 130. Tsalikian E, Fox L, Weinzimer S, Buckingham B, White NH, Beck R, et al. Feasibility of prolonged continuous glucose monitoring in toddlers with type 1 diabetes. Pediatr Diabetes. 2012; 13:301-7. 131. Englert K, Ruedy K, Coffey J, Caswell K, Steffen A, Levandoski L, et al. Skin and adhesive issues with continuous glucose monitors: a sticky situation. Journal of diabetes science and technology. 2014; 8:745-51. 132. Heinemann L, Kamann S. Adhesives Used for Diabetes Medical Devices: A Neglected Risk With Serious Consequences? Journal of diabetes science and technology. 2016; 10:1211-5. 133. Choudhary P, Olsen BS, Conget I, Welsh JB, Vorrink L, Shin JJ. Hypoglycemia Prevention and User Acceptance of an Insulin Pump System with Predictive Low Glucose Management. Diabetes Technol Ther. 2016; 18:288-91. 134. Mack-Fogg JE, Orlowski CC, Jospe N. Continuous subcutaneous insulin infusion in toddlers and children with type 1 diabetes mellitus is safe and effective. Pediatric Diabetes. 2005; 6:17-21. 135. Brink S, Joel D, Laffel L, Lee WW, Olsen B, Phelan H, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Sick day management in children and adolescents with diabetes. Pediatr Diabetes. 2014; 15 Suppl 20:193-202. 136. Pankowska E, Skorka A, Szypowska A, Lipka M. Memory of insulin pumps and their record as a source of information about insulin therapy in children and adolescents with type 1 diabetes. Diabetes Technol Ther. 2005; 7:308-14. 137. Sullivan-Bolyai S, Knafl K, Tamborlane W, Grey M. Parents' reflections on managing their children's diabetes with insulin pumps. J Nurs Scholarsh. 2004; 36:316-23. 138. Sundberg F, Viberg C, Soderlund T, Forsander G. CGM related skin problems are most common in very young users but not associated with atopy. Pediatric Diabetes. 2015; 16:(suppl 21) abstract P157.

34

139. Schober E, Rami B. Dermatological side effects and complications of continuous subcutaneous insulin infusion in preschool-age and school-age children. Pediatr Diabetes. 2009; 10:198-201. 140. Wolfsdorf JI, Allgrove J, Craig ME, Edge J, Glaser N, Jain V, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014; 15 Suppl 20:154-79. 141. Johnson SR, Cooper MN, Davis EA, Jones TW. Hypoglycaemia, fear of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents. Diabet Med. 2013; 30:1126-31. 142. Barnard K, Thomas S, Royle P, Noyes K, Waugh N. Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. BMC Pediatr. 2010; 10:50. 143. O'Connell SM, Cooper MN, Bulsara MK, Davis EA, Jones TW. Reducing rates of severe hypoglycemia in a population-based cohort of children and adolescents with type 1 diabetes over the decade 2000-2009. Diabetes Care. 2011; 34:2379-80. 144. Cengiz E, Xing D, Wong JC, Wolfsdorf JI, Haymond MW, Rewers A, et al. Severe hypoglycemia and diabetic ketoacidosis among youth with type 1 diabetes in the T1D Exchange clinic registry. Pediatr Diabetes. 2013; 14:447-54. 145. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study G. Prolonged nocturnal hypoglycemia is common during 12 months of continuous glucose monitoring in children and adults with type 1 diabetes. Diabetes Care. 2010; 33:1004-8. 146. Buckingham B, Wilson DM, Lecher T, Hanas R, Kaiserman K, Cameron F. Duration of nocturnal hypoglycemia before seizures. Diabetes Care. 2008; 31:2110-2. 147. Golicki DT, Golicka D, Groele L, Pankowska E. Continuous Glucose Monitoring System in children with type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetologia. 2008; 51:233-40. 148. Phillip M, Danne T, Shalitin S, Buckingham B, Laffel L, Tamborlane W, et al. Use of continuous glucose monitoring in children and adolescents (*). Pediatr Diabetes. 2012; 13:215-28. 149. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion. Diabet Med. 2008; 25:765-74. 150. Bergenstal RM, Klonoff DC, Garg SK, Bode BW, Meredith M, Slover RH, et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013; 369:224-32. 151. Ly TT, Nicholas JA, Retterath A, Lim EM, Davis EA, Jones TW. Effect of sensor- augmented insulin pump therapy and automated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type 1 diabetes: a randomized clinical trial. JAMA. 2013; 310:1240-7. 152. Åkesson K, Eriksson E, Fureman A, Gudbjornsdottir S, Hanberger L, Pundziute-Lycka A, et al. Data from the Swedish National Paediatric Diabetes Registry (SWEDIABKIDS). 2015. 153. McTavish L, Wiltshire E. Effective treatment of hypoglycemia in children with type 1 diabetes: a randomized controlled clinical trial. Pediatr Diabetes. 2011; 12:381-7. 154. Brodows RG, Williams C, Amatruda JM. Treatment of insulin reactions in diabetics. JAMA. 1984; 252:3378-81. 155. Pham-Short A, Donaghue KC, Ambler G, Chan AK, Craig ME. Coeliac disease in Type 1 diabetes from 1990 to 2009: higher incidence in young children after longer diabetes duration. Diabet Med. 2012; 29:e286-9. 156. Cerutti F, Chiarelli F, Lorini R, Meschi F, Sacchetti C. Younger age at onset and sex predict celiac disease in children and adolescents with type 1 diabetes. Diabetes Care. 2004; 27:1294–8. 157. Frohlich-Reiterer EE, Kaspers S, Hofer S, Schober E, Kordonouri O, Pozza SB, et al. Anthropometry, metabolic control, and follow-up in children and adolescents with type 1 diabetes mellitus and biopsy-proven celiac disease. J Pediatr. 2011; 158:589-93 e2.

35

158. Kordonouri O, Klingensmith G, Knip M, Holl RW, Aanstoot HJ, Menon PS, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Other complications and diabetes-associated conditions in children and adolescents. Pediatr Diabetes. 2014; 15 Suppl 20:270-8. 159. Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman F, Laffel L, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005; 28:186-212. 160. Dashiff C, Riley BH, Abdullatif H, Moreland E. Parents' experiences supporting self- management of middle adolescents with type 1 diabetes mellitus. Pediatr Nurs. 2011; 37:304-10. 161. Botello-Harbaum M, Nansel T, Haynie DL, Iannotti RJ, Simons-Morton B. Responsive parenting is associated with improved type 1 diabetes-related quality of life. Child Care Health Dev. 2008; 34:675-81. 162. Kovacs M. Children’s Depression Inventory. Multi-Health Systems, Inc., North Tonawanda, NY, 1992. 163. Radloff LS. The CES-D scale: A self-report depression scale for research in the general population. Applied Psychological Measurement. 1977; 1:385-401. 164. Varni JW, Burwinkle TM, Jacobs JR, Gottschalk M, Kaufman F, Jones KL. The PedsQL in type 1 and type 2 diabetes: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales and type 1 Diabetes Module. Diabetes Care. 2003; 26:631-7. 165. Markowitz JT, Volkening LK, Butler DA, Antisdel-Lomaglio J, Anderson BJ, Laffel LM. Re- examining a measure of diabetes-related burden in parents of young people with Type 1 diabetes: the Problem Areas in Diabetes Survey - Parent Revised version (PAID-PR). Diabet Med. 2012; 29:526- 30. 166. Markowitz JT, Volkening LK, Butler DA, Laffel LM. Youth-Perceived Burden of Type 1 Diabetes: Problem Areas in Diabetes Survey-Pediatric Version (PAID-Peds). Journal of diabetes science and technology. 2015; 9:1080-5. 167. Siminerio LM, Albanese-O'Neill A, Chiang JL, Hathaway K, Jackson CC, Weissberg- Benchell J, et al. Care of young children with diabetes in the child care setting: a position statement of the American Diabetes Association. Diabetes Care. 2014; 37:2834-42. 168. Bratina N, Battelino T. Insulin pumps and continuous glucose monitoring (CGM) in preschool and school-age children: how schools can integrate technology. Pediatr Endocrinol Rev. 2010; 7 Suppl 3:417-21. 169. Kumar KM, Saboo B, Rao PV, Sarda A, Viswanathan V, Kalra S, et al. Type 1 diabetes: Awareness, management and challenges: Current scenario in India. Indian journal of endocrinology and metabolism. 2015; 19:S6-8. 170. Willi SM, Miller KM, DiMeglio LA, Klingensmith GJ, Simmons JH, Tamborlane WV, et al. Racial-ethnic disparities in management and outcomes among children with type 1 diabetes. Pediatrics. 2015; 135:424-34. 171. Kamps JL, Hempe JM, Chalew SA. Racial disparity in A1C independent of mean blood glucose in children with type 1 diabetes. Diabetes Care. 2010; 33:1025-7. 172. Parrinello CM, Sharrett AR, Maruthur NM, Bergenstal RM, Grams ME, Coresh J, et al. Racial Differences in and Prognostic Value of Biomarkers of Hyperglycemia. Diabetes Care. 2016; 39:589-95. 173. Rotchford AP, Rotchford KM, Machattie T, Gill GV. Assessing diabetic control-- reliability of methods available in resource poor settings. Diabet Med. 2002; 19:195-200. 174. Daneman D, Frank M, Perlman K, Wittenberg J. The infant and toddler with diabetes: Challenges of diagnosis and management. Paediatrics & child health. 1999; 4:57-63.