Eur Child Adolesc Psychiatry DOI 10.1007/s00787-014-0597-9
ORIGINAL CONTRIBUTION
Minor neurodevelopmental impairments are associated with increased occurrence of ADHD symptoms in children born extremely preterm Silje Katrine Elgen • Kristian Sommerfelt • Katrine Tyborg Leversen • Trond Markestad
Received: 18 February 2014 / Accepted: 6 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract ADHD is more common in children born preterm than at term. The purpose of the study was to examine if, and to what extent, ADHD symptoms are associated with minor neurodevelopmental impairments (NDI) in extremely preterm children. In a national population-based cohort with gestational age 22–27 weeks or birth weight \1,000 g assessed at 5 years of age, scores on Yale Children’s Inventory (YCI) scales (seven scales) were related to normal functions vs. NDI defined as mild impairments in cognitive function (IQ 70–84), motor function (Movement Assessment Battery for children score [ the 95th percentile or freely ambulatory cerebral palsy), vision (correctable), and hearing (no hearing aid). YCI was completed for 213 of 258 eligible children (83 %). Children with minor NDIs (n = 98) had significantly higher scores (more ADHD symptoms) than those without NDI (n = 115) on the YCI scales of Attention, Tractability, Adaptability and Total score. Increasing numbers of minor NDIs were associated with higher mean YCI scores. In multivariate analysis only decreased hearing, IQ, and male gender were significantly associated with scores on the Attention scale. Thirty-three children (16 %) had scores[3 on the Attention scale (probably ADHD), and the proportion was significantly higher for those with mild NDIs compared to those without (Odds ratio = 2.7, 95 % CI 1.3–6.0). Children born extremely preterm with minor NDIs were more likely to have ADHD symptoms than S. K. Elgen (&) K. Sommerfelt T. Markestad Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway e-mail: [email protected] S. K. Elgen K. Sommerfelt K. T. Leversen T. Markestad Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
those with no NDI, and increasing number of minor NDIs were associated with more ADHD symptoms. Keywords Extremely preterm infants Attention deficit hyperactivity disorder Neurodevelopmental impairment Mental health
Introduction Children born extremely preterm (EP, children born before 28 weeks gestation), or with extremely low birth weight (ELBW, birth weight less than 1,000 g) are at increased risk of Attention Deficit/Hyperactivity Disorders (ADHD) [1–6], as well as neurodevelopmental deficits of cognition, vision, hearing or motor function (including cerebral palsy-CP) [7– 12], compared to children born at term. The few previous studies on relationships between ADHD symptoms and such deficits in these children have reported positive associations, but children with severe deficits, including intellectual disability, have usually been included [1–3, 5]. If so, reported frequencies of inattention may be inaccurate due to use of assessment tools for ADHD that were not validated for children with intellectual disability [13, 14]. A more detailed understanding of associations between minor neurodevelopmental impairments (minor NDIs) and ADHD symptoms may have implications for counseling of parents of EP/ELBW children, follow-up and educational strategies. The aims of the present study were 1) to investigate if EP/ELBW children with mild impairments related to vision, hearing, motor abilities and cognition (minor NDIs), are at increased risk of having ADHD symptoms compared to EP/ELBW children without NDI, and 2) to investigate if increasing numbers of minor NDIs increases the risk of ADHD symptoms in EP/ELBW children.
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Eur Child Adolesc Psychiatry
Patients and methods
ADHD symptoms
Population
ADHD symptoms were assessed with the Yale Children’s inventory (YCI) which is a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD including inattention, impulsivity, and hyperactivity [20–24]. Each item is scored from 1 to 4 with the highest score representing the most severe impairment. Items are allocated to six subscales with two to seven items in each. An item is only used in one subscale. The six subscales are: (1) Attention: easily distracted, does not finish; (2) Tractability: difficult to manage, destructive behavior; (3) Adaptability: difficulties in adapting to new situations; (4) Impulsivity: noisy, does not wait for turn; (5) Activity: always in action, fidgets, squirms, and (6) Negative affect: difficulties getting friends [22]. An additional Total YCI score was created by collapsing all subscales into one scale. The Attention subscale has been validated to be the most important scale when predicting risk of ADHD. It is rare for children without ADHD to score above 3 on the Attention subscales [21, 23]. Missing responses on an YCI item were replaced by the mean score of the subscale for that specific child. All YCI items were completed for 177 children while one item was missing for 29 and 2–3 items for seven children. The YCI has been shown to have high sensitivity (88 %) and specificity (94 %) in diagnosing ADHD, and has a high test/retest reliability [21, 24]. YCI was developed in the USA and there are no normative data for Norwegian children at 5 years of age. The YCI questionnaire was administrated to the parents by mail.
The study population was a national cohort of all EP and ELBW children with no or minor NDI born in Norway in 1999 and 2000 [15]. The children were prospectively followed from birth until 5 years of age. Neurodevelopmental and sensory outcome at 2 and 5 years of age have been published previously [7, 16]. The present study is based on evaluation at 5 years of age when the children were assessed by pediatricians, psychologists and physiotherapists, independently of each other [7]. Pediatric examination, cognitive and motor tests A pediatrician performed a general clinical and neurological examination, and classified the gross motor function for children with cerebral palsy (CP) according to the five-level gross motor function classification for CP (GMFCS). In short, those in class 1 are freely ambulatory, class 2 are unable to run or jump, class 3 are dependent on devices for walking, and classes 4 and 5 are nonambulatory CP [17]. A psychologist tested cognitive abilities with The Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R). Reference mean for the full IQ (FIQ) score is 100 and one standard deviation (SD) is 15 [18]. A physiotherapist assessed motor function with the Movement Assessment Battery for children (ABC test). The ABC test consists of eight tasks in three major fields; Manual dexterity, ball skills and balance (static and dynamic). In the present study, increasing scores mean poorer function. A total score [95th percentile was classified as a motor problem [19]. All children in Norway have a vision screening at 4 years of age and pure tone audiometry at five. Any significant deviation results in referral to an ophthalmologist or otolaryngologist. Minor NDI Minor NDI was defined as freely ambulatory CP, i.e. CP class 1, according to the GMFCS [17], mild motor problems (scores on the ABC test [95th percentile [19]), mild cognitive impairment (IQ 70–84 on the WPPSI-R [18]), mild visual impairments (squint or refractive errors but no loss of vision after correction), and/or mild hearing loss (no need for hearing aids) [7]. Children with moderate and severe neurodevelopmental deficits [7] were excluded as the study assessment tools regarding ADHD symptoms have not been validated for children with such deficits.
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Statistical analysis The main statistical analyses were performed in five stages. Neonatal characteristics of the children that were assessed or not assessed at 5 years of age were compared to discover potential selection bias (Stage 1). Thereafter, background characteristics for those with minor and no NDI were compared to discover factors needed to be adjusted for in further analyses (Stage 2). In Stage 3 we analyzed whether EP/ELBW children with NDIs were at increased risk of ADHD symptoms. First, mean YCI subscale and Total YCI scores were compared for the children with minor vs. no NDI. The analyses were performed separately for each sex and adjusted for significant differences in background variables (p \ 0.05), including GA and bronchopulmonary dysplasia (BPD), using backward stepwise regression analysis. Since GA and BW were closely related, only GA (continuous) was included. Second, the Attention scale was dichotomized as [3 vs. B3, and a cross-tab analysis with the dichotomized Attention scale was performed. This was repeated for each sex. In Stage 4 we analyzed whether the risk of ADHD increased with the number of NDIs.
Eur Child Adolesc Psychiatry
ANOVA analyses were used to compare mean score on the YCI scales according to number of minor NDIs, i.e. no, one or 2–4 minor NDIs. Post hoc analyses with t tests were performed. In addition, multivariate post hoc analyses were performed adjusting for GA using multiple regression analyses with forced entry of variables, with each of the YCI subscales as dependent variable, and GA (continuous) and number of NDI impairments as independent variables. In Stage 5 exploratory analyses of whether attention problems were related to specific NDIs were performed using backward multiple linear regression analyses. The YCI Attention subscale was dependent variable while independent variables were mild visual impairment, mild hearing loss, IQ 70–84 (each categorized as 0–1), motor impairment (categorized as 0 for no motor impairments, 1 for ABC score [95th percentile and 2 for freely ambulatory CP), and gender. The identified significant independent variables were then used in a new linear regression analysis with forced entry of variables to exclude as few cases as possible due to missing data. In all univariate analyses Chi-square tests were used for categorical and independent samples t test for continuous data. A p value less than 0.05 was considered statistically significant, and 95 % confidence intervals (CI) were calculated where appropriate. SPSS statistical package version 19.0 was used for all analyses. The study was approved by the Regional Committee on Medical Research Ethics and the Norwegian Data Inspectorate, and parents gave written informed consent.
Results Population Of the 372 EP/ELBW children alive at 5 years of age, 306 were assessed. Forty-eight were excluded from the present study due to moderate and severe neurodevelopmental deficits. Of the remaining 258 eligible children with no (n = 140) or mild (n = 118) NDIs, 213 (83 %) completed the YCI (Fig. 1). Of the 213 attending children, 47 (22 %) were born with GA C 28 weeks. There were no statistically significant differences between children assessed or not regarding maternal, perinatal and neonatal variables, or in proportions with minor NDIs (results not shown). There were no statistically significant differences in mean YCI scores between children with GA \ 28 weeks and GA C 28 weeks (results not shown). Minor vs. no NDI and ADHD symptoms Of the 213 EP/ELBW children with YCI data, 115 (54 %) had no NDI, and 98 (46 %) minor NDIs. Those with minor
638 children born 174 stillborn or died in the delivery room
2 refused to participate 462 admitted to NICU d
86 died in the NICU 376 discharged from NICU 4 died after discharge (2 SIDSe, 1 congenital syndrome and 1 tetraplegic cerebral palsy) 372 alive at 5 years of age
1 with Down’s syndrome excluded
65 lost to follow up
306 somatically examined at 5 years of age 48 excluded due to Moderate/Severe f neurodevelopmental deficits e (NDD)
45 with Nog or Minorh NDI lost to YCI follow up 213 with No or Minor NDI completed YCI screening at 5 years of age
Fig. 1 Description of the cohort of children born Extremely Preterma (EP) in Norway in 1999–2000 and screened for ADHDb at 5 years of age using the Yale Children’s inventoryc (YCI). aGestational age 22–27 weeks or birth weight 500–999 g. bAttention Deficit/Hyperactivity Disorder. cParental screening questionnaire consisting of 27 items targeting core symptoms of ADHD. dNeonatal Intensive Care Unit. eSudden infant death syndrome. fModerate/severe NDD: CP class 2–5, FIQ \ 70, severe visual impairment or blindness, need of hearing aid or deafness. gNo NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing. hMinor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/ refractive error, and/or mild hearing loss
NDIs had lower mean GA and BW, and higher proportions were boys and had experienced BPD (Table 1). The children with minor NDIs had significantly higher mean YCI scores (indicating more problems) on the Attention, Tractability, and Adaptability scales and the
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Eur Child Adolesc Psychiatry Table 1 Clinical characteristics of the assessed extremely preterm (EP) children with minor and no neurodevelopmental impairment (NDI) born in Norway 1999–2000 Minor NDI n = 98
No NDI n = 115
p valuea
Mothers age, years (mean, SD)
30 (5)
31 (6)
0.12
Mother high educationb (n, %)
42 (43)
59 (51)
0.25
Prenatal steroids (n, %) Preeclampsia (n, %)
70 (71) 21 (22)
83 (72) 31 (27)
0.90 0.35
Cesarean section (n, %)
66 (68)
80 (69)
0.96
Gestational age, weeks (mean, IQRc)
26 (25, 27)
27 (25, 29)
Birth weight, gram (mean, SD)
820 (180)
898 (158)
0.004 0.001
Gestational age \ 28 weeks (n, %)
81 (84)
85 (73)
0.06
Small for gestational aged (n, %)
21 (22)
22 (19)
0.7
Multiple births (n, %)
23 (24)
28 (24)
0.88
Boys (n, %)
58 (60)
54 (47)
0.04
Bronchopulmonary dysplasiae (n, %)
52 (53)
43 (37)
0.02
NECf (proven or suspected) (n, %)
3 (3)
6 (5)
0.44
Normal cerebral ultrasound (n, %)
72 (74)
83 (72)
0.93
No retinopathy of prematurity (n, %)
63 (66)
92 (79)
0.07
Extremely preterm (EP): gestational age 22–27 weeks or birth weight 500–999 g Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss No NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing a
Chi-square test or independent samples t test as appropriate
b
At least 3 years of college education or a university degree
c
Interquartile range
d
Birth weight \5th percentile for gestational age
e
Assisted ventilation or oxygen supplementation at 36 weeks of postconceptional age
f
Necrotizing enterocolitis
Total YCI scale than those with no NDI (Table 2). When stratified by sex, this finding was limited to girls (Table 2). Adjusting for GA did not change the results significantly (Table 2). The infants with BPD had significantly lower GA. In the multiple linear regression analyses in Table 2 only GA was corrected for as inclusion of BPD in the same analysis did not change the results. Overall, 33 (16 %) of the children had an Attention score above 3. The respective figures were 22 (22 %) for the children with minor NDI and 11 (10 %) for the children without NDI (OR: 2.7, 95 % CI; 1.3–6.0, p = 0.01, Table 2). Number and nature of NDIs and ADHD Of the 98 children with minor NDIs, 61 had one and 37 had 2–4 impairments (Table 3). Mean Attention, Tractability, Adaptability and Total YCI scores increased significantly with increasing number of minor NDIs (Table 4). In an explorative multiple linear regression analysis, mild hearing loss, mild cognitive impairment and male gender, but not mild visual problems, motor problems or GA, were independently associated with
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attention problems (score on the YCI Attention subscale), and mild hearing loss had the largest impact (Table 5). The hearing and cognitive impairments accounted for 12 % of the variance (Adjusted R square) in the Attention subscale in this model.
Discussion In the present study, EP/ELBW children with minor NDIs had a small, but significantly, increased risk of having ADHD symptoms compared to EP/ELBW children with no NDI. Increasing numbers of minor NDIs were associated with increasing risk of ADHD symptoms, as was mild hearing loss and mild cognitive impairment, but not mild visual or motor problems. Strengths of the present study included a populationbased design with a large national cohort, a high followup rate and very little variability in age of the children when assessed. Only one source of information on the children’s behavior and presence of ADHD symptoms was a weakness, and lack of information on the duration of ADHD symptoms was a weakness. Another
Eur Child Adolesc Psychiatry Table 2 ADHD symptoms according to scores on the Yale Children’s inventory (YCI) in children born extremely preterm with Minor or no neurodevelopmental impairment (NDI) Minor NDI Mean (SD)
No NDI Mean (SD)
Mean difference
95 % CI
p value
Adjusteda p value
All
n = 98
n = 115
Attention
2.4 (0.6)
2.1 (0.6)
-0.3
-0.4 to -0.13
0.000
0.000
Tractability
1.7 (0.6)
1.6 (0.5)
-0.2
-0.3 to -0.03
0.02
0.02
Adaptability
2.0 (0.7)
1.8 (0.6)
-0.2
-0.4 to -0.04
0.02
0.009
Impulsivity
2.3 (0.6)
2.3 (0.5)
-0.1
-0.2 to 0.1
0.42
0.48
Activity
2.5 (1.0)
2.5 (0.8)
-0.1
-0.3 to 0.2
0.65
0.70
Negative affect Total YCI
2.0 (0.7) 13 (3.1)
1.9 (0.6) 12 (2.7)
-0.1 -0.8
-0.2 to 0.1 -0.6 to -0.1
0.45 0.04
0.74 0.04
Girls
n = 39
n = 62
Attention
2.3 (0.6)
2.0 (0.6)
-0.3
-0.5 to -0.1
0.005
0.02
Tractability
1.7 (0.6)
1.5 (0.4)
-0.2
-0.4 to -0.02
0.03
0.09
Adaptability
2.0 (0.8)
1.7 (0.6)
-0.3
-0.6 to -0.03
0.03
0.02
Impulsivity
2.2 (0.7)
2.2 (0.5)
0.0
-0.2 to 0.2
0.97
0.43
Activity
2.5 (1.0)
2.5 (0.8)
0.0
-0.3 to 0.4
0.83
0.95
Negative affect
1.9 (0.6)
1.9 (0.6)
-0.1
-0.3 to 0.2
0.50
0.78
Total YCI
13 (3.5)
12 (2.7)
-0.9
-0.2 to 0.4
0.16
0.23
Boys
n = 59
n = 53
Attention
2.4 (0.6)
2.2 (0.5)
-0.2
-0.4 to -0.02
0.07
0.20
Tractability
1.8 (0.6)
1.7 (0.6)
-0.1
-0.3 to 0.1
0.34
0.63
Adaptability
2.0 (0.6)
1.9 (0.6)
-0.1
-0.4 to 0.1
0.33
0.61
Impulsivity
2.4 (0.6)
2.3 (0.6)
-0.1
-0.4 to 0.1
0.37
0.66
Activity Negative affect
2.5 (0.9) 2.0 (0.7)
2.4 (0.8) 1.9 (0.6)
-0.2 -0.1
-0.5 to 0.2 -0.3 to 0.2
0.35 0.74
0.24 0.86
Total YCI
13 (2.9)
12 (2.8)
-0.7
-1.9 to 0.2
0.20
0.37
Likelihood of ADHD
Minor NDI n (%)
No NDI n (%)
All Most likely ADHD (Attention [ 3)
n = 98 22 (22)
n = 115 11 (10)
OR
95 % CI
p value
2.7
1.3 to 6.0
0.01
ADHD Attention Deficit/Hyperactivity Disorder YCI: a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD Extremely preterm: gestational age 22–27 weeks or birth weight 500–999 g Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss No NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing a
Adjusted for gestational age using multiple regression analyses. Same analysis were done adjusting for both gestational age and bronchopulmonal dysplasia, however, the results did not change
weakness was that the YCI has only been validated in relatively few studies. Due to insufficient statistical power we could not reliably estimate whether specific combinations of minor NDIs were associated with particular risks of having ADHD symptoms. Since YCI has not been validated for Norwegian children and we did not include a control group born at term, we cannot make any firm statement as to the risk of ADHD symptoms due to prematurity per se. However, in a previous study we found that only 5 % [25] of randomly
selected 5-year-old children born at term had scores on the Attention scale of more than 3 [25] compared to 16 % in the present study supporting the generally reported finding that EP/ELBW children are at much higher risk of developing ADHD symptoms. Several studies have found cognitive impairment to be a strong predictor of behavior problems and ADHD symptoms in EP/ELBW children [1, 2, 26]. However, in these studies children with intellectual disability and other severe neurodevelopmental deficits were included and may have
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Eur Child Adolesc Psychiatry Table 3 Number and types of minor neurodevelopmental impairments in children born extremely preterm with minor or no neurodevelopmental impairment (NDI) born in Norway 1999–2000 Number with minor NDI
Total n (%)
Boys n (%)
Girls n (%)
0 Impairments
115 (54)
53 (47)
62 (62)
1 Impairment
61 (29)
34 (30)
27 (27)
IQa
20
12
8
CPb
1
0
1
Visionc
20
11
9
9
5
4
Motor problem 2 Impairments
11 26 (13)
5 18 (16)
6 8 (8)
Hearing and vision
4
3
1
Hearing and motor problem
2
2
0
Hearing and IQ
1
1
0
Hearingd e
Vision and motor problem
6
5
1
Vision and IQ
6
3
3
Vision and CP
2
1
1
IQ and CP
1
1
0
Motor problem and IQ
4
2
2
3 Impairments
10 (4)
6 (5)
4 (4)
IQ, motor problem and vision
4
3
1
Hearing, motor problem and IQ
1
1
0
Hearing, vision and motor problem
3
2
1
IQ, CP and vision
1
0
1
Hearing, vision, IQ 4 Impairments
1 1 (0.5)
0 1 (1)
1 0
Vision, hearing, motor problem and IQ
1
1
0
Total
213
112
101
Extremely preterm: gestational age 22–27 weeks or birth weight 500–999 g Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss No NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing a
Mild cognitive impairment with an IQ: 70–84
b
CP class 1 with the GMFCS
c
Squint, refractive error
d
Hearing loss, but no device
e
According to ABC test, score [95th percentile, but not CP
been responsible for the reported effect. The significance of various milder sensory, cognitive and motor impairments in relation to later behavior problems such as ADHD symptoms, have received minimal attention in the extensive follow-up research on EP/ELBW children. In the present study we found that mild cognitive impairment (IQ 70–84) was a significant, although weak predictor, which is in contrast to the EPICure study [1]. Increasing risk of ADHD symptoms with mild hearing impairment, as found in the present study, supports the findings in the only previous informative study we have found [1]. However, that study did not exclude children with intellectual disability which may have confounded their results. In contrast to the EPICure [1] and Epipage [27] studies we did not
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find that motor problems were associated with ADHD symptoms. Again, those with intellectual disability were not excluded from analysis of attention problems and tools to assess attention problems may not have been valid for such children. Children with intellectual disability would have an increased frequency of cerebral palsy, possibly explaining the finding of associations between attention problems and motor problems in those studies. It is well known that children with intellectual disability, regardless of GA and BW, commonly also have motor problems [28]. Our findings of a relatively small, but significantly increased risk of ADHD symptoms in EP/ELBW children with minor cognitive and hearing impairment, and with increasing number of minor NDIs in general, are useful
Eur Child Adolesc Psychiatry Table 4 ADHD symptoms according to the Yale Children’s inventory (YCI) with increasing numbers of minor neurodevelopmental impairments (NDI) in children born extremely preterm (EP) in Norway 1999–2000 YCI
Attention
Noa NDI
Minor NDI(s)
n = 115
One NDI n = 61
Mean (SD)
Mean (SD)
Mean difference
95 % CI
Mean (SD)
Mean difference
95 % CI
2.3 (0.5)
-0.2
-0.4 to -0.03
2.5 (0.6)
-0.2
-0.5 to 0.02
2.1 (0.6)
ANOVA p value
2–4 NDI’s n = 37
0.000b,
Tractability
1.6 (0.5)
1.7 (0.6)
-0.1
-0.3 to 0.02
1.8 (0.6)
-0.1
-0.3 to 0.1
0.040
Adaptability
1.8 (0.6)
1.9 (0.7)
-0.1
-0.3 to 0.06
2.1 (0.7)
-0.2
-0.5 to 0.1
0.015c
Impulsivity
2.3 (0.5)
2.2 (0.7)
0.0
-0.2 to 0.20
2.5 (0.5)
-0.2
-0.5 to -0.03
0.13c
Activity
2.5 (0.8)
2.5 (1.0)
0.0
-0.3 to 0.24
2.6 (1.0)
-0.1
-0.5 to 0.3
0.87
1.9 (0.6)
1.9 (0.7)
0.0
-0.2 to 0.19
2.0 (0.7)
-0.1
-0.4 to 0.1
0.45
12.0 (2.7)
12.5 (3.1)
-1.4 to 0.4
13.5 (3.2)
-0.9
-2.2 to 0.3
0.034c
Negative effect Total YCI
-0.5
c
c
Post hoc analysis with multiple regressions was done to adjust for gestational age. The results were basically identical when adjusting for gestational age, with no difference in significant findings ADHD Attention Deficit/Hyperactivity Disorder Yale Children’s inventory (YCI); a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD Minor NDI; CP class 1, FIQ 70-84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss Extremely preterm (EP); gestational age 22–27 weeks or birth weight 500–999 g p value \ 0.05 in post hoc analysis (t test), comparing 2–4 NDI impairments with one NDI impairment a
No NDI; No CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing
b
p value \ 0.05 in post hoc analysis (t test), comparing one NDI impairment with no NDI impairment
c
p value \ 0.05 in post hoc analysis (t test), comparing 2–4 NDI impairments with no NDI impairment
Table 5 Result of forced entry regression analysis of minor neurodevelopmental impairments and gender as predictors of attention problems according to score on the Attention subscale of the Yale Children’s inventory (YCI) Dependent variable: Attention subscale (YCI) b
95 % CI
p value
0.23
0.21–0.72
0.000
Independent variables Mild hearing impairmenta Mild cognitive impairment
b
Male gender
0.21
0.14–0.55
0.001
0.17
0.05–0.38
0.009
Mild vision, motor problems (including mild CP, class 1) and gestational age were not significantly associated with outcome in an initial analysis and, therefore, excluded from the final analysis presented in the table to minimize exclusion of cases Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss Yale Children’s inventory (YCI): a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD a
No need of hearing aid
b
IQ 70–84 (categorical 0–1)
when counseling parents and other caregivers as accurately as possible. It may also be useful when designing rehabilitation and follow-up programs and when designing further research involving follow-up of preterm infants. Acknowledgments The study was funded by the Norwegian Foundation for Health and Rehabilitation through The Unexpected
Child Death Society of Norway, the Research Council of Norway, Helse Vest Hospital Trust, University of Bergen, and Uni Health Center for Child and Adolescent Mental Health. Other members of the Norwegian Extreme Prematurity Study are as follows: Pediatrics: Arild Rønnestad, Oslo University Hospital, Rikshospitalet, Oslo; Per Ivar Kaaresen, University Hospital of North Norway, Tromsø; Theresa Farstad, Akershus University Hospital, Lørenskog; Janne Skranes, Oslo University Hospital, Ulleva˚l University Hospital, Oslo; Ragnhild Støen, St Olav‘s Hospital, Trondheim University Hospital, Trondheim; Siren Rettedal, Stavanger University Hospital, Stavanger, and Haukeland University Hospital, Bergen; Lorentz M Irgens, University of Bergen, Bergen; Sven Harald Andersen, Østfold Hospital, Fredrikstad; Jørgen Hurum, Innlandet Hospital, Lillehammer; Sveinung Slinde, Telemark Hospital, Skien; Jorunn Ulriksen and Ka˚re Danielsen, Sørlandet Hospital, Kristiansand; Jon Skranes, Sørlandet Hospital, Arendal; Sabine Bru¨gman, Buskerud Hospital, Drammen; Lars Tveiten, Innlandet Hospital, Elverum; Fabian Bergqvist, Førde Hospital, Førde; Andreas Andreassen, Fonna Hospital, Haugesund, ˚ lesund Hospital, A ˚ lesund; Ingebjørg Fagerli, NordLutz Nietsch, A land Hospital, Bodø; Bjørn Myklebust, Levanger Hospital, Levanger. For technical assistance, we thank Inger Elise Engelund and Magnhild Viste, Medical Birth Registry of Norway, Locus of Registry-Based Epidemiology. The authors thank biostatistician Geir Egil Eide for advice on statistics. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standards This study has been approved by the Regional Committee on Medical Research Ethics and the Norwegian Data Inspectorate, and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Prior to their inclusion in the study, parents gave written informed consent.
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References 1. Samara M et al (2008) Pervasive behavior problems at 6 years of age in a total-population sample of children born at \/ = 25 weeks of gestation. Pediatrics 122(3):562–573 2. Delobel-Ayoub M et al (2009) Behavioral problems and cognitive performance at 5 years of age after very preterm birth: the EPIPAGE study. Pediatrics 123(6):1485–1492 3. Anderson PJ et al (2011) Attention problems in a representative sample of extremely preterm/extremely low birth weight children. Dev Neuropsychol 36(1):57–73 4. Elgen SK et al (2012) Mental health at 5 years among children born extremely preterm: a national population-based study. Eur Child Adolesc Psychiatry 21(10):583–589 5. Hack M et al (2009) Behavioral outcomes of extremely low birth weight children at age 8 years. J Dev Behav Pediatr 30(2): 122–130 6. Lindstrom K, Lindblad F, Hjern A (2011) Preterm birth and attention-deficit/hyperactivity disorder in schoolchildren. Pediatrics 127(5):858–865 7. Leversen KT et al (2011) Prediction of neurodevelopmental and sensory outcome at 5 years in Norwegian children born extremely preterm. Pediatrics 127(3):e630–e638 8. Johnson S et al (2009) Neurodevelopmental disability through 11 years of age in children born before 26 weeks of gestation. Pediatrics 124(2):e249–e257 9. Marlow N et al (2005) Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 352(1):9–19 10. Bhutta AT et al (2002) Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA 288(6):728–737 11. Larroque B et al (2008) Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 371(9615):813–820 12. Hack M et al (2005) Chronic conditions, functional limitations, and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s. JAMA 294(3):318–325 13. Kaptein S et al (2008) Mental health problems in children with intellectual disability: use of the strengths and difficulties questionnaire. J Intellect Disabil Res 52(Pt 2):125–131 14. Emerson E (2005) Use of the strengths and difficulties questionnaire to assess the mental health needs of children and adolescents with intellectual disabilities. J Intellect Dev Disabil 30(1):14–23 15. Markestad T et al (2005) Early death, morbidity, and need of treatment among extremely premature infants. Pediatrics 115(5): 1289–1298
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16. Westby Wold SH et al (2009) Neonatal mortality and morbidity in extremely preterm small for gestational age infants: a population based study. Arch Dis Child Fetal Neonatal Ed 94(5):F363–F367 17. Palisano R et al (1997) Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol 39(4):214–223 18. Wechsler D (1999) Wechsler preschool and primary scale of intelligence-revised, Swedish edn. Psykologfo¨rlaget AB, Stockholm 19. Henderson S, Sugden D (1996) The movement assessment battery for children, Swedish edn. Psykologfo¨rlaget AB, Stockholm 20. Shaywitz SE et al (1986) Yale Children’s Inventory (YCI): an instrument to assess children with attentional deficits and learning disabilities. I. Scale development and psychometric properties. J Abnorm Child Psychol 14(3):347–364 21. Shaywitz SE, Shaywitz BA, Jamner AH, Gillespie SM (1986b) Diagnosis of attention deficit disorder: development and validation of a diagnostic rule utilizing the Yale Children’s inventory. Annals of Neurology 20:415 (abstract) 22. Shaywitz SE et al (1988) Concurrent and predictive validity of the Yale Children’s Inventory: an instrument to assess children with attentional deficits and learning disabilities. Pediatrics 81(4):562–571 23. Shaywitz BA, Shaywitz SE (1989) Pediatric neurology, principles and practice. Learning disabilities and attention disorders. Mosby Company, St. Louis 24. Shaywitz SE, Holahan JM, Marchione KE, Sadler AE and Shaywitz BA (1992) The Yale Children’s Inventory: normative data and their implications for the diagnosis of attention deficit disorder in children. In: Shaywitz SE and Shaywitz BA (eds) Attention deficit disorder comes of age; toward the 21st century. Pro’ed, Series Editors 25. Sommerfelt K et al (2001) Behavior in term, small for gestational age preschoolers. Early Hum Dev 65(2):107–121 26. Johnson S et al (2010) Psychiatric disorders in extremely preterm children: longitudinal finding at age 11 years in the EPICure study. J Am Acad Child Adolesc Psychiatry 49(5):453–463 e1 27. Arnaud C et al (2007) Prevalence and associated factors of minor neuromotor dysfunctions at age 5 years in prematurely born children: the EPIPAGE study. Arch Pediatr Adolesc Med 161(11):1053–1061 28. Smits-Engelsman B, Hill EL (2012) The relationship between motor coordination and intelligence across the IQ range. Pediatrics 130(4):e950–e956
ORIGINAL CONTRIBUTION
Minor neurodevelopmental impairments are associated with increased occurrence of ADHD symptoms in children born extremely preterm Silje Katrine Elgen • Kristian Sommerfelt • Katrine Tyborg Leversen • Trond Markestad
Received: 18 February 2014 / Accepted: 6 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract ADHD is more common in children born preterm than at term. The purpose of the study was to examine if, and to what extent, ADHD symptoms are associated with minor neurodevelopmental impairments (NDI) in extremely preterm children. In a national population-based cohort with gestational age 22–27 weeks or birth weight \1,000 g assessed at 5 years of age, scores on Yale Children’s Inventory (YCI) scales (seven scales) were related to normal functions vs. NDI defined as mild impairments in cognitive function (IQ 70–84), motor function (Movement Assessment Battery for children score [ the 95th percentile or freely ambulatory cerebral palsy), vision (correctable), and hearing (no hearing aid). YCI was completed for 213 of 258 eligible children (83 %). Children with minor NDIs (n = 98) had significantly higher scores (more ADHD symptoms) than those without NDI (n = 115) on the YCI scales of Attention, Tractability, Adaptability and Total score. Increasing numbers of minor NDIs were associated with higher mean YCI scores. In multivariate analysis only decreased hearing, IQ, and male gender were significantly associated with scores on the Attention scale. Thirty-three children (16 %) had scores[3 on the Attention scale (probably ADHD), and the proportion was significantly higher for those with mild NDIs compared to those without (Odds ratio = 2.7, 95 % CI 1.3–6.0). Children born extremely preterm with minor NDIs were more likely to have ADHD symptoms than S. K. Elgen (&) K. Sommerfelt T. Markestad Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway e-mail: [email protected] S. K. Elgen K. Sommerfelt K. T. Leversen T. Markestad Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
those with no NDI, and increasing number of minor NDIs were associated with more ADHD symptoms. Keywords Extremely preterm infants Attention deficit hyperactivity disorder Neurodevelopmental impairment Mental health
Introduction Children born extremely preterm (EP, children born before 28 weeks gestation), or with extremely low birth weight (ELBW, birth weight less than 1,000 g) are at increased risk of Attention Deficit/Hyperactivity Disorders (ADHD) [1–6], as well as neurodevelopmental deficits of cognition, vision, hearing or motor function (including cerebral palsy-CP) [7– 12], compared to children born at term. The few previous studies on relationships between ADHD symptoms and such deficits in these children have reported positive associations, but children with severe deficits, including intellectual disability, have usually been included [1–3, 5]. If so, reported frequencies of inattention may be inaccurate due to use of assessment tools for ADHD that were not validated for children with intellectual disability [13, 14]. A more detailed understanding of associations between minor neurodevelopmental impairments (minor NDIs) and ADHD symptoms may have implications for counseling of parents of EP/ELBW children, follow-up and educational strategies. The aims of the present study were 1) to investigate if EP/ELBW children with mild impairments related to vision, hearing, motor abilities and cognition (minor NDIs), are at increased risk of having ADHD symptoms compared to EP/ELBW children without NDI, and 2) to investigate if increasing numbers of minor NDIs increases the risk of ADHD symptoms in EP/ELBW children.
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Patients and methods
ADHD symptoms
Population
ADHD symptoms were assessed with the Yale Children’s inventory (YCI) which is a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD including inattention, impulsivity, and hyperactivity [20–24]. Each item is scored from 1 to 4 with the highest score representing the most severe impairment. Items are allocated to six subscales with two to seven items in each. An item is only used in one subscale. The six subscales are: (1) Attention: easily distracted, does not finish; (2) Tractability: difficult to manage, destructive behavior; (3) Adaptability: difficulties in adapting to new situations; (4) Impulsivity: noisy, does not wait for turn; (5) Activity: always in action, fidgets, squirms, and (6) Negative affect: difficulties getting friends [22]. An additional Total YCI score was created by collapsing all subscales into one scale. The Attention subscale has been validated to be the most important scale when predicting risk of ADHD. It is rare for children without ADHD to score above 3 on the Attention subscales [21, 23]. Missing responses on an YCI item were replaced by the mean score of the subscale for that specific child. All YCI items were completed for 177 children while one item was missing for 29 and 2–3 items for seven children. The YCI has been shown to have high sensitivity (88 %) and specificity (94 %) in diagnosing ADHD, and has a high test/retest reliability [21, 24]. YCI was developed in the USA and there are no normative data for Norwegian children at 5 years of age. The YCI questionnaire was administrated to the parents by mail.
The study population was a national cohort of all EP and ELBW children with no or minor NDI born in Norway in 1999 and 2000 [15]. The children were prospectively followed from birth until 5 years of age. Neurodevelopmental and sensory outcome at 2 and 5 years of age have been published previously [7, 16]. The present study is based on evaluation at 5 years of age when the children were assessed by pediatricians, psychologists and physiotherapists, independently of each other [7]. Pediatric examination, cognitive and motor tests A pediatrician performed a general clinical and neurological examination, and classified the gross motor function for children with cerebral palsy (CP) according to the five-level gross motor function classification for CP (GMFCS). In short, those in class 1 are freely ambulatory, class 2 are unable to run or jump, class 3 are dependent on devices for walking, and classes 4 and 5 are nonambulatory CP [17]. A psychologist tested cognitive abilities with The Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R). Reference mean for the full IQ (FIQ) score is 100 and one standard deviation (SD) is 15 [18]. A physiotherapist assessed motor function with the Movement Assessment Battery for children (ABC test). The ABC test consists of eight tasks in three major fields; Manual dexterity, ball skills and balance (static and dynamic). In the present study, increasing scores mean poorer function. A total score [95th percentile was classified as a motor problem [19]. All children in Norway have a vision screening at 4 years of age and pure tone audiometry at five. Any significant deviation results in referral to an ophthalmologist or otolaryngologist. Minor NDI Minor NDI was defined as freely ambulatory CP, i.e. CP class 1, according to the GMFCS [17], mild motor problems (scores on the ABC test [95th percentile [19]), mild cognitive impairment (IQ 70–84 on the WPPSI-R [18]), mild visual impairments (squint or refractive errors but no loss of vision after correction), and/or mild hearing loss (no need for hearing aids) [7]. Children with moderate and severe neurodevelopmental deficits [7] were excluded as the study assessment tools regarding ADHD symptoms have not been validated for children with such deficits.
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Statistical analysis The main statistical analyses were performed in five stages. Neonatal characteristics of the children that were assessed or not assessed at 5 years of age were compared to discover potential selection bias (Stage 1). Thereafter, background characteristics for those with minor and no NDI were compared to discover factors needed to be adjusted for in further analyses (Stage 2). In Stage 3 we analyzed whether EP/ELBW children with NDIs were at increased risk of ADHD symptoms. First, mean YCI subscale and Total YCI scores were compared for the children with minor vs. no NDI. The analyses were performed separately for each sex and adjusted for significant differences in background variables (p \ 0.05), including GA and bronchopulmonary dysplasia (BPD), using backward stepwise regression analysis. Since GA and BW were closely related, only GA (continuous) was included. Second, the Attention scale was dichotomized as [3 vs. B3, and a cross-tab analysis with the dichotomized Attention scale was performed. This was repeated for each sex. In Stage 4 we analyzed whether the risk of ADHD increased with the number of NDIs.
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ANOVA analyses were used to compare mean score on the YCI scales according to number of minor NDIs, i.e. no, one or 2–4 minor NDIs. Post hoc analyses with t tests were performed. In addition, multivariate post hoc analyses were performed adjusting for GA using multiple regression analyses with forced entry of variables, with each of the YCI subscales as dependent variable, and GA (continuous) and number of NDI impairments as independent variables. In Stage 5 exploratory analyses of whether attention problems were related to specific NDIs were performed using backward multiple linear regression analyses. The YCI Attention subscale was dependent variable while independent variables were mild visual impairment, mild hearing loss, IQ 70–84 (each categorized as 0–1), motor impairment (categorized as 0 for no motor impairments, 1 for ABC score [95th percentile and 2 for freely ambulatory CP), and gender. The identified significant independent variables were then used in a new linear regression analysis with forced entry of variables to exclude as few cases as possible due to missing data. In all univariate analyses Chi-square tests were used for categorical and independent samples t test for continuous data. A p value less than 0.05 was considered statistically significant, and 95 % confidence intervals (CI) were calculated where appropriate. SPSS statistical package version 19.0 was used for all analyses. The study was approved by the Regional Committee on Medical Research Ethics and the Norwegian Data Inspectorate, and parents gave written informed consent.
Results Population Of the 372 EP/ELBW children alive at 5 years of age, 306 were assessed. Forty-eight were excluded from the present study due to moderate and severe neurodevelopmental deficits. Of the remaining 258 eligible children with no (n = 140) or mild (n = 118) NDIs, 213 (83 %) completed the YCI (Fig. 1). Of the 213 attending children, 47 (22 %) were born with GA C 28 weeks. There were no statistically significant differences between children assessed or not regarding maternal, perinatal and neonatal variables, or in proportions with minor NDIs (results not shown). There were no statistically significant differences in mean YCI scores between children with GA \ 28 weeks and GA C 28 weeks (results not shown). Minor vs. no NDI and ADHD symptoms Of the 213 EP/ELBW children with YCI data, 115 (54 %) had no NDI, and 98 (46 %) minor NDIs. Those with minor
638 children born 174 stillborn or died in the delivery room
2 refused to participate 462 admitted to NICU d
86 died in the NICU 376 discharged from NICU 4 died after discharge (2 SIDSe, 1 congenital syndrome and 1 tetraplegic cerebral palsy) 372 alive at 5 years of age
1 with Down’s syndrome excluded
65 lost to follow up
306 somatically examined at 5 years of age 48 excluded due to Moderate/Severe f neurodevelopmental deficits e (NDD)
45 with Nog or Minorh NDI lost to YCI follow up 213 with No or Minor NDI completed YCI screening at 5 years of age
Fig. 1 Description of the cohort of children born Extremely Preterma (EP) in Norway in 1999–2000 and screened for ADHDb at 5 years of age using the Yale Children’s inventoryc (YCI). aGestational age 22–27 weeks or birth weight 500–999 g. bAttention Deficit/Hyperactivity Disorder. cParental screening questionnaire consisting of 27 items targeting core symptoms of ADHD. dNeonatal Intensive Care Unit. eSudden infant death syndrome. fModerate/severe NDD: CP class 2–5, FIQ \ 70, severe visual impairment or blindness, need of hearing aid or deafness. gNo NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing. hMinor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/ refractive error, and/or mild hearing loss
NDIs had lower mean GA and BW, and higher proportions were boys and had experienced BPD (Table 1). The children with minor NDIs had significantly higher mean YCI scores (indicating more problems) on the Attention, Tractability, and Adaptability scales and the
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Eur Child Adolesc Psychiatry Table 1 Clinical characteristics of the assessed extremely preterm (EP) children with minor and no neurodevelopmental impairment (NDI) born in Norway 1999–2000 Minor NDI n = 98
No NDI n = 115
p valuea
Mothers age, years (mean, SD)
30 (5)
31 (6)
0.12
Mother high educationb (n, %)
42 (43)
59 (51)
0.25
Prenatal steroids (n, %) Preeclampsia (n, %)
70 (71) 21 (22)
83 (72) 31 (27)
0.90 0.35
Cesarean section (n, %)
66 (68)
80 (69)
0.96
Gestational age, weeks (mean, IQRc)
26 (25, 27)
27 (25, 29)
Birth weight, gram (mean, SD)
820 (180)
898 (158)
0.004 0.001
Gestational age \ 28 weeks (n, %)
81 (84)
85 (73)
0.06
Small for gestational aged (n, %)
21 (22)
22 (19)
0.7
Multiple births (n, %)
23 (24)
28 (24)
0.88
Boys (n, %)
58 (60)
54 (47)
0.04
Bronchopulmonary dysplasiae (n, %)
52 (53)
43 (37)
0.02
NECf (proven or suspected) (n, %)
3 (3)
6 (5)
0.44
Normal cerebral ultrasound (n, %)
72 (74)
83 (72)
0.93
No retinopathy of prematurity (n, %)
63 (66)
92 (79)
0.07
Extremely preterm (EP): gestational age 22–27 weeks or birth weight 500–999 g Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss No NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing a
Chi-square test or independent samples t test as appropriate
b
At least 3 years of college education or a university degree
c
Interquartile range
d
Birth weight \5th percentile for gestational age
e
Assisted ventilation or oxygen supplementation at 36 weeks of postconceptional age
f
Necrotizing enterocolitis
Total YCI scale than those with no NDI (Table 2). When stratified by sex, this finding was limited to girls (Table 2). Adjusting for GA did not change the results significantly (Table 2). The infants with BPD had significantly lower GA. In the multiple linear regression analyses in Table 2 only GA was corrected for as inclusion of BPD in the same analysis did not change the results. Overall, 33 (16 %) of the children had an Attention score above 3. The respective figures were 22 (22 %) for the children with minor NDI and 11 (10 %) for the children without NDI (OR: 2.7, 95 % CI; 1.3–6.0, p = 0.01, Table 2). Number and nature of NDIs and ADHD Of the 98 children with minor NDIs, 61 had one and 37 had 2–4 impairments (Table 3). Mean Attention, Tractability, Adaptability and Total YCI scores increased significantly with increasing number of minor NDIs (Table 4). In an explorative multiple linear regression analysis, mild hearing loss, mild cognitive impairment and male gender, but not mild visual problems, motor problems or GA, were independently associated with
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attention problems (score on the YCI Attention subscale), and mild hearing loss had the largest impact (Table 5). The hearing and cognitive impairments accounted for 12 % of the variance (Adjusted R square) in the Attention subscale in this model.
Discussion In the present study, EP/ELBW children with minor NDIs had a small, but significantly, increased risk of having ADHD symptoms compared to EP/ELBW children with no NDI. Increasing numbers of minor NDIs were associated with increasing risk of ADHD symptoms, as was mild hearing loss and mild cognitive impairment, but not mild visual or motor problems. Strengths of the present study included a populationbased design with a large national cohort, a high followup rate and very little variability in age of the children when assessed. Only one source of information on the children’s behavior and presence of ADHD symptoms was a weakness, and lack of information on the duration of ADHD symptoms was a weakness. Another
Eur Child Adolesc Psychiatry Table 2 ADHD symptoms according to scores on the Yale Children’s inventory (YCI) in children born extremely preterm with Minor or no neurodevelopmental impairment (NDI) Minor NDI Mean (SD)
No NDI Mean (SD)
Mean difference
95 % CI
p value
Adjusteda p value
All
n = 98
n = 115
Attention
2.4 (0.6)
2.1 (0.6)
-0.3
-0.4 to -0.13
0.000
0.000
Tractability
1.7 (0.6)
1.6 (0.5)
-0.2
-0.3 to -0.03
0.02
0.02
Adaptability
2.0 (0.7)
1.8 (0.6)
-0.2
-0.4 to -0.04
0.02
0.009
Impulsivity
2.3 (0.6)
2.3 (0.5)
-0.1
-0.2 to 0.1
0.42
0.48
Activity
2.5 (1.0)
2.5 (0.8)
-0.1
-0.3 to 0.2
0.65
0.70
Negative affect Total YCI
2.0 (0.7) 13 (3.1)
1.9 (0.6) 12 (2.7)
-0.1 -0.8
-0.2 to 0.1 -0.6 to -0.1
0.45 0.04
0.74 0.04
Girls
n = 39
n = 62
Attention
2.3 (0.6)
2.0 (0.6)
-0.3
-0.5 to -0.1
0.005
0.02
Tractability
1.7 (0.6)
1.5 (0.4)
-0.2
-0.4 to -0.02
0.03
0.09
Adaptability
2.0 (0.8)
1.7 (0.6)
-0.3
-0.6 to -0.03
0.03
0.02
Impulsivity
2.2 (0.7)
2.2 (0.5)
0.0
-0.2 to 0.2
0.97
0.43
Activity
2.5 (1.0)
2.5 (0.8)
0.0
-0.3 to 0.4
0.83
0.95
Negative affect
1.9 (0.6)
1.9 (0.6)
-0.1
-0.3 to 0.2
0.50
0.78
Total YCI
13 (3.5)
12 (2.7)
-0.9
-0.2 to 0.4
0.16
0.23
Boys
n = 59
n = 53
Attention
2.4 (0.6)
2.2 (0.5)
-0.2
-0.4 to -0.02
0.07
0.20
Tractability
1.8 (0.6)
1.7 (0.6)
-0.1
-0.3 to 0.1
0.34
0.63
Adaptability
2.0 (0.6)
1.9 (0.6)
-0.1
-0.4 to 0.1
0.33
0.61
Impulsivity
2.4 (0.6)
2.3 (0.6)
-0.1
-0.4 to 0.1
0.37
0.66
Activity Negative affect
2.5 (0.9) 2.0 (0.7)
2.4 (0.8) 1.9 (0.6)
-0.2 -0.1
-0.5 to 0.2 -0.3 to 0.2
0.35 0.74
0.24 0.86
Total YCI
13 (2.9)
12 (2.8)
-0.7
-1.9 to 0.2
0.20
0.37
Likelihood of ADHD
Minor NDI n (%)
No NDI n (%)
All Most likely ADHD (Attention [ 3)
n = 98 22 (22)
n = 115 11 (10)
OR
95 % CI
p value
2.7
1.3 to 6.0
0.01
ADHD Attention Deficit/Hyperactivity Disorder YCI: a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD Extremely preterm: gestational age 22–27 weeks or birth weight 500–999 g Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss No NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing a
Adjusted for gestational age using multiple regression analyses. Same analysis were done adjusting for both gestational age and bronchopulmonal dysplasia, however, the results did not change
weakness was that the YCI has only been validated in relatively few studies. Due to insufficient statistical power we could not reliably estimate whether specific combinations of minor NDIs were associated with particular risks of having ADHD symptoms. Since YCI has not been validated for Norwegian children and we did not include a control group born at term, we cannot make any firm statement as to the risk of ADHD symptoms due to prematurity per se. However, in a previous study we found that only 5 % [25] of randomly
selected 5-year-old children born at term had scores on the Attention scale of more than 3 [25] compared to 16 % in the present study supporting the generally reported finding that EP/ELBW children are at much higher risk of developing ADHD symptoms. Several studies have found cognitive impairment to be a strong predictor of behavior problems and ADHD symptoms in EP/ELBW children [1, 2, 26]. However, in these studies children with intellectual disability and other severe neurodevelopmental deficits were included and may have
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Eur Child Adolesc Psychiatry Table 3 Number and types of minor neurodevelopmental impairments in children born extremely preterm with minor or no neurodevelopmental impairment (NDI) born in Norway 1999–2000 Number with minor NDI
Total n (%)
Boys n (%)
Girls n (%)
0 Impairments
115 (54)
53 (47)
62 (62)
1 Impairment
61 (29)
34 (30)
27 (27)
IQa
20
12
8
CPb
1
0
1
Visionc
20
11
9
9
5
4
Motor problem 2 Impairments
11 26 (13)
5 18 (16)
6 8 (8)
Hearing and vision
4
3
1
Hearing and motor problem
2
2
0
Hearing and IQ
1
1
0
Hearingd e
Vision and motor problem
6
5
1
Vision and IQ
6
3
3
Vision and CP
2
1
1
IQ and CP
1
1
0
Motor problem and IQ
4
2
2
3 Impairments
10 (4)
6 (5)
4 (4)
IQ, motor problem and vision
4
3
1
Hearing, motor problem and IQ
1
1
0
Hearing, vision and motor problem
3
2
1
IQ, CP and vision
1
0
1
Hearing, vision, IQ 4 Impairments
1 1 (0.5)
0 1 (1)
1 0
Vision, hearing, motor problem and IQ
1
1
0
Total
213
112
101
Extremely preterm: gestational age 22–27 weeks or birth weight 500–999 g Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss No NDI: no CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing a
Mild cognitive impairment with an IQ: 70–84
b
CP class 1 with the GMFCS
c
Squint, refractive error
d
Hearing loss, but no device
e
According to ABC test, score [95th percentile, but not CP
been responsible for the reported effect. The significance of various milder sensory, cognitive and motor impairments in relation to later behavior problems such as ADHD symptoms, have received minimal attention in the extensive follow-up research on EP/ELBW children. In the present study we found that mild cognitive impairment (IQ 70–84) was a significant, although weak predictor, which is in contrast to the EPICure study [1]. Increasing risk of ADHD symptoms with mild hearing impairment, as found in the present study, supports the findings in the only previous informative study we have found [1]. However, that study did not exclude children with intellectual disability which may have confounded their results. In contrast to the EPICure [1] and Epipage [27] studies we did not
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find that motor problems were associated with ADHD symptoms. Again, those with intellectual disability were not excluded from analysis of attention problems and tools to assess attention problems may not have been valid for such children. Children with intellectual disability would have an increased frequency of cerebral palsy, possibly explaining the finding of associations between attention problems and motor problems in those studies. It is well known that children with intellectual disability, regardless of GA and BW, commonly also have motor problems [28]. Our findings of a relatively small, but significantly increased risk of ADHD symptoms in EP/ELBW children with minor cognitive and hearing impairment, and with increasing number of minor NDIs in general, are useful
Eur Child Adolesc Psychiatry Table 4 ADHD symptoms according to the Yale Children’s inventory (YCI) with increasing numbers of minor neurodevelopmental impairments (NDI) in children born extremely preterm (EP) in Norway 1999–2000 YCI
Attention
Noa NDI
Minor NDI(s)
n = 115
One NDI n = 61
Mean (SD)
Mean (SD)
Mean difference
95 % CI
Mean (SD)
Mean difference
95 % CI
2.3 (0.5)
-0.2
-0.4 to -0.03
2.5 (0.6)
-0.2
-0.5 to 0.02
2.1 (0.6)
ANOVA p value
2–4 NDI’s n = 37
0.000b,
Tractability
1.6 (0.5)
1.7 (0.6)
-0.1
-0.3 to 0.02
1.8 (0.6)
-0.1
-0.3 to 0.1
0.040
Adaptability
1.8 (0.6)
1.9 (0.7)
-0.1
-0.3 to 0.06
2.1 (0.7)
-0.2
-0.5 to 0.1
0.015c
Impulsivity
2.3 (0.5)
2.2 (0.7)
0.0
-0.2 to 0.20
2.5 (0.5)
-0.2
-0.5 to -0.03
0.13c
Activity
2.5 (0.8)
2.5 (1.0)
0.0
-0.3 to 0.24
2.6 (1.0)
-0.1
-0.5 to 0.3
0.87
1.9 (0.6)
1.9 (0.7)
0.0
-0.2 to 0.19
2.0 (0.7)
-0.1
-0.4 to 0.1
0.45
12.0 (2.7)
12.5 (3.1)
-1.4 to 0.4
13.5 (3.2)
-0.9
-2.2 to 0.3
0.034c
Negative effect Total YCI
-0.5
c
c
Post hoc analysis with multiple regressions was done to adjust for gestational age. The results were basically identical when adjusting for gestational age, with no difference in significant findings ADHD Attention Deficit/Hyperactivity Disorder Yale Children’s inventory (YCI); a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD Minor NDI; CP class 1, FIQ 70-84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss Extremely preterm (EP); gestational age 22–27 weeks or birth weight 500–999 g p value \ 0.05 in post hoc analysis (t test), comparing 2–4 NDI impairments with one NDI impairment a
No NDI; No CP, FIQ C 85, ABC test score B95th percentile, and normal vision and hearing
b
p value \ 0.05 in post hoc analysis (t test), comparing one NDI impairment with no NDI impairment
c
p value \ 0.05 in post hoc analysis (t test), comparing 2–4 NDI impairments with no NDI impairment
Table 5 Result of forced entry regression analysis of minor neurodevelopmental impairments and gender as predictors of attention problems according to score on the Attention subscale of the Yale Children’s inventory (YCI) Dependent variable: Attention subscale (YCI) b
95 % CI
p value
0.23
0.21–0.72
0.000
Independent variables Mild hearing impairmenta Mild cognitive impairment
b
Male gender
0.21
0.14–0.55
0.001
0.17
0.05–0.38
0.009
Mild vision, motor problems (including mild CP, class 1) and gestational age were not significantly associated with outcome in an initial analysis and, therefore, excluded from the final analysis presented in the table to minimize exclusion of cases Minor NDI: CP class 1, FIQ 70–84, ABC test score [95th percentile, squint/refractive error, and/or mild hearing loss Yale Children’s inventory (YCI): a parental screening questionnaire consisting of 27 items targeting core symptoms of ADHD a
No need of hearing aid
b
IQ 70–84 (categorical 0–1)
when counseling parents and other caregivers as accurately as possible. It may also be useful when designing rehabilitation and follow-up programs and when designing further research involving follow-up of preterm infants. Acknowledgments The study was funded by the Norwegian Foundation for Health and Rehabilitation through The Unexpected
Child Death Society of Norway, the Research Council of Norway, Helse Vest Hospital Trust, University of Bergen, and Uni Health Center for Child and Adolescent Mental Health. Other members of the Norwegian Extreme Prematurity Study are as follows: Pediatrics: Arild Rønnestad, Oslo University Hospital, Rikshospitalet, Oslo; Per Ivar Kaaresen, University Hospital of North Norway, Tromsø; Theresa Farstad, Akershus University Hospital, Lørenskog; Janne Skranes, Oslo University Hospital, Ulleva˚l University Hospital, Oslo; Ragnhild Støen, St Olav‘s Hospital, Trondheim University Hospital, Trondheim; Siren Rettedal, Stavanger University Hospital, Stavanger, and Haukeland University Hospital, Bergen; Lorentz M Irgens, University of Bergen, Bergen; Sven Harald Andersen, Østfold Hospital, Fredrikstad; Jørgen Hurum, Innlandet Hospital, Lillehammer; Sveinung Slinde, Telemark Hospital, Skien; Jorunn Ulriksen and Ka˚re Danielsen, Sørlandet Hospital, Kristiansand; Jon Skranes, Sørlandet Hospital, Arendal; Sabine Bru¨gman, Buskerud Hospital, Drammen; Lars Tveiten, Innlandet Hospital, Elverum; Fabian Bergqvist, Førde Hospital, Førde; Andreas Andreassen, Fonna Hospital, Haugesund, ˚ lesund Hospital, A ˚ lesund; Ingebjørg Fagerli, NordLutz Nietsch, A land Hospital, Bodø; Bjørn Myklebust, Levanger Hospital, Levanger. For technical assistance, we thank Inger Elise Engelund and Magnhild Viste, Medical Birth Registry of Norway, Locus of Registry-Based Epidemiology. The authors thank biostatistician Geir Egil Eide for advice on statistics. Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standards This study has been approved by the Regional Committee on Medical Research Ethics and the Norwegian Data Inspectorate, and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Prior to their inclusion in the study, parents gave written informed consent.
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Eur Child Adolesc Psychiatry
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