Functional outcome at school age of

preterm-born children treated with low-

dose dexamethasone

Suzanne Verhage (S2420309)

Facultair begeleider: prof. dr. A.F. Bos

Uitgevoerd in het UMCG, afdeling neonatologie

http://delivery.acm.org/10.1145/2510000/2501855/p38hannon.pdf?ip=192.87.23.102&id=2501855&acc=ACTIVE%20SERVICE&key=0C390721DC3021FF%2E1C9CFA1F94F14792%2E4D4702B0C3E38B35%2E4D4702B0C3E38B35&CFID=

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2

Index

Page 3 Samenvatting (NL)

Page 4 Abstract (ENG)

Page 5 Introduction

Page 7 Methods

Page 11 Results

Page 17 Discussion

Page 19 Conclusion

Page 21-24 References

3

Samenvatting

Achtergrond Postnatale dexamethason (DXM) behandeling wordt gegeven aan prematuur

geboren kinderen om bronchopulmonale dysplasie (BPD) te voorkomen of te behandelen. Het

is bekend dat kinderen die behandeld zijn met een hoge dosering DXM negatieve effecten

ervaren op het gebied van motoriek, cognitie en gedrag. Op korte termijn lijken kinderen die

behandeld zijn met een lage dosering DXM beter te functioneren dan kinderen die behandeld

zijn met een hoge dosering DXM. Het is echter onbekend hoe deze kinderen functioneren op

schoolleeftijd.

Doelen Het doel van deze studie was het evalueren van motoriek, cognitie en gedrag op

schoolleeftijd bij kinderen die behandeld werden met een lage dosering DXM in de neonatale

periode. Ons tweede doel was om onze studieresultaten te vergelijken met de scores van een

Nederlandse normgroep en, waar mogelijk, een prematuur geboren normgroep.

Studieopzet In een observationele cohort studie werden 23 kinderen geïncludeerd, geboren na

een gestatieduur <32 weken, die werden behandeld met een lage dosering DXM

(startdosering van 0,25 mg/kg/dag) gedurende hun opname op de Neonatale Intensive Care

Unit van het UMCG tussen 2002 en 2008.

Resultaten De kinderen die behandeld werden met een lage dosering DXM scoorden

significant lager op totale Movement-ABC score, handvaardigheid, balvaardigheid en

evenwicht ten opzichte van de Nederlandse normgroep (P<.001 voor alle onderdelen), met

een abnormale score (<5de

percentiel (P5)) voor respectievelijk 78%, 48%, 47% en 58% van

de kinderen. Twee van de 23 kinderen hadden cerebrale parese (Gross Motor Function

Classification Scale, GMFCS, van 4). Twintig procent van de kinderen behandeld met een

lage dosering DXM scoorden een intelligentiequotiënt (IQ) van ≤76 (i.e. <P5, abnormaal). Dit

waren significant meer kinderen die abnormaal scoorden wanneer vergeleken werd met de

Nederlandse norm groep (P=.002). Performaal IQ (PIQ) was erger aangedaan dan verbaal IQ

(VIQ) met respectievelijk 40% en 10% van de kinderen die abnormaal scoorden. Hiernaast

scoorden significant meer kinderen, vergeleken met de Nederlandse norm groep, abnormaal

op geheugen en lange termijn geheugen (respectievelijk 15% en 25%, P=.04 en P<.001).

Selectieve aandacht en controle waren ook aangedaan met respectievelijk 25% en 50% van de

kinderen die abnormaal scoorden. Dit verschilde significant (P=<.001 en P=<.001) van de

hoeveelheid kinderen die abnormaal scoorden op deze test binnen de Nederlandse normgroep.

Visuele waarneming en taalkundigheid waren beiden niet significant aangedaan vergeleken

met de Nederlandse normgroep. Significant meer kinderen hadden gedragsproblemen

wanneer vergeleken met de Nederlandse normgroep (P=.022 en P =.001, respectievelijk) met

negen procent van de kinderen die abnormaal scoorden op totale gedragsproblemen, getest

met de Child Behavioral CheckList questionnaire, en 30% van de kinderen op hyperactiviteit,

getest met de Strengths and Difficulties questionnaire. Wanneer onze testresultaten werden

vergeleken met een prematuur geboren normgroep werden geen significante verschillen

gevonden met betrekking tot het IQ. Binnen onze studiegroep scoorden de kinderen wel

significant slechter op de alle subtests van de Movement-ABC (P<.001) vergeleken met een

prematuur geboren normgroep.

Conclusie Onze resultaten suggereren dat kinderen die behandeld werden met een lage

dosering DXM gedurende de neonatale periode slechter scoorden dan de kinderen uit de

Nederlandse normgroep op motoriek, IQ, geheugen, aandacht, gedragsproblemen en

hyperactiviteit op schoolleeftijd. Intelligentie was niet meer aangedaan in kinderen die

behandeld werden met een lage dosering DXM in vergelijking met een prematuur geboren

normgroep. Deze kinderen scoorden echter wel significant slechter op de Movement-ABC.

Het lijkt dat motoriek het meeste is aangedaan door de behandeling met een lage dosering

DXM vergeleken met de andere functionele uitkomstmaten.

4

Abstract Background Postnatal dexamethasone (DXM) treatment is given to preterm children to

prevent or treat bronchopulmonary dysplasia (BPD). It is known that preterm children treated

with high-dose DXM have adverse motor, cognitive and behavioral outcome at school age.

However, it is largely unknown whether the functional outcome at school age is affected

when the children are treated with low-dose DXM.

Aims The aim of this study was to assess the motor skills, cognition, and behavioral problems

at school age, in a cohort of preterm born infants who were treated with low-dose DXM in the

neonatal period. Our second aim was to compare the outcome measures with a preterm

reference group, if available, derived from recently published meta-analyses.

Study design In an observational cohort study, we included 23 preterm infants born <32

weeks of gestation who were treated with low-dose DXM (starting dose of 0.25 mg/kg/day)

during their admission to the neonatal intensive care unit of University Medical Center

Groningen between 2002 and 2008.

Results Low-dose DXM treated children scored significantly poorer on motor skills as

compared with a Dutch norm group (P<.001 for all subgroups) with 78%, 48%, 47%, and

58% of these children scoring abnormal (< fifth percentile (P5)) on total Movement-ABC,

fine motor skills, ball skills, and balance, respectively. Two out of 23 included children had

cerebral paresis, with a Gross Motor Function Classification Scale (GMFCS) of 4.

Furthermore, 20% of the low-dose DXM treated children scored an intelligence quotient (IQ)

of ≤76 (i.e. <P5, classified as abnormal), which was significantly more often as compared

with a Dutch norm group (P=.002). Performance IQ (PIQ) was more often affected than

verbal IQ (VIQ), as respectively 40% and 10% of the low dose DXM treated children scored

abnormal. We also found significantly more children scoring abnormal (<P5) on verbal

learning and verbal long-term memory as compared with the Dutch norm group (15% and

25%, P=0.04 and P<.001, respectively). Selective attention and attentional control were also

impaired as compared with the Dutch norm group with 25% and 50% of the children scoring

abnormal (<P5) (P<.001, P<.001, respectively). Visual perceptive ability and language skills

were not impaired as compared with the Dutch norm group. Finally, there were significantly

more behavioral problems in the group of low-dose DXM treated children as compared with a

Dutch norm group (P=.022 and P =.001, respectively) with 9% of the included children

scoring abnormal (>P98) on total behavioral problems using the Child Behavioral CheckList

questionnaire and 30% of the children scoring abnormal (>P90) on the hyperactivity scale of

the Strengths and Difficulties questionnaire. When comparing the low-dose DXM treated

children with a preterm reference group, they scored poorer on all the subscales of the

Movement ABC (P<.001), but not on total intelligence.

Conclusion This study showed that children treated with low-dose DXM scored poorer on

motor skills, IQ, memory, attention, and behavioral problems at school age as compared with

a Dutch norm group. Motor skills were affected the most when considering all tested

functional domains. When comparing our movement-ABC and WISC-III test scores with a

preterm reference group, scores on total intelligence was no longer lower in low-dose DXM

treated children, but those on Movement-ABC still were significantly poorer. At school age,

low-dose DXM treatment during the neonatal period seems to have more negative functional

effects on motor skills than on cognitive skills.

5

1. Introduction

In 2010, the estimated prevalence of preterm live births worldwide was 11.1%. Preterm birth

is defined as all births that occur before 37 completed weeks of gestation. It is important to

decrease this percentage as it is thought that 50% of all premature deaths is caused by this

prematurity. Early preterm birth (gestational age <32 weeks) is accountable for 16% of all

preterm births.(1)

Preterm birth is associated with adverse neurodevelopmental and behavioral sequelae in

survivors (e.g. dyslexia, motor impairment, cerebral palsy and attention deficit hyperactivity

disorder (ADHD)), family/economic and societal effects. Several complications of

prematurity may increase the risk of adverse development. One of these complications is

bronchopulmonary dysplasia (BPD).(1) BPD rates in Europe vary between 10.5 and 21.5% in

children born <32 weeks of gestation.(2)

The definition of BPD differs between infants born <32 weeks and ≥32 weeks. This study

assesses children born <32 weeks of gestation. To define BPD in this group, the children are

assessed at 36 weeks of postmenstrual age (PMA), i.e gestational age plus postnatal age in

weeks. BPD is diagnosed if children have been treated with >21% of oxygen for at least 28

days. Next, the classification of the diagnosis of BPD includes mild, moderate, and severe

BPD. The percentage of oxygen that the child requires at the moment of assessment at 36

weeks PMA determines how the infant is classified. A child is diagnosed with mild BPD if

breathing room air at 36 weeks. If the child is treated with 22 to 30% of oxygen at 36 weeks,

the BPD is classified as moderate. If the child needs >30% of oxygen and/or positive pressure

(Positive Pressure Ventilation or Nasal Continuous Positive Airway Pressure) at 36 weeks of

gestation, it is classified as severe BPD.(3)

The etiology of BPD is multifactorial. Factors such as prenatal infection and inflammation,

mechanical ventilation, oxygen toxicity with decreased host antioxidant defenses, patent

ductus arteriosus and postnatal infection can increase the risk of the child developing BPD.

However, the greatest risk factor associated with developing BPD is prematurity.(4)

Pathophysiologically two kinds of BPD are distinguished: old BPD and new BPD. The main

risk factors for developing old BPD are mechanical ventilation and exposure to high

concentrations of inspired oxygen. Antenatal corticosteroids, surfactant replacement therapy

(started in 1980) and a conservative approach to respiratory care have reduced the prevalence

of old BPD. However, despite improvements in treating infants born preterm, the overall

presence of BPD has never changed. This is because of the improved survival rate among

infants born at earlier gestational ages. Where there is a decline in old BPD, new BPD

emerges. The main risk factors for developing new BPD are prematurity and intrauterine

growth restriction. The morphological features of the lung of new BPD differ from those of

old BPD. In old BPD, there is an intense inflammation in the lung as well as a disruption of

normal pulmonary structures. In new BPD, a reduced alveolar development is present.

Consequently, the infants have fewer and larger alveoli, which results in a loss of surface area

for the exchange of gasses.(5)

BPD is associated with increased hospital stay, rehospitalization during early childhood,

higher sensibility to lower respiratory infections, and neurodevelopmental impairment(2).

These consequences make that neonatologists aim to prevent and treat BPD.

6

For a long time BPD has been treated with dexamethasone (DXM). DXM is a corticosteroid,

of which it is suggested that it might prevent BPD. The adrenal gland produces two classes of

corticosteroids. The first class has primarily a mineralocorticoid effect, whereas the second

has primarily a glucocorticoid effect. Aldosteron is a physiological example of a

mineralocorticoid. This class of corticosteroids influences the regulation of water and sodium.

Cortisol is a physiological example of a glucocorticoid.(6) Glucocorticoids stimulate the

gluconeogenesis and reduce the glucose absorption in peripheral tissue. They also influence

the metabolism of carbohydrates, proteins and fat. The production of cortisol depends on the

secretion of adrenocorticotropic-hormone (ACTH) from the pituitary gland. The secretion of

ACTH is dependent on the stimulation of corticotropin-releasing hormone (CRH) from the

hypothalamus.(7)

DXM is a semi-synthetic derivate of cortisol. It has a very small mineralocorticoid effect, and

the glucocorticoid effect is 25 times as high as that of the natural hormone. DXM is given to

preterm infants, because of the anti-inflammatory effect of the glucocorticoid. This anti-

inflammatory effect comes from the influence glucocorticoids have on the metabolism of

proteins. Therefore formation of granulation tissue is inhibited. Glucocorticoids also have a

stabilizing effect on the membrane of lysosomes and they reduce the formation of exudate,

due to their vasoconstrictive effect.(7) These anti-inflammatory effects can be observed when

evaluating tracheobronchial aspirate from preterm born infants at high risk for BPD. After

having received treatment with DXM, the number of neutrophils were decreased.

Furthermore, tests comparing the aspirates before and after treatment showed that the

concentrations of leukotriene B4, interleukin-1, elastase-alpha1-protease inhibitor, and

albumin had gone down.(8)

The treatment of DXM also has side effects. Acute side effects are hyperglycemia, glycosuria,

high blood pressure, severe retinopathy of prematurity (ROP) and hypertrophic

cardiomyopathy.(9) There is in particular concern for the long term negative effects on the

brain. Children treated with a high dose of DXM (starting dose: 0.5 mg/kg) experience more

difficulties in the long term when it comes to motor performance (especially fine motor

skills), intelligence (more likely to have an IQ <85), visual perception, visuomotor

integration, selective attention, attentional control, and internalizing behavior than preterm

born children who were not treated with DXM.(10) In 2014 an article was published in Cells

that reviewed the cause of these neuromotor/cognitive deficits. It is suggested that

glucocorticoid therapy disrupts the cerebellar development, because of the induction of

apoptosis in the cerebellar external granule layer (EGL). This layer is responsible for the

production of 90% of the neurons in the cerebellum. Normally, endogenous glucocorticoid

stimulation eliminates the EGL when the production of the neurons is complete.(11)

Out of concern for the long-term side effects on the infants’ neurodevelopmental outcome ,

the American Academy of Pediatrics (AAP) has recommended against routine systemic DXM

therapy for the prevention or treatment of BPD in preterm infants, in 2002. The AAP advises

to consider treatment with DXM only for infants that cannot be extubated >7 days after birth,

and to minimalize the dosage and duration of the corticosteroid therapy.(12) Neonatologists

all over the world have followed this advice, changing their methods of starting DXM therapy

and reducing the dosage. Nevertheless, it remains difficult to pin down the exact causes of the

poor neurodevelopmental outcomes in children with BPD. Whether they stem from the

underlying disease, BPD, or rather from its treatment, high-dose DXM, remains under debate.

7

After 2002, certain studies report that low dose DXM treatment (0.25 mg/kg/d) reduces short-

term neurological side effects. The majority of infants that received low-dose DXM, showed a

normal neurodevelopment at the age of 12-36 months(13). However, there is a lack of data

with regards to the long-term neurological and developmental outcomes. Therefore, the aim

of this study was to assess the motor skills, cognition, and behavioral problems that might

occur at school age, in a cohort of preterm born infants who were treated with low-dose

DXM. Our second aim was to compare the outcome measures with Dutch norms and with a

preterm reference group, if available, derived from recently published meta-analyses.(14)(15)

We hypothesized that, even with the low-dose of DXM, functional outcome is impaired in

preterm-born children at school age. When compared with the high-dose DXM children, we

expect that less children will experience these impairments and that the consequences of these

impairments will be less severe in the children treated with the low-dose DXM.

2. Methods

2.1 Study design and patients

This was an observational cohort study. We selected all preterm infants who were born <32

weeks of gestation, and who were treated with low dose DXM during their admission to the

neonatal intensive care unit of the University Medical Center Groningen between 2002 and

2008. Indications for treatment with low dose DXM were: ventilator dependency with

ventilatory mean airway pressure >12 cm H2O and/or fractional oxygen requirement > 0.50

after the 7th

postnatal day where weaning was not possible. A tapering course of DXM was

given, starting with 0.25 mg/kg/d for the first three days. The duration of the DXM treatment

was either 6 days (total dose of 1.125 mg/kg) or 14 days (total dose of 2.075 mg/kg),

depending on the clinical course. In some exceptional cases the DXM course was prolonged.

Preterm infants with major congenital anomalies and tracheotomies were not included due to

their influence on the functional outcome of these children.

There are two types of DXM schemes: a short and a long tapering course of DXM. Table 1

shows the differences in dosage between the two schemes as noted in the UMCG BPD

protocol of April 2002. In both cases, the starting dosage is 0,25 mg/kg/day given in two

administrations. If the child can be extubated 3 days after starting with the DXM, a short

reduction scheme should be given to that child. If the child is responding but cannot be

extubated within three days, a long scheme should be used. If there is no improvement of the

conditions of the ventilator, DXM should be stopped immediately.

Table 1 Dexamethasone dosing differences between short- and long tapering courses of dexamethasone

Short tapering course dexamethasone Long tapering course dexamethasone

Day 1 - 3 0.25 mg / kg / day in 2dd Day 1 – 3 0.25 mg / kg / day in 2dd

Day 4 - 6 0.125 mg / kg / day in 2dd Day 4 – 6 0.15 mg / kg / day in 2dd

Day 7 Stop Day 7 – 9 0.125 mg / kg / day in 2dd

Day 10-14 0.1 mg / kg / day in 2dd

Day 15 Stop

8

The UMCG BPD protocol of April 2002 advises to start with the DXM reduction scheme

when newborns are older than 7 to 14 days. In March 2013, a new protocol was made; despite

being very similar to the older version, there were a few adjustments. The new protocol

advises the treatment to start on day 10-14 after birth, and suggests a lower dosage of the

DXM on day 13-15 of the treatment (0.05 mg/kg/day in 1dd). Contra-indications of DXM are:

a patent ductus arteriosus, recent (<5 days before start DXM treatment) surgical procedures

and recent severe infections (for example a pneumonia or sepsis).

At school age, when the children were 6 to 13 years, we performed follow-up of the surviving

children. It consisted of an assessment of motor and cognitive skills, and an evaluation of

behavioural problems.

2.2 Motor outcome

We used the following tests to assess the motor skills:

- Movement Assessment Battery for Children (Movement-ABC). Everyday motor skills

were assessed with this test. The test has 3 domains: Manual Dexterity, Ball Skills and

Statis & Dynamic balance. Every age group has a different group of age-specific

subtests. Raw scores were used to calculate percentiles using age scales standards.(16)

- Dutch version of the Developmental Coordination Disorder (DCD) Questionnaire. The

scores of this questionnaire were used to screen for coordination disorders. The

parents answered 15 questions on the coordination of their child compared to other

children of the same age. With the sum of the scores an indication was made for

DCD.(17)

2.3 Cognitive outcome

We used the following tests to asses cognitive outcome:

- Wechsler Intelligence Scale for Children, third edition, Dutch version (WISC-III).

This test assesses the intelligence quotient (IQ) of children. The test consists of 8

subtests. We used 4 subtests to calculate an estimate total IQ. Two of these subtests,

vocabulary and similarities, were used to estimate the verbal IQ (VIQ). Two tests that

assess performance IQ (PIQ) were stories and block patterns.(18)

- Verbal memory was assessed using the Dutch version of Rey’s Auditory Verbal

Learning Test (AVLT). A CD provided the children fifteen words in 5 trials. After

each trial the children needed to recall as many words as they remembered. Long

term-memory was tested 20 minutes later, delayed recall, when the children were

asked to name the words they remembered. Directly after the delayed recall 30 words

were named by the examinator. Fifteen of these words were distractor words. The

children were asked which words were provided in the five trials and which words

were the distractor words.(19)

- Test of Everyday Attention for Children (TEA-ch). Attention abilities were measured

with this test. Two subtests were used to respectively measure selective attention and

attentional control; map search and opposite world.(20)

- To assess an individual’s visual perceptual ability we used three subtests of the Test of

Visual and Perceptual Skills (TVPS); Visual discrimination, Form Constancy and

Visual Closure. (21)

9

- Visual-motor deficits were assessed by using the Beery-Buktenica Developmental

Test of Visual-Motor Integration, 6th

Edition (BEERY VMI). The children were asked

to copy geometric figures of increasing difficulty.(22)

- Three subtests were performed on the language domain of the translated version of the

Developmental NEuroPSYchological Assessment (NEPSY-II). One of these subtests

was comprehension of instructions. This subtest assessed the ability to receive,

process, and execute oral instructions of increasing complexity. The second subtest

was speeded naming. This subtest assessed rapid semantic access to and production of

names of colors, shapes, sizes, letters or numbers. The third and last subtest was word

generation which assessed the verbal productivity through the ability to generate

words within specific semantic categories.(23)

- To assess the executive functioning in daily life the parent(s) filled in a Behavior

Rating Inventory of Executive Function (BRIEF) questionnaire.(24)

2.4 Behavioral outcome

- The Child Behavior Checklist (CBCL) (25) was used to measure behavioral and

emotional competencies and problems.

- To assess behavioral and emotional competencies and problems an Attention Deficit

Hyperactivity Disorder (ADHD) questionnaire (26) was used.

- A Strength and Difficulties Questionnaire (SDQ) (27) was used to score the social and

emotional well-being of the participating children.

2.5 Statistical analysis

In this study we compared our test results with two reference groups, first according to the

Dutch norms (as stated in the manuals), and second according to a preterm reference, derived

from two meta-analyses available in literature.(14,15) The cut-off points of this preterm

reference group comprised those of the movement ABC and the full scale IQ of the WISC-III,

and were calculated using Cohen’s d.

Comparing with Dutch norms

The outcome of the tests was classified into three groups: normal (>15th

percentile),

borderline (5-15th

percentile) and abnormal (<5th

percentile). The outcome of the DCD-Q and

the BRIEF were classified into two groups: normal and borderline/abnormal.

See Table 2 for the cut off points of the questionnaires.

Table 2 Cut off points questionnaires

Normal Borderline Abnormal

AVL <P90 P90-P94 >P95

SDQ <P80 P80-90 ≥P90

SDQ-prosocial >P20 P10-20 ≤P10

CBCL <P93 P93-98 >P98

DCD-Q >P15 ≤P15

BRIEF <P91 ≥P91

10

Comparing with preterm references (WISC-III and movement ABC)

The outcome of the WISC-III and the Movement-ABC were not only analyzed using the

norm population, but also using a preterm reference. Literature describes that preterm born

children score lower on these tests, with a normal distribution of the test scores. This means

that the cut-off points are lower for our preterm born group, if we want to assess additional

negative effects of low dose DXM. We used Cohen’s d to calculate these cut-off points of the

Movement-ABC and the WISC-III full scale IQ for preterm children. The Movement-ABC

had a Cohen’s d score of -0.65, -0.77, -0.34, -0.62 for respectively overall score, balance

skills, ball skills and fine motor skills according to a meta-analysis.(28) The WISC-III full

scale IQ score had a Cohen’s d score of -0.92 according to another meta-analysis.(29)

Table 3 describes these cut-off points for borderline and abnormal for preterm infants

regarding the subscales of the Movement-ABC and the full scale IQ of the WISC-III.

Table 3 Cut off points subscales Movement -ABC

Normal Borderline Abnormal

Overall score > P38 P19-38 ≤ P18

Balance skills > P42 P22-42 ≤ P21

Ball skills > P24 P11-24 ≤ P10

Fine motor skills > P34 P16-34 ≤ P15

WISC-III, full scale IQ > P46a

P24-46 a ≤ P24

a

a IQ values corresponding with the percentiles are: >P46: >97, P24-46: 88-97, <P24: <88.

Statistical tests

To asses if significant differences were present between the participating inclusion group and

the not participating inclusion group, we used the Mann-Whitney U test.

Distribution of the infants into normal, borderline and abnormal categories was compared

with the norm population using the Chi-square test. We also compared our study results of

the Movement-ABC and the full scale score of the WISC-III with a preterm reference group

using the chi-square test with cut-off points as presented in Table 3.

To compare the Z-scores of the study group with the norm group, we used the one sample T-

test.

Univariate linear regression analysis was performed to test the influence of the cumulative

DXM dose on the outcome of the neuropsychological tests.

11

N = 59 infants treated

with DXM between

2002-2008

N =17 died

N = 2 major congenital anomalities

- 1 Esophageal atresia with fistel

- 1 Marfans disease

N = 35 study

group

N = 23 included

N = 5 refusal

N = 6 replied / seen after research elective

N = 2 tracheacanule

N = 3 insufficient amount of information,

UMCG not the primary treating hospital

N = 1 unable to test

- 1 severe eyesight handicap

N = 2 GMFCS ≥ 3

N = 1 lost to follow up

3. Results

Between 2002 and 2008 59 preterm infants were treated with low dose DXM during their

admission to the NICU of the UMCG. Seventeen (10%) children died during this admission.

Nineteen children were not included due to various reasons (Figure 1). Twenty three children

were included for the follow-up at school age. Twenty children were tested and three of these

children were unable to take the tests because of major handicaps and only filled in the

questionnaires.

Figure 1 Flow chart of DXM-treated children who were included for follow-up at school age

12

3.1 Patient characteristics

Table 4 shows the characteristics of the 23 children who were included and participated in this

study. There were no significant baseline differences between the included children (N=23)

and eligible not participating children (N=12).

Table 4 Differences in patient demographics of participating and not participating DXM treated children

included (n=23) (not participating)

(n=12)

p-value

Boys/girls 12/11 10/2 0.074

Twin pairs 9 (39%) 1 (8%) 0.059

Gestational age (weeks) 26.7 (25,6-27,3) 27 (25.9-28.2) 0.321

Birth weight (grams) 810 (750-970) 850 (720-890) 0.702

Intrauterine growth restriction (<P10) 5 (22%) 4 (33%)

33

0.463

Head circumference (cm) 24,5 (23-25) 23.8 (23-24.7) 0.421

Head circumference (z-score) -0.8 ± 0.7 -1.3 ± 1 0.135

Apgar-5 7 (5-9) 8 (6.3-9) 0.274

Patent ductus arteriosus 18 (78%) 7 (58%) 0.222

Late-onset morbidity

Late-onset sepsisa 9 (39%) 7 (58%) 0.286

Necrotizing enterocolitis 1 (4%) 2 (11%) 0.223

Retinopathy of prematurity ≥ II 6 (26%) 4 (33%) 0.657

Bronchopulmonary dysplasiab 23 (100%) 12 (100%) 1

Duration mechanical ventilation (days) 40 (26-51) 34.5 (29.3-45) 0.497

Cerebral pathology

No 3 (13%) 3 (25%) 1

Periventricular echodensity > 7 days 11 (48%) 6 (50%) 0.904

Mildc 8 (35%) 3 (25%) 0.560

Severed 1 (4%) - 0.470

Corticosteroids

Antenatal 21 (91%) 11 (92%) 0.971

Dutration treatment DXM (days) 8.5 (6-16) 7.5 (6-13) 0.416

Postnatal day DXM started 24 (21-32) 29.5 (17.5-40) 0.543

Post menstrual age DXM started (wk) 30.7 (28.7-33) 31 (29.1-32.9) 0.639

Cumulative dose DXM (mg) (mg)(mg/kg)

2.112 ± 2.041 4.193 ± 9.519 0.776

Mothers level of educatione

<11 years 2 (10%) - -

12-13 years 5 (25%) - -

>14 years 13 (65%) - -

a Positive bloodculture within the time of admission

b O2 at 36 weeks post menstrual age

c Grade I/II germinal matrix-intraventricular haemorrhage (GMH-IVH)

d Grade III GMH-IVH, periventricular haemorrhagic infarction, post haemorrhagic ventricular dilation (lateral

ventricle size of >0.33 according to Evans’ index), and cystic periventricular leukomalacia. e Primary school: 6 years, MAVO: 4 years, HAVO: 5years, VWO: 6 years, MBO: 3 years, HBO: 5years,

University: 6years.

13

3.2 Motor outcome and cognition, Z-scores compared to the norm group

First, we analyzed the significance of the deviation from the mean of the Z-scores of various

motor and cognitive tests. The Z-scores of the NEPSY could not be analyzed due to lack of

transformation of raw scores into Z-scores in the manual; only categorization of the NEPSY

raw scores is possible. Similarly, the scores on the subtests of the Movement ABC were not

transformed into z-scores, but only categorized.

In Figure 1 we present distribution of the Z-scores in our study group and the significance of

deviation of the means compared with the norms.

Performance IQ, total IQ, total Movement-ABC score, selective attention, attentional control

and verbal long term memory deviated significantly from the mean of the norm group.

Figure 2 Z-scores of motor and cognitive test results

Boxes represent individual means with 25-75th

percentile. The wiskers represent the range of testresults without

outliers. These outliers are represented by the O. # signifies a significant deviation from mean of the norm

group.

3.3 Motor outcome, compared with the norm group

In Table 5 we present the distribution of normal, borderline and abnormal subgroups of the

tests and the questionnaire about motor skills.

Two of the 23 included children had cerebral paresis (CP) with a Gross Motor Function Scale

(GMFCS (30)) of 4, one was visually severely handicapped, and one child was incompletely

tested. Of the 19 tested children, 78% had an abnormal total score on the Movement-ABC.

Compared with the norm, the DXM treated children scored significantly worse on all scales of

the Movement-ABC.

14

The expectation according to the norm is that 5% of the DXM treated children will categorize

as abnormal in the scales. However, there were 15.6 times more children that scored abnormal

(78 vs 5%) regarding the total score than expected. Regarding fine motor skills, ball skills,

and balance 9.6, 15.7, and 11.6 times more children than expected, respectively, scored

abnormal.

The Developmental-Coordination-Disorder (DCD) questionnaire confirms that children

treated with DXM had significantly more chance of developing DCD. According to the

questionnaire, 48% of the children had signs of DCD. This is 3.2 times more than expected.

Table 5 Distribution of test results concerning motor skills in normal, borderline and abnormal categories

compared to norm population.

N Normal Borderline Abnormal Normal vs.

borderline and

abnormal

Normal and

borderline

vs. abnormal

Movement-ABC totalA 19 2 (11%) 2 (11%) 15 (78%) <0.001* <0.001*

Fine motor skills 19 5 (26%) 5 (26%) 9 (48%) <0.001* <0.001*

Ball skills 19 7 (37%) 3 (16%) 9 (47%) <0.001* <0.001*

Balance 19 4 (21%) 4 (21%) 11 (58%) <0.001* <0.001*

DCD-Q 23 12 (52%) 11 (48%)a

<0.001*

NS: non-significant. *Significant when P<0.05. a Indication DCD.

bAbnormally elevated.

a For one child it was not possible to obtain the test-results of the Movement-ABC as it was tested within the

wrong age group

3.4 Cognitive outcome, compared with the norm group

In Table 6 we present the distribution of normal, borderline and abnormal subgroups of the

cognitive testresults. Table 6 Distribution of test results concerning cognition in normal, borderline and abnormal categories

compared with the norm population.

NS: non-significant. *Significant when P<0.05. aIndication DCD.

bAbnormally elevated.

N Normal Borderline Abnormal Normal vs.

borderline and

abnormal

Normal and

borderline

vs. abnormal

WISC

Total intelligence 20 12 (60%) 4 (20%) 4 (20%) 0.002* 0.002*

Verbal intelligence 20 17 (85%) 1 (5%) 2 (10%) 1.000 0.305

Performance intelligence 20 10 (50%) 2 (10%) 8 (40%) <0.001* <0.001*

AVLT

Verbal learning 20 16 (80%) 1 (5%) 3 (15%) 0.531 0.04*

Verbal long-term memory 20 15 (75%) - 5 (25%) 0.21 <0.01*

TeaCh

Selective attention 20 12 (60%) 3 (15%) 5 (25%) 0.002* <0.001*

Attentional control 20 10 (50%) - 10 (50%) <0.001* <0.001*

Visual perceptual ability

Visual discrimination 20 20 (100%) - - NS NS

Form constancy 20 16 (80%) 1 (5%) 3 (15%) 0.531 0.04*

Visual closure 20 18 (90%) 2 (10%) - 0.531 NS

NEPSY

Comprehension of instructions 20 20 (100%) - - NS NS

Speeded naming

20 15 (83%) 2 (11%) 1 (6%) 0.414 0.914

Word generation 20 14 (70%) 4 (20%) 2 (10%) 0.06 0.305

15

Twenty percent of the DXM treated children had a total intelligence ≤76 (i.e. <P5, classified

as abnormal). This is 4 times more children than expected based on the percentages of the

norm group. PIQ was affected the most when compared to VIQ.

Compared with the norm group, 3 and 4 times more children scored abnormal on verbal

learning and verbal long-term memory, respectively. The DXM treated children also scored

significantly more often poorer on selective attention and attentional control.

3.5 Behavioral outcome, compared with the norm group

In Table 7 we present the distribution of children presenting with normal, borderline and

abnormal scores, regarding the questionnaires concerning behavior.

Significantly more children treated with DXM scored as abnormal in the total behavioral

problems subclass of the CBCL questionnaire.

Hyperactivity was scored with two questionnaires. The AVL-Q and a subgroup of questions

in the SDQ. The children in our study group did not show significant differences in the

distribution between normal, borderline and abnormal in all subclasses of the AVL

(attentional problems, hyperactivity and impulsivity). The amount of children that scored

abnormal on the subclass hyperactivity score on the SDQ was 6.0 fold increased than

expected

Table 7 Distribution of children scoring normal, borderline and abnormal on the questionnaires concerning

behavior.

N Normal Borderline Abnormal Normal vs.

borderline and

abnormal

Normal and

borderline

vs. abnormal

CBCL

Total behavioral problems 23 20 (87%) 1 (4%) 2 (9%) 0.256 0.022*

Internalizing problems 23 19 (83%) 4 (17%) - 0.051 NS

Externalizing problems 23 22 (96%) - 1 (4%) 0.618 0.421

AVL

Attentional problems 23 19 (83%) 3 (12%) 1 (4%) 0.237 0.416

Hyperactivity 23 18 (78%) 2 (9%) 3 (13%) 0.237 0.077

Impulsivity 23 21 (91%) - 2 (9%) 0.627 0.416

BRIEF

Inhibition 23 22 (96%) 1 (4%)b 0.436

Shift 23 22 (96%) 1 (4%)b 0.436

Emotional control 23 22 (96%) 1 (4%)b 0.436

Initiate 23 22 (96%) 1 (4%)b 0.436

Working memory 23 22 (96%) 1 (4%)b 0.436

Planning and organizing 23 21 (91%) 2 (9%)b 0.959

Organization of materials 23 23 (100%) - NS

Monitoring function 23 22 (96%) 1 (4%)b 0.436

Global executive composite 23 23 (100%) - NS

SDQ

Total difficulties score 23 19 (83%) 2 (9%) 2 (9%) 0.754 0.835

Emotional problems score 23 18 (78%) 2 (9%) 3 (13%) 0.835 0.627

Conduct problems score 23 21 (91%) - 2 (9%) 0.175 0.835

Hyperactivity score 23 16 (70%) - 7 (30%) 0.211 0.001*

Peer problems score 23 17 (74%) 1 (4%) 5 (22%) 0.466 0.061

Prosocial score 23 21 (91%) - 2 (9%) 0.175 0.835

NS: non-significant. *Significant when P<0.05. a Indication DCD.

bAbnormally elevated.

16

3.6 Study results compared with the preterm reference group

The motor outcome of the preterm born children who were treated with DXM still scored

significantly poorer on all scales of the Movement-ABC. There were 5.3, 3.1, 4.7, and 2.8

times more children that scored abnormal on the movement-ABC total score, fine motor

skills, ball skills, and balance, respectively, when compared with the preterm references.

The cognitive measure that could be analyzed with a preterm reference was the IQ according

to the WISC-III. We did not find significant differences between the DXM study group and

the preterm reference group.

In Table 8 we present the levels of significance of the Movement-ABC and the WISC-III.

Table 8 Level of significance Movement-ABC and WISC-III test results compared to preterm reference group

N Normal Borderline Abnormal Normal vs.

borderline

and

abnormal

Normal

and

borderline

vs.

abnormal

Movement-ABC total 19 2 (11%) 2 (11%) 15 (78%) <0.001* <0.001*

Fine motor skills 19 5 (26%) 5 (26%) 9 (48%) <0.001* <0.001*

Ball skills 19 7 (37%) 3 (16%) 9 (47%) <0.001* <0.001*

Balance 19 4 (21%) 4 (21%) 11 (58%) 0.001* <0.001*

WISC

Total intelligence 20 12 (60%) 4 (20%) 4 (20%) 0.590 0.675

P significant when <0.05.

3.7 Cumulative DXM dose as a predictive variable

Table 9 shows the relation between cumulative doses of DXM and several test outcomes.

For none of the outcome measures cumulative dose of DXM was a significant predictor.

Table 9 Cumulative dose of dexamethasone as a predictor for abnormal test scores, using linear regression

analyses.

B 95% confidence interval for B Beta Significance

Lower bound Upper bound

Verbal IQ -0.063 -0.331 0.205 -0.115 0.629

Performance IQ -0.136 -0.448 0.175 -0.212 0.370

Total IQ -0.092 -0.348 0.163 -0.176 0.457

Total score Movement-ABC -0.064 -0.261 0.133 -0.164 0.501

Selective attention 0.088 -0.071 0.248 0.264 0.261

Attentional control 0.007 -0.241 0.254 0.014 0.955

Visual motor integration 0.096 -0.157 0.349 0.185 0.434

Verbal learning 0.129 -0.101 0.358 0.268 0.254

Verbal long term memory 0.169 -0.055 0.393 0.350 0.131

Form constancy -0.022 -0.336 0.291 -0.035 0.883

Visual closure -0.023 -0.276 0.231 -0.044 0.853

Visual discrimination -0.096 -0.273 0.081 -0.260 0.269

17

4. Discussion

In this study, we assessed functional outcome at school age in children that were treated with

low-dose DXM during the neonatal period. Our main finding was that preterm infants treated

with low-dose DXM in the neonatal period scored poorer on motor skills, total IQ, memory,

and attention at school-age, compared with Dutch norms. Of all functional domains we tested

in this study, DXM treatment seemed to affect motor skills the most. Furthermore, these

children had more behavioral problems, especially on the hyperactivity scale. Visual

perceptual abilities and language skills were not affected by the DXM treatment. When we

used cut off points from a preterm reference group, the low-dose DXM treated children still

scored poorer on motor skills but not on total-IQ. Regarding their motor skills they still scored

3 to 5 times more often abnormal, both on the total score and the subscales. Finally, we did

not find a dose-response effect regarding the cumulative DXM dose on any functional

domain.

Two studies determined neurodevelopmental outcome after low-dose DXM treatment in the

neonatal period in preterm children at the age of three months and two years using the same

low-dose DXM tapering course as we did. One reported that, at the age of three months, the

motor optimality score (MOS) was significantly higher and the presence of CP lower in the

low-dose DXM group as compared with the high-dose DXM group.(13) The other indicated

that no significant differences were found at the age of two years between low-dose DXM

treatment and a placebo when investigating the mental developmental index (MDI) and

psychomotor developmental index (PDI). They could also not find a lower prevalence of CP

in the placebo group.(31) All together, these results indicate that low-dose DXM treatment

probably has less side effects considering motor skills as compared with high-dose DXM

treatment. However, little is known about the effect at school age of children treated with low-

dose DXM. On the short term the side effects seemed less severe but our results indicate that

low-dose DXM treated children still experience moderate to severe motor impairments as

compared with children who did not receive low-dose DXM treatment. Apparently this is not

reflected in CP, as the prevalence of CP in our study group is relatively low, but it is reflected

in poor gross and fine motor skills required in daily life.

Previous studies suggest that a higher starting dose of DXM is an important risk factor for

adverse functional outcome.(32,33) Therefore we also compared the functional outcome of

our study group with children treated with high-dose DXM during the neonatal period.(10)

We hypothesized that impairment in functional outcome was less severe in the low-dose

DXM treated children as compared with high-dose DXM. However, contrary to our

hypothesis, no differences were found when comparing our results to the group of high-dose

DXM treated children as stated in the study of Hitzert et al. This suggests that the children did

not benefit from the lower starting dose and cumulative DXM dose although this was

suggested in several studies investigating short term functional outcomes.(13)(31)

We thought about possible explanations why the children on low dose DXM experience less

impairments on the short term than children with high-dose DXM, while this difference is not

noticeable on the long term. It could be due to differences between the two groups in risk

factors for functional impairments. In the present study the mean days of mechanical

ventilation is 1.74 times higher than those in the high-dose DXM study of Hitzert et al.(10).

Furthermore, in our study 100% of the children had BPD in contrast to the 68% of children in

the high-dose DXM study. It could be that our study group had a higher risk of poor outcomes

18

aside from the DXM treatment because of the increased severity of illness in our study group.

This could explain the lack of improvement in incidence and severity of the outcomes.(10)

Although we found little differences between the test outcomes of our study group and the

high-dose DXM treated children, there were considerably less children in our study group

who developed cerebral palsy as compared with high-dose DXM treatment.(10) This finding

is supported by the two studies looking at the short term functional outcome of low-dose

DXM treatment. One study reported that at the short term the prevalence of CP was decreased

in low-dose DXM treated children when compared to high-dose DXM treatment. The other

study found no difference in prevalence of CP between the low-dose DXM treatment and a

placebo.(13)(31) We could not demonstrate that higher cumulative doses of DXM were

associated with more impairment of motor skills. Even so, our data suggest that, if there is a

dose-response effect, it is reflected in prevalence of CP, but not in prevalence of motor

impairments in general.

Our study indicates that, in children treated with low-dose DXM, several cognitive skills were

also impaired, such as IQ, memory and attention. Low-dose DXM treated children scored

significantly poorer on intelligence as compared with a term control group with 2.5 times

more children scoring a total IQ of less than 85(<P15). Performance IQ was more severely

affected than verbal IQ with 4 times more children scoring less than 85. A previous study that

assessed performance and verbal IQ in a cohort of preterm infants born at a gestational age

below 32 weeks reported 4.5 times more children who scored abnormal on performance IQ

when compared with verbal IQ, as compared with a term control group.(15) Our results

indicate that the use of low-dose DXM does not shift this distribution, as performance IQ was

still the most affected. As stated earlier, visual perceptual abilities and language skills were

not affected by the DXM treatment. Research is missing on the effect of low-dose DXM

treatment on cognitive outcome in children at school age.

We have thought about explanations for our findings. It is known that DXM treatment causes

changes in the hippocampus. The hippocampus is highly sensitive for this treatment because

neurons in most areas of the brain stop dividing after the third trimester. However, the

neurons in the hippocampus dentate gyrus continue to divide long after term age which makes

them very vulnerable for influences of this treatment.(34) The consequence of DXM on the

hippocampus consists of decreased long term potentiation and induced long term

depression.(35) Long term potentiation is a biochemical mechanism involved in long-term

memory by reinforcement of repeated excitation at the spines of the cortical dendrites. Long

term depression has an opposite effect to long term potentiation.(36) Also, a decreased

hippocampal volume on the left and right side of the brain as a consequence of DXM

treatment has been described. Hippocampal volume itself is associated with memory,

cognition, and IQ.(37) This is also in line with our findings regarding IQ and memory.

The reduced function and volume of the hippocampus, however, does not explain the

extremely high prevalence of impaired motor skills in our study. A possible explanation for

this high prevalence is the effect of DXM on the white matter of the brain. DXM treatment

decreases the volume of white and grey matter, thalamus, basal ganglia and total brain

volume.(38) (39) Other studies reported that white matter damage is associated with severe

cognitive delay, psychomotor delay, CP, and neurosensory impairment.(40) The association

between white matter damage and motor skills is proved in other studies. In one of these

19

studies, a impairment in quality of general movements was found, at the ages of one and three

months, if white matter damage was present.(41)

Another explanation for the impaired motor skills is the high prevalence of hyperactivity in

our study group. Previous research suggests that motor skills are more likely to be impaired in

children with ADHD in general. Three hypotheses on why ADHD could influence motor

skills are comorbidity, attention deficit, or lack of inhibition.(42)

To summarize, the cognitive and motor impairment of the children treated with DXM could

be due to changes in hippocampal function and volume, and damaged white and grey matter

of the brain. Our results suggest that even with the administration of low dose DXM, adverse

effects of the treatment are still present. This could mean that the damage of grey and white

matter, and the changes in function and volume of the hippocampus are equally present in the

low-dose DXM treated children as compared with the high-dose DXM treated children.

This study has some limitations. First, the number of children participating in this study was

relatively small. Second, we did not perform the complete battery of tests but several subtests.

Hereby, the outcomes of the tests are an estimated performance level of the participating

children. Third, the children with a GMFCS ≥3 did not participate in the tests but the parents

of these children only filled in a questionnaire. This means that our study results could be an

underestimation of the outcome of our study group. Fourth, we recognize that several

confounding variables, as stated in the introduction, may have influenced the outcomes of the

tests. Most importantly this relates to a considerably more severe lung disease before low-

dose DXM was considered after the alarming reports on neurological side effects of high-dose

DMX. Being a cohort study, it is very hard to disentangle the effects of the DXM treatment

and the illness severity of the children. The strength of this study is the broad spectrum of

tests which gives a detailed description of the outcomes in our studygroup.

Our study might have implications. Increasingly more extreme premature children receive

active treatment and are kept alive than previously. These children are born with a very high

risk of getting new BPD. It is expected that more and more children will need DXM rescue

treatment to wean them from ventilatory support. This is one of the reasons why it is so

important to research the possibilities of improving this rescue treatment for the benefit of

these children. A lot of research is done on this field of the neonatology. The UMCG changed

their protocol from using high-dose DXM to low-dose DXM for improvement of the short

and long term side effects of this treatment. Other hospitals changed DXM to hydrocortisone

or even lower dosages of DXM. What the ideal treatment is, is as yet unknown. Our study

indicates that low-dose DXM is still associated with several long-term functional

impairments. It also shows that it is important to do long-term follow-up. So far, the long-

term side effects of low-dose DXM treatment were unknown. Future research needs to be

done to investigate the optimal type and dose of corticosteroid treatment to treat and prevent

BPD.

5. Conclusion

This study showed that children treated with low-dose DXM scored poorer on motor skills,

IQ, memory, and attention as compared with a term born norm group at school age. They also

had more hyperactivity on behavioral scales. Motor skills were affected the most considering

all functional domains. Compared with high-dose DXM treatment we found no differences in

functional outcome. Only the prevalence of CP in our study was lower suggesting that

20

children treated with low-dose DXM have impaired motor skills, but the severity may be less

when the starting dose is lower.

It is possible that because of the increased caution taken by neonatologists when currently

starting DXM treatment, the children are sicker when given the treatment. Because a lot of

variables present in the children treated with DXM (BPD, preterm birth, and the

complications of preterm birth) also have an effect on the functional outcome it is difficult to

entangle the exact cause of the impaired functional outcome found in this study. Is it because

higher prevalence of comorbidities that cause worse functional outcome in our study group, or

is it because of the severity of illness before given the low-dose DXM treatment? This is why

more research is necessary for a greater understanding on the long-term functional outcomes

of DXM treated children. In this way it is possible to treat the children in a way where their

futures are harmed as little as possible.

21

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