Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm Birth

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
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
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.

 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.
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’

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PEDIATRICS Volume 145, number 2, February 2020:e20192087                                                                                                              ARTICLE
Researchers 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
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                                                                                           3
impairment 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 al
TABLE 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)
                                                                                                                   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.

visuomotor 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)
       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 al
                                                                                                   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                                                                                            7
PEDIATRICS (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

    1. Marret S, Marchand-Martin L, Picaud               8. Linsell L, Johnson S, Wolke D, et al.                impairment in adolescents born
       JC, et al; EPIPAGE Study Group. Brain                Cognitive trajectories from infancy to               preterm. Brain. 2012;135(pt 12):
       injury in very preterm children and                  early adulthood following birth before               3781–3798
       neurosensory and cognitive disabilities              26 weeks of gestation: a prospective,
                                                                                                             17. Barre N, Morgan A, Doyle LW, Anderson
       during childhood: the EPIPAGE cohort                 population-based cohort study. Arch Dis
                                                                                                                 PJ. Language abilities in children who
       study. PLoS One. 2013;8(5):e62683                    Child. 2018;103(4):363–370
                                                                                                                 were very preterm and/or very low
    2. Serenius F, Källén K, Blennow M, et al;           9. Breeman LD, Jaekel J, Baumann N,                     birth weight: a meta-analysis. J Pediatr.
       EXPRESS Group. Neurodevelopmental                    Bartmann P, Wolke D. Preterm cognitive               2011;158(5):766–774.e1
       outcome in extremely preterm infants                 function into adulthood. Pediatrics.
                                                            2015;136(3):415–423                              18. Woodward LJ, Moor S, Hood KM, et al.
       at 2.5 years after active perinatal care
                                                                                                                 Very preterm children show
       in Sweden. JAMA. 2013;309(17):                   10. Mangin KS, Horwood LJ, Woodward LJ.                  impairments across multiple
       1810–1820                                            Cognitive development trajectories of                neurodevelopmental domains by age
    3. Larroque B, Ancel PY, Marret S, et al;               very preterm and typically developing                4 years. Arch Dis Child Fetal Neonatal
       EPIPAGE Study group.                                 children. Child Dev. 2017;88(1):282–298              Ed. 2009;94(5):F339–F344
       Neurodevelopmental disabilities and              11. Pyhälä R, Lahti J, Heinonen K, et al.            19. Putnick DL, Bornstein MH, Eryigit-
       special care of 5-year-old children born             Neurocognitive abilities in young adults             Madzwamuse S, Wolke D. Long-term
       before 33 weeks of gestation (the                    with very low birth weight. Neurology.               stability of language performance in
       EPIPAGE study): a longitudinal cohort                2011;77(23):2052–2060                                very preterm, moderate-late preterm,
       study. Lancet. 2008;371(9615):813–820
                                                        12. Hack M, Flannery DJ, Schluchter M,                   and term children. J Pediatr. 2017;181:
    4. Anderson P, Doyle LW; Victorian Infant               Cartar L, Borawski E, Klein N. Outcomes              74–79.e3
       Collaborative Study Group.                           in young adulthood for very-low-birth-
                                                                                                             20. Ford RM, Griffiths S, Neulinger K,
       Neurobehavioral outcomes of school-                  weight infants. N Engl J Med. 2002;
                                                                                                                 Andrews G, Shum DH, Gray PH. Impaired
       age children born extremely low birth                346(3):149–157
                                                                                                                 prospective memory but intact episodic
       weight or very preterm in the 1990s.             13. Eryigit Madzwamuse S, Baumann N,                     memory in intellectually average 7- to 9-
       JAMA. 2003;289(24):3264–3272                         Jaekel J, Bartmann P, Wolke D. Neuro-                year-olds born very preterm and/or
    5. Wood NS, Marlow N, Costeloe K, Gibson                cognitive performance of very preterm                very low birth weight. Child
       AT, Wilkinson AR. Neurologic and                     or very low birth weight adults at                   Neuropsychol. 2017;23:954–979
       developmental disability after                       26 years. J Child Psychol Psychiatry.
                                                            2015;56(8):857–864                               21. Sripada K, Løhaugen GC, Eikenes L, et al.
       extremely preterm birth. EPICure Study
                                                                                                                 Visual-motor deficits relate to altered
       Group. N Engl J Med. 2000;343(6):                14. Luu TM, Ment L, Allan W, Schneider K,                gray and white matter in young adults
       378–384                                              Vohr BR. Executive and memory                        born preterm with very low birth
    6. Marlow N, Wolke D, Bracewell MA,                     function in adolescents born very                    weight. Neuroimage. 2015;109:493–504
       Samara M; EPICure Study Group.                       preterm. Pediatrics. 2011;127(3).
                                                            Available at:            22. Wechsler D. Wechsler Abbreviated Scale
       Neurologic and developmental
                                                            content/full/127/3/e639                              of Intelligence, 2nd ed. Bloomington,
       disability at six years of age after
                                                                                                                 MN: Pearson; 2011
       extremely preterm birth. N Engl J Med.           15. Anderson PJ, Doyle LW; Victorian Infant
       2005;352(1):9–19                                     Collaborative Study Group. Executive             23. Wechsler D. Wechsler Adult Intelligence
                                                            functioning in school-aged children who              Scale-Fourth Edition (WAIS-IV)
    7. Johnson S, Fawke J, Hennessy E, et al.
                                                            were born very preterm or with                       Administration and Scoring Manual.
       Neurodevelopmental disability through
                                                            extremely low birth weight in the 1990s.             San Antonio, TX: Psychological
       11 years of age in children born before
                                                            Pediatrics. 2004;114(1):50–57                        Corporation; 2008
       26 weeks of gestation. Pediatrics.
       2009;124(2). Available at: www.                  16. Northam GB, Liégeois F, Tournier JD,             24. Alloway TP. Automated Working Memory               et al. Interhemispheric temporal lobe                Assessment. London, United Kingdom:
       e249                                                 connectivity predicts language                       Pearson Assessment; 2007

                                       Downloaded from by guest on April 22, 2021
8                                                                                                                                             O’REILLY et al
25. Whiteside DM, Kealey T, Semla M, et al.          Neuropsychological Assessment. San                neuropsychological correlates and
     Verbal fluency: language or executive             Antonio, TX: Psychological Testing                predictors of attainment. Dev
     function measure? Appl Neuropsychol              Corporation; 1998                                 Neuropsychol. 2011;36(1):
     Adult. 2016;23(1):29–34                      30. Kaufman AS, Kaufman NL. Kaufman                   74–95
 26. Shao Z, Janse E, Visser K, Meyer AS.             Assessment Battery for Children. Circle       34. Johnson S, Strauss V, Gilmore C, Jaekel
     What do verbal fluency tasks measure?             Pines, MN: American Guidance Service,             J, Marlow N, Wolke D. Learning
     Predictors of verbal fluency                      Inc; 1983                                         disabilities among extremely preterm
     performance in older adults. Front           31. Jaekel J, Baumann N, Bartmann P,                  children without neurosensory
     Psychol. 2014;5:772                              Wolke D. General cognitive but not                impairment: comorbidity,
 27. Benton AL, Hamsher K, Sivan AB.                  mathematic abilities predict very                 neuropsychological profiles and
     Multilingual Aphasia Examination. Iowa           preterm and healthy term born adults’             scholastic outcomes. Early Hum Dev.
     City, IA: AJA Associates; 1994                   wealth. PLoS One. 2019;14(3):                     2016;103:69–75
 28. Beery KE, Beery NA. The Beery-                   e0212789                                      35. Taylor HG, Klein N, Anselmo MG, Minich
     Buktenica Developmental Test of Visual-      32. Johnson S, Hennessy E, Smith R, Trikic            N, Espy KA, Hack M. Learning problems
     Motor Integration (Beery VMI) With               R, Wolke D, Marlow N. Academic                    in kindergarten students with
     Supplemental Developmental Tests of              attainment and special educational                extremely preterm birth. Arch Pediatr
     Visual Perception and Motor                      needs in extremely preterm children at            Adolesc Med. 2011;165(9):
     Coordination and Stepping Stones Age             11 years of age: the EPICure study. Arch          819–825
     Norms: Administration, Scoring and               Dis Child Fetal Neonatal Ed. 2009;94(4):      36. Holman L, Head ML, Lanfear R, Jennions
     Teaching Manual, 6th ed. Minneapolis,            F283–F289                                         MD. Evidence of experimental bias in
     MN: NCS Pearson; 2010                        33. Johnson S, Wolke D, Hennessy E,                   the life sciences: why we need blind
 29. Korkman M, Kirk U, Kemp S. Manual for            Marlow N. Educational outcomes in                 data recording. PLoS Biol. 2015;13(7):
     the NEPSY: A Developmental                       extremely preterm children:                       e1002190

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PEDIATRICS Volume 145, number 2, February 2020                                                                                                9
Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm
  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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Neuropsychological Outcomes at 19 Years of Age Following Extremely Preterm
  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;

 The online version of this article, along with updated information and services, is
                        located on the World Wide Web at:

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