Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm Birth
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Neuropsychological Outcomes at
19 Years of Age Following Extremely
Preterm Birth
Helen O’Reilly, PhD,a,b Samantha Johnson, PhD,c Yanyan Ni, PhD,a Dieter Wolke, PhD, Dr rer nat h.c,d Neil Marlow, DM, FMedScia
Children born extremely preterm (EP) (,26 weeks’ gestation) have
BACKGROUND AND OBJECTIVES: abstract
lower cognitive scores and an increased rate of cognitive impairment compared with their
term-born peers. However, the neuropsychological presentation of these EP individuals in
adulthood has not been described. The aim of this study was to examine neuropsychological
outcomes in early adulthood after EP birth in the 1995 EPICure cohort and to investigate if the
rate of intellectual impairment changed longitudinally.
A total of 127 young adults born EP and 64 term-born controls had a
METHODS:
neuropsychological assessment at 19 years of age examining general cognitive abilities (IQ),
visuomotor abilities, prospective memory, and aspects of executive functions and language.
RESULTS: Adults born EP scored significantly lower than term-born controls across all
neuropsychological tests with effect sizes (Cohen’s d) of 0.7 to 1.2. Sixty percent of adults born
EP had impairment in at least 1 neuropsychological domain; deficits in general cognitive
functioning and visuomotor abilities were most frequent. The proportion of EP participants
with an intellectual impairment (IQ ,70) increased by 6.7% between 11 and 19 years of age
(P = .02). Visuospatial functioning in childhood predicted visuomotor functioning at 19 years.
Adults born EP continue to perform lower than their term-born peers in general
CONCLUSIONS:
cognitive abilities as well as across a range of neuropsychological functions, indicating that
these young adults do not show improvement overtime. The prevalence of intellectual
impairment increased from 11 years into adulthood.
a
Institute for Women’s Health, University College London, London, United Kingdom; bDepartment of Psychology, WHAT’S KNOWN ON THIS SUBJECT: Children born
University College Dublin, Dublin, Ireland; cDepartment of Health Sciences, George Davies Centre, University of extremely preterm (EP) are at increased risk of
Leicester, Leicester, United Kingdom; and dDivision of Mental Health and Wellbeing, Department of Psychology, cognitive impairment compared with their term-born
Warwick Medical School, University of Warwick, Coventry, United Kingdom
peers, and the prevalence of serious disability remains
Dr O’Reilly assisted in the design of the 19-year follow-up study, collected the data, and drafted and stable throughout childhood.
revised the manuscript; Dr Johnson conceptualized and designed the study, obtained funding, and
critically reviewed and revised the manuscript for intellectual content; Dr Ni conducted the
WHAT THIS STUDY ADDS: Young adults born EP
statistical analyses and critically reviewed and revised the manuscript for intellectual content; continue to perform below the level of their term-born
Dr Wolke conceptualized and designed the 19-year follow-up study, collected the 6-year follow-up peers across a range of neuropsychological functions.
data, and critically reviewed and revised the manuscript; Mr Marlow conceptualized and designed The rate of intellectual impairment increased from
the study, obtained funding, supervised data collection, and critically reviewed and revised the childhood into adulthood among those born EP.
manuscript; and all authors approved the final manuscript as submitted and agree to be
accountable for all aspects of the work.
DOI: https://doi.org/10.1542/peds.2019-2087
Accepted for publication Oct 24, 2019 To cite: O’Reilly H, Johnson S, Ni Y, et al. Neuropsychological
Outcomes at 19 Years of Age Following Extremely Preterm
Address correspondence to Helen O’Reilly, PhD, Department of Psychology, University College Dublin, Birth. Pediatrics. 2020;145(2):e20192087
Dublin 4, Ireland. E-mail: h.o’reilly@ucl.ac.uk
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PEDIATRICS Volume 145, number 2, February 2020:e20192087 ARTICLEResearchers examining outcomes of guide the developmental participants had died since being
preterm birth in infancy and expectations of both caregivers discharged from the hospital
childhood have reported a high and professionals as well as to after birth.
prevalence of neurodevelopmental identify potential areas in which to
impairments, with disability target interventions. Procedure
increasing with decreasing All participants gave informed
Here, we present neuropsychological
gestational age.1–4 The EPICure written consent to take part in the
outcomes at 19 years of age in the
studies have followed a cohort of 19-year assessment. For participants
1995 EPICure cohort. The study
infants born extremely preterm (EP) with severe cognitive impairment,
aimed to address the following
(,26 weeks’ gestation) in the United consent was obtained from a parent
questions. (1) Do adults born EP
Kingdom and Ireland during 1995. or guardian. The neuropsychological
perform significantly below the level
Assessments of this population at assessment was conducted by
of their term-born peers across
2.5, 6, and 11 years of age found a single psychologist (H.O.) at
neuropsychological domains? (2)
that as a group, children born EP 19 years and took place at University
In which neuropsychological
performed 1.1 to 1.6 SDs lower on College Hospital, London. The study
domains do adults born EP
measures of general cognitive was designed to be examiner blind;
display the greatest prevalence of
function in comparison with however, the majority of participants
impairment? (3) Does the rate
standardized norms and/or term- disclosed their group allocation
of intellectual impairment remain
born controls5–7 and were at during the course of the assessment.
stable from childhood into early
increased risk of cognitive Eleven participants were assessed
adulthood? (4) Does visuospatial
impairment.6,7 at home because of disability or
functioning in childhood predict
other personal commitments.
later visuomotor abilities in early
The prevalence of Socioeconomic status (SES) was
adulthood?
neurodevelopmental disability in the classified at 19 years on the basis of
EPICure cohort at 6 and 11 years, parent occupation by using the UK
defined as impairment in cognitive, METHODS Office for National Statistics’
motor, or sensory function, was Socioeconomic Classification 2010
similar at 45% and 46%, respectively, Participants system and categorized as (1)
with cognitive impairment being the Of 306 participants from the EPICure higher managerial, administrative,
most common deficit.7 Furthermore, birth cohort, 129 adults born EP and professional occupations; (2)
longitudinal investigation revealed (61 male participants) along with intermediate occupations; (3)
that mean cognitive scores among EP 65 term-born controls (25 male routine and manual occupations;
participants remained stable from 2.5 participants) participated in the or (4) other (long-term unemployed,
to 19 years of age.8 This is consistent 19-year follow-up. Of these, 127 adults student, unclassifiable because
with studies of very preterm (,32 born EP (59 male participants) and of missing data). Ethical approval
weeks’ gestation) and/or very low 64 controls (25 male participants) was granted by the South
birth weight (,1500 g birth weight) had a neuropsychological assessment. Central – Hampshire A Research
individuals,9,10 which confirm that This represents 42% of EP Ethics Committee (reference 13/
adults born very preterm/very low participants from the original SC/0514).
birth weight continue to function cohort and 42% of term-born
below the level of their peers.11,12 controls assessed at 11 years. Neuropsychological Assessment at
Individuals born very preterm and/or Neuropsychological assessment was 19 Years
very low birth weight are also at not completed for 2 EP participants General cognitive functioning was
risk for impairment in other (1 missed appointment; 1 acute assessed by using the Wechsler
neuropsychological domains such psychiatric episode) and 1 term-born Abbreviated Scale of Intelligence,
as executive function (EF),13–15 control (missed appointment). Second Edition (WASI-II).22 The 4-
language,16–19 prospective memory,20 Recruitment and participation subtest version was administered
and visuomotor skills.21 However, through each of the previous study comprising block design, matrix
the range and extent of phases has been described reasoning, vocabulary, and
neuropsychological deficits in elsewhere.5–7 EP and term-born similarities, from which an estimate
adulthood after birth before 26 participants not seen at 19 years had of full-scale IQ (FSIQ) was derived
weeks’ gestation have not been either declined participation, had (mean: 100; SD: 15), with FSIQ being
described. Understanding the asked not to be contacted by the the primary outcome measure. In
longer-term outcomes for study team, or did not respond to addition, verbal comprehension index
individuals born EP will help to several attempted contacts. Nine EP (VCI) and perceptual reasoning index
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2 O’REILLY et al(PRI) standardized scores were derived for each task (mean: 100; being asked, and (4) remembers
derived (mean: 100, SD: 15). Three SD: 15). immediately.
EP participants had severe cognitive 3. Verbal fluency tasks are
impairment; these participants were Neuropsychological Assessment in
considered a measure of both Childhood
assigned an FSIQ score of 40 and language ability and EFs.25,26 The
a VCI and PRI score of 45, verbal fluency test consisted of 2 At 6 and 11 years, visuomotor
corresponding to the lowest score on tasks: the F-A-S version of integration was assessed by using 2
each scale. Scores were not imputed phonemic verbal fluency27 (PVF) subtests from the Developmental
for any other measure. Additionally, 2 and semantic verbal fluency (SVF) Neuropsychological Assessment
EP participants with severe motor using the category "animals". For (NEPSY)29, design copying and
impairment could not complete PVF, the participant had 1 minute arrows, which comprise the
the block design subtest; their to generate as many words as visuospatial processing core domain
FSIQ scores were calculated by possible beginning with each of score (mean: 100; SD: 15). IQ was
using the 2-subtest version of the the letters “F,” “A,” and “S” assessed by using the Kaufman
WASI-II. separately. The number of correct Assessment Battery for Children30
words generated for each (mean: 100; SD: 15).
Three tasks were used to assess
components of EFs. letter alone and summed together
Data Analysis
was recorded. For SVF, the
1. The digit span forward and Data were analyzed by using Stata
participant had 1 minute to
backward tasks from the Wechsler 15.1 (Stata Corp, College Station, TX).
spontaneously generate as many
Adult Intelligence Scale, Fourth Mean scores with SDs were calculated
words as possible from the word
Edition,23 were used to measure for all neuropsychological measures
category “animal,” and the total
verbal short-term memory and for EP participants and term-born
number of correct responses
working memory, respectively. The controls. Effect sizes were calculated
was recorded.
examiner read out a series of by using Cohen’s d with a large
numbers that the participant had Visuomotor integration was assessed
effect size classified as $0.8. The
to verbally repeat (forward by using the Beery-Buktenica
performance of EP participants was
condition), beginning with a 2- Developmental Test of Visual-Motor
compared to that of the controls by
number sequence and increasing Integration, Sixth Edition (Beery
using linear regression models.
to a 9-number sequence. For the VMI).28 This test was composed of 3 Unadjusted and adjusted (sex and
backward task, the examiner read tasks. For the visuomotor integration SES) mean differences between
out a series of numbers that the task, participants copied drawings of groups and their 95% confidence
participant had to repeat in geometric shapes. The visual intervals (CIs) are reported. Similar
reverse order. A scaled score perception task involved matching
analyses were conducted to examine
(mean: 10; SD: 3) was calculated a target shape within similar
sex differences within the EP group.
for each task. distractor shapes. The motor
Differences in verbal working
coordination task involved copying
2. Two subtests from the Automated memory and visual working memory
Working Memory Assessment24 geometric drawings within a trail. were examined after further
(AWMA), dot matrix and spatial Each task produced a standardized controlling for verbal short-term
recall, were selected to measure score (mean: 100; SD: 15). memory and visual short-term
visuospatial short-term memory Prospective memory, comprising both memory, respectively. Odds ratios
and working memory, respectively. memory and EF skills, involves (ORs) for rates of impairment across
Participants completed this task remembering to conduct a required all measures for EP participants
on a laptop computer. The short- task or action in the future when compared to those of term-born
term memory task involved cued. This was assessed by using an controls were estimated by using
recalling the location of a series of event-based task with a 2-hour time binary logistic regression models.
dots presented within a 4 3 4 delay. Participants were requested to Term-born controls were used as
matrix on the computer screen. write their name on an envelope a reference group, and impairment
The number of dots to recall unprompted when handed one by was classified as a score .2 SDs
increased sequentially. the examiner later that day. The below their mean score. This was
Visuospatial working memory was participant’s response was scored only completed for those measures in
assessed through a mental by using the following nominal which the controls displayed scores
rotation judgement task combined categories: (1) does not remember, .2 SDs below the mean. Similar
with simultaneous dot location (2) remembers something but does adjusted analyses were performed. In
recall. A standardized score was not know what, (3) remembers after addition, ORs of intellectual
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PEDIATRICS Volume 145, number 2, February 2020 3impairment in EP and term-born or SES at 19 years (calculated by those who had a cognitive
participants were examined by using using a t test or x2 test; all P values impairment at 11 years were at
the traditional cutoff value of an IQ ..05). In comparison with their term- increased risk of deficit at 19 years
score of ,70. The McNemar test was born peers, adults born EP had (RR [95% CI]: 3.56 [2.32 to 5.46];
used to analyze whether the rate of significantly lower scores for FSIQ, P , .001). None of the term-born
intellectual impairment remained VCI, and PRI; visuomotor integration, controls had a cognitive impairment
stable from childhood into early visual perception, and motor at 11 years and 2 (3.1%) had
adulthood. To examine whether coordination; verbal and visual short- a cognitive impairment at 19 years.
EP participants with cognitive term and working memory; and Deficits among EP participants were
impairment at 11 years were at verbal fluency (Table 1). Adjustment most common in general cognitive
increased risk of impairment at for multiple comparisons was made functioning and visuomotor abilities.
19 years, relative risks (RRs) were by using Bonferroni correction Sixty percent of EP participants had
estimated by using generalized linear (critical value = 0.004) with all impairment in at least 1 domain
models. Correlation analyses and findings remaining significant. In compared with 21% of term-born
linear regression analyses were used comparison to term-born controls, controls, with 35% of EP participants
to examine visuospatial scores significantly fewer EP participants displaying deficits in $4 domains
longitudinally. correctly completed the prospective (see Fig 1).
memory task (Table 2). All between-
Longitudinal analyses revealed that
group differences remained
RESULTS Beery VMI scores at 19 years were
statistically significant after
highly correlated with NEPSY
Dropout Analysis controlling for sex and SES at
visuospatial processing core domain
19 years. A large effect size was
No difference was found in birth scores at 6 years (EP [n = 109]:
reported across the following
weight, gestational age, or sex r = 0.484, P , .001; control [n = 53]:
measures: the greatest effect was in
between the young adults born EP r = 0.417, P = .002) and 11 years (EP
FSIQ followed by PRI, visuospatial
who participated in the 19-year study [n = 115]: r = 0.695, P , .001; control
working memory, motor coordination,
(n = 129) and dropouts (n = 177) (see [n = 64]: r = 0.389, P = .002). Even
PVF, visual-motor integration,
Supplemental Table 3). Compared after adjustment for sex and SES,
visuospatial short-term memory,
with dropouts, a greater proportion NEPSY visuospatial processing core
visual perception, VCI, and verbal
of the 19-year EP cohort came from domain scores at 6 and 11 years were
working memory.
higher socioeconomic backgrounds as both significant predictors of Beery
recorded at 2.5, 6, and 11 years. VMI score at 19 years for both control
Of 119 EP participants assessed at
Furthermore, dropouts had lower and EP participants (control: P = .001;
both 11 and 19 years, 10 EP
mean IQ and/or cognitive scores at EP: P , .001; see Supplemental
participants (8.4%) at 11 years and
each of the previous assessment Table 4).
18 EP participants (15.1%) at
points, and a greater proportion
19 years had an IQ score ,70 Among EP participants, sex differences
scored in the intellectual disability
(McNemar’s x2 = 5.33; P = .021), were present in the WASI-II VCI and
range (IQ score ,70) at the 6- and
which is the standard clinical cutoff the Beery VMI and motor coordination
11-year visits compared with those
for classifying intellectual disability tasks, with EP female participants
who participated at 19 years.
(see Supplemental Fig 3); those who achieving higher mean scores than
There was no difference between the scored in the intellectual disability those of male participants (Table 1).
term-born controls who participated range at 11 years were at increased After adjustment for SES, only the
in the study at 19 years compared risk of scoring in this range at difference in motor coordination
with dropouts in terms of SES or 19 years (RR [95% CI]: 8.72 [4.48 to remained significant. IQ scores were
cognitive function measured at 16.99]; P , .001). None of the evenly distributed across SES
11 years; however, a greater controls had an IQ score ,70 at categories for both EP participants
proportion of dropouts were from either 11 or 19 years. Impairment and term-born controls (see Fig 2).
low to medium SES at 6 years of age. was also classified by using scores
,22 SDs with the controls as the
Neuropsychological Outcomes at reference (see Table 2). Using these DISCUSSION
19 Years criteria, 42 (35.3%) EP participants At 19 years of age, the young adults
The sample characteristics of the EP had a cognitive impairment at born EP in the EPICure cohort
and term participants are shown in 11 years and 53 (44.5%) had continued to function below their
Supplemental Table 3; there were no a cognitive impairment at 19 years term-born peers, particularly in
between-group differences in age, sex, (McNemar’s x2 = 4.84; P = .028); general cognitive functioning (IQ) and
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4 O’REILLY et alTABLE 1 Neuropsychological Performance of EP Young Adults and Term-Born Controls
EP (n = 127), Mean 6 SD Term-Born Controls (n = 64), Mean 6 SD EP Females Versus Male Participants, EP Versus Term, Mean Difference (95% CI)
Mean Difference (95% CI)
Male Female All Male Female All Unadjusted Adjusted for SES Unadjusted** Adjusted for Sex Adjusted for Sex, SES, Cohen’s
and SES** and Othersa d
IQ WASIb
FSIQc 82.8 6 17.7 88.6 6 15.5 85.9 6 16.7 104.4 6 11.9 103.6 6 9.2 103.9 6 10.2 5.8 (20.0 to 11.6) 5.3 (20.8 to 11.5) 218.0 (222.5 to 217.8 (222.3 to — 1.21
(n = 59) (n = 68) (n = 127) (n = 25) (n = 39) (n = 64) 213.5) 213.2)
VCIc 85.9 6 16.9 91.5 6 13.2 88.9 6 15.2 102.4 6 11.3 102.3 6 9.1 102.4 6 9.9 5.6 (0.3 to 10.9)* 5.1 (20.4 to 10.7) 213.4 (217.6 to 213.2 (217.4 to — 0.98
(n = 59) (n = 68) (n = 127) (n = 25) (n = 39) (n = 64) 29.3) 29.0)
PRIc 83.0 6 18.6 87.7 6 17.6 85.6 6 18.1 105.4 6 12.8 103.9 6 10.3 104.5 6 11.3 4.7 (21.7 to 11.1) 4.6 (2.2 to 11.4) 218.9 (223.8 to 219.0 (224.0 to — 1.17
(n = 57) (n = 68) (n = 125) (n = 25) (n = 39) (n = 64) 214.0) 214.0)
Beery VMI
Visuomotor 73.4 6 17.1 79.7 6 16.9 76.9 6 16.9 90.4 6 11.5 92.8 6 8.3 91.8 6 9.7 6.3 (0.3 to 12.4)* 5.9 (20.6 to 12.3) 215.0 (219.5 to 214.4 (219.0 to — 1.00
integration (n = 55) (n = 68) (n = 123) (n = 25) (n = 39) (n = 64)
PEDIATRICS Volume 145, number 2, February 2020
210.4) 29.8)
Visual 82.7 6 15.2 83.8 6 17.1 83.3 6 16.2 98.4 6 7.2 96.0 6 7.6 97.0 6 7.5 1.2 (24.7 to 7.0) 0.3 (25.9 to 6.4) 213.7 (217.9 to 213.6 (218.0 to — 0.98
perception (n = 55) (n = 68) (n = 123) (n = 25) (n = 39) (n = 64) 29.4) 29.3)
Motor 67.7 6 17.2 78.7 6 15.7 73.8 6 16.9 85.8 6 11.0 93.3 6 8.6 90.3 6 10.2 11.0 (5.2 to 16.8)* 10.6 (4.5 to 16.6)* 216.5 (221.1 to 215.5 (219.9 to — 1.10
coordination (n = 55) (n = 68) (n = 123) (n = 25) (n = 39) (n = 64) 212.0) 211.1)
Verbal fluency
Letter F 7.2 6 3.3 7.4 6 3.8 7.3 6 3.6 11.0 6 4.9 11.2 6 3.8 11.1 6 4.2 0.2 (21.1 to 1.5) 0.3 (21.0 to 1.7) 23.8 (24.9 to 23.8 (25.0 to — 0.99
(n = 56) (n = 68) (n = 124) (n = 25) (n = 39) (n = 64) 22.6) 22.6)
Letter A 6.4 6 3.1 6.6 6 3.4 6.5 6 3.3 10.0 6 4.2 9.1 6 3.6 9.5 6 3.8 0.2 (21.0 to 1.3) 0.2 (21.0 to 1.4) 23.0 (24.1 to 23.0 (24.1 to — 0.86
(n = 56) (n = 68) (n = 124) (n = 25) (n = 39) (n = 64) 21.9) 22.0)
Letter S 8.7 6 3.5 10.0 6 4.5 9.4 6 4.1 13.4 6 3.8 12.6 6 3.9 12.9 6 3.8 1.3 (20.2 to 2.7) 1.4 (20.2 to 2.9) 23.5 (24.8 to 23.6 (24.8 to — 0.87
(n = 56) (n = 68) (n = 124) (n = 25) (n = 39) (n = 64) 22.3) 22.3)
PVF total 22.3 6 8.5 24.0 6 10.6 23.2 6 9.7 34.4 6 11.6 33.0 6 9.7 33.5 6 10.4 1.7 (21.8 to 5.1) 1.9 (21.7 to 5.5) 210.3 (213.4 to 210.4 (213.5 to — 1.03
(n = 56) (n = 68) (n = 124) (n = 25) (n = 39) (n = 64) 27.3) 27.3)
SVF 16.2 6 5.6 17.1 6 5.9 16.7 6 5.8 22.3 6 5.7 20.1 6 5.9 21.0 6 5.9 1.0 (21.1 to 3.1) 1.2 (20.8 to 3.1) 24.3 (26.0 to 24.3 (26.0 to — 0.73
(n = 56) (n = 67) (n = 123) (n = 25) (n = 39) (n = 64) 22.5) 22.5)
Verbal memoryd
Short-term 8.6 6 2.8 8.1 6 2.8 8.3 6 2.8 10.2 6 3.3 10.4 6 3.0 10.3 6 3.1 20.5 (21.5 to 0.5) 20.7 (21.7 to 22.0 (22.9 to 22.0 (22.9 to — 0.69
memory (n = 56) (n = 68) (n = 124) (n = 25) (n = 39) (n = 64) 0.3) 21.1) -1.1)
Working 8.2 6 2.5 8.5 6 2.6 8.3 6 2.6 10.1 6 3.0 10.7 6 2.9 10.5 6 2.9 0.3 (20.7 to 1.2) 0.3 (20.6 to 1.3) 22.1 (22.9 to 22.1 (22.9 to 21.1 (21.9 to 20.4)* 0.78
memory (n = 56) (n = 67) (n = 123) (n = 25) (n = 39) (n = 64) 21.3) 21.3)
Visuo-spatial
memorye
Short-term 0.99
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82.3 6 14.8 82.2 6 13.5 82.2 6 14.1 97.9 6 15.5 95.7 6 15.0 96.5 6 15.1 20.1 (25.3 to 5.1) 20.9 (26.4 to 214.4 (218.8 to 214.0 (218.5 to —
memory (n = 52) (n = 65) (n = 117) (n = 24) (n = 39) (n = 63) 4.6) 29.9) 29.4)
Working 87.8 6 12.4 87.4 6 12.5 87.6 6 12.4 103.3 6 15.9 102.5 6 15.7 102.8 6 15.6 20.5 (25.2 to 4.2) 21.5 (26.3 to 215.2 (219.5 to 215.1 (219.5 to 28.1 (212.0 to 24.2)** 1.11
memory (n = 49) (n = 64) (n = 113) (n = 23) (n = 39) (n = 62) 3.5) 211.0) 210.7)
—, not applicable.
a Mean differences in verbal working memory and visuospatial working memory when further adjusting for verbal short-term memory and visuospatial short-term memory, respectively.
b IQ WASI indicates the WASI-II.
c PRI.
d Verbal short-term and working memory indicates digit span forward and backward tasks from the Wechsler Adult Intelligence Scale, Fourth Edition.
e Visuospatial short-term and working memory indicates the dot matrix and spatial recall tasks from the AWMA.
*P , .05
**P , .001.
5visuomotor skills, as well as in Although the EP participants were Sixteen percent of the EP participants
prospective memory and aspects of found to be functioning significantly scored in the intellectual disability
language and EFs. Even after below the level of their peers, on range (IQ ,70) at 19 years. However,
adjustment for sex and SES, group average, their performance on when using the term-born controls as
differences remained significant. standardized measures was within a reference group with impairment
These results are in line with studies the low average range. Pyhälä et al11 classified as a score ,22 SD, 44.5% of
of very preterm and/or very low suggest that although the scores of the EP participants were found to have
birth weight individuals9–21; but here, preterm individuals may fall a cognitive impairment in comparison
we extend these findings to an EP within the normal range, poorer with 3% of controls. Using the term-
population for the first time. neuropsychological functioning could born controls as a reference group
Underperformance relative to their result in lower educational allowed us to identify EP participants
term-born peers extended across attainment, earning potential and with deficits relative to their same-aged
a range of neuropsychological poorer physical health. Indeed, peers and who may not be receiving
functions, with 35% of EP general cognitive abilities were found the support they need because they do
participants displaying deficits in to predict adult wealth in a study of not fall in clinically defined range of
$4 domains, again corroborating very preterm and/or very low birth disability. Studies of school-aged EP
previous studies of very preterm weight, with the very preterm and/or children have reported that despite
and/or very low birth weight.13,18 very low birth weight adults also presenting with learning difficulty or
Mean cognitive performance of EP having significantly lower wealth than intellectual disability, a large proportion
participants at 19 years was the term-born controls.31 Previous are not receiving additional school
comparable to that reported at the research by the EPICure study group support, suggesting they have unmet
previous follow-up visits in has revealed that EP children are at educational needs.34,35
childhood,5–7 indicating that these markedly high risk of poor academic
young adults do not show substantial attainment32 and that cognitive The number of EP participants
catch-up over time.8 ability is a predictive factor.33 scoring in the intellectual disability
TABLE 2 Neuropsychological Impairment in EP Young Adults and Term-Born Controls
EP, % (n of N) Term-Born Controls, % (n of N) Unadjusted OR (95% CI) Adjusted for Sex and SES, OR (95% CI)
a
IQ WASI
FSIQb 44.9 (57 of 127) 3.1 (2 of 64) 25.2 (5.9 to 107.7)* 48.5 (6.5 to 362.6)*
FSIQc 15.8 (20 of 127) 0.0 (0 of 64) — —
VCIb 33.1 (42 of 127) 1.6 (1 of 64) 31.1 (4.1 to 232.3)* 30.8 (4.1 to 232.0)*
VCIc 11.0 (14 of 127) 0.0 (0 of 64) — —
PRIb 36.0 (25 of 125) 1.6 (1 of 64) 35.4 (4.8 to 264.2)* —
PRIc 19.2 (24 of 125) 0.0 (0 of 64) — —
Beery VMI
Visuomotor integration 36.6 (45 of 123) 4.7 (3 of 64) 11.7 (3.5 to 39.6)* 10.9 (3.2 to 37.4)*
Visual perception 39.8 (49 of 123) 6.3 (4 of 64) 9.9 (3.4 to 29.1)* 10.2 (3.4 to 30.2)*
Motor coordination 31.7 (39 of 123) 4.7 (3 of 64) 9.4 (2.8 to 32.0)* 8.7 (2.5 to 30.3)*
Verbal fluency
Letter F 8.1 (10 of 124) 0.0 (0 of 64) — —
Letter A 3.2 (4 of 124) 0.0 (0 of 64) — —
Letter S 17.7 (22 of 124) 1.6 (1 of 64) 13.6 (1.8 to 103.3)* 12.6 (1.6 to 96.5)*
PFV total 15.3 (19 of 124) 0.0 (0 of 64) — —
SVF 12.2 (15 of 123) 1.6 (1 of 64) 8.8 (1.1 to 67.8)* 8.6 (1.1 to 67.0)*
Verbal memoryd
Short-term memory 8.1 (10 of 124) 1.6 (1 of 64) 5.5 (0.7 to 44.2) 5.4 (0.7 to 43.9)
Working memory 9.8 (12 of 123) 0.0 (0 of 64) — —
Visuospatial memorye
Short-term memory 12.0 (14 of 117) 0.0 (0 of 63) — —
Working memory 0.0 (0 of 113) 0.0 (0 of 62) — —
Prospective memory
Score ,4 17.9 (22 of 123) 4.7 (3 of 64) 4.4 (1.3 to 15.4)* 4.0 (1.1 to 14.1)*
—, not applicable.
a IQ WASI indicates the WASI-II.
b PRI.
c Using traditional cutoffs to define intellectual disability (score ,70).
d Verbal short-term and working memory indicates digit span forward and backward tasks from the Wechsler Adult Intelligence Scale, Fourth Edition.
e Visuospatial short-term and working memory indicates the dot matrix and spatial recall tasks from the AWMA.
*P , .05.
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6 O’REILLY et alCONCLUSIONS
Young adults born EP continue to
function below the level of their term-
born peers in general cognitive
functioning, with the prevalence of
intellectual impairment increasing
significantly from 11 to 19 years.
These adults born EP had impairment
in multiple neuropsychological
domains, with deficits in general
FIGURE 1 cognitive functioning and visuomotor
Number of neuropsychological domains in abilities being the greatest. The
which impairment is present.
FIGURE 2 current results highlight the need for
IQ versus SES for EP participants and term- early and ongoing neuropsychological
range (IQ ,70) increased from born controls at 19 years of age.
and educational assessment in EP
11 to 19 years (8.4% vs 15.1%, children to ensure these children
respectively). For a small proportion receive appropriate support in school
participants remained significant.
of EP individuals, intellectual and for planned educational
This suggests that EP males may
impairment may only become pathways.
catch up to their EP female peers in
apparent later in adolescence or
general cognitive function over the
adulthood when cognitive
course of adolescence. ACKNOWLEDGMENTS
demands become more complex,
highlighting the need for ongoing We thank the EPICure study group and
A total of 57.8% of the EP
neuropsychological assessment over all the EPICure participants and their
participants were lost to follow-up by
the course of childhood and families for their participation in this
19 years. The dropout analysis
adolescence. The majority of EP study.
revealed that those who were lost
individuals who shifted into the to follow-up were from lower
impaired range of IQ functioning at socioeconomic backgrounds and had
19 years had borderline scores (IQ ABBREVIATIONS
lower IQ and/or cognitive scores;
score: 70–79) at the 11-year additionally, a greater proportion of AWMA: Automated Working
assessment (Supplemental Fig 3), dropouts scored in the intellectual Memory Assessment
which would account for the reported disability range at 6 and 11 years Beery VMI: Beery-Buktenica Devel-
high correlation in mean cognitive compared with those who opmental Test of
functioning over time.8 Visuospatial participated. This suggests that the Visual-Motor
abilities were also found to be highly cognitive disparity observed between Integration, Sixth
correlated from childhood to young the term-born controls and EP Edition
adulthood. These findings are in participants at 19 years may be CI: confidence interval
keeping with previous research in which underestimated. Analysis using EF: executive function
authors reported that cognitive function multiple imputation at 11 years to EP: extremely preterm
remains stable from early childhood account for such selective loss to FSIQ: full-scale IQ
onward in those born very preterm follow-up suggested that cognitive NEPSY: Developmental
and/or very low birth weight.9,11 disability was 5% greater than Neuropsychological
Sex differences in cognitive function reported.7 In addition, some of the Assessment
were reported in the EPICure 11-year 95% CIs are wide, as seen in Table 2, OR: odds ratio
cohort,7 with EP male participants reflecting the small sample size. An PRI: perceptual reasoning index
demonstrating lower IQ scores in additional limitation was the PVF: phonemic verbal fluency
comparison with EP female breached blinding of the study due RR: relative risk
participants. Similar differences were to accidental group disclosure SES: socioeconomic status
seen at 19 years on the VCI, visual- by participants. However, SVF: semantic verbal fluency
motor integration, and motor because objective standardized VCI: verbal comprehension index
coordination. However, after instruments were used to assess WASI-II: Wechsler Abbreviated
adjustment for SES, only the neuropsychological outcomes, the Scale of Intelligence,
difference in motor coordination likelihood of bias is minimized but Second Edition
between EP female and male cannot be excluded.36
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PEDIATRICS Volume 145, number 2, February 2020 7PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2020 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Funded by the Medical Research Council United Kingdom (Medical Research Council reference MR/J01107X/1).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-3359.
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PEDIATRICS Volume 145, number 2, February 2020 9Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm
Birth
Helen O'Reilly, Samantha Johnson, Yanyan Ni, Dieter Wolke and Neil Marlow
Pediatrics 2020;145;
DOI: 10.1542/peds.2019-2087 originally published online January 10, 2020;
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Helen O'Reilly, Samantha Johnson, Yanyan Ni, Dieter Wolke and Neil Marlow
Pediatrics 2020;145;
DOI: 10.1542/peds.2019-2087 originally published online January 10, 2020;
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