cognitive abilities in preterm and term-born adolescents
TRANSCRIPT
Cognitive Abilities in Preterm and Term-Born Adolescents
Luke A. Schneider, PhD1, Nicholas R. Burns, PhD2, Lynne C. Giles, PhD3, Ryan D. Higgins, BSc1, Theodore J. Nettelbeck, PhD2,
Michael C. Ridding, PhD1, and Julia B. Pitcher, PhD1
Objective To investigate the influence of a range of prenatal and postnatal factors on cognitive development inpreterm and term-born adolescents.Study design Woodcock-Johnson III Tests of Cognitive Abilities were used to assess general intellectual abilityand 6 broad cognitive abilities in 145 young adolescents aged approximately 12.5 years and born 25-41 weeksgestational age (GA). To study potential links between neurophysiologic and cognitive outcomes, corticomotorexcitability was measured using transcranial magnetic stimulation and surface electromyography. The influenceof various prenatal and postnatal factors on cognitive development was investigated using relative importanceregression modeling.Results Adolescents with greater GA tended to have better cognitive abilities (particularly general intellectual abil-ity, working memory, and cognitive efficiency) and higher corticomotor excitability. Corticomotor excitability ex-plained a higher proportion of the variance in cognitive outcome than GA. But the strongest predictors ofcognitive outcome were combinations of prenatal and postnatal factors, particularly degree of social disadvantageat the time of birth, birthweight percentile, and height at assessment.Conclusions In otherwise neurologically healthy adolescents, GA accounts for little interindividual variability incognitive abilities. The association between corticomotor excitability and cognitive performance suggests thatreduced connectivity, potentially associated with brain microstructural abnormalities, may contribute to cognitivedeficits in preterm children. It remains to be determined if the effects of low GA on cognitive outcomes attenuateover childhood in favor of a concomitant increase in the relative importance of heritability, or alternatively, ifcognitive development is more heavily influenced by the quality of the postnatal environment. (J Pediatr2014;-:---).
In developed countries, 6%-12% of all births annually are preterm (ie, <37 completed weeks gestation).1 A plethora ofstudies have shown associations between preterm birth and later suboptimal neurodevelopmental outcomes. In termsof identifying the actual effects of reduced gestational age (GA) on neurodevelopment, most have arguably been
confounded by not differentiating GA from birthweight percentile (BW%), and/or including children with clinical historiesof brain lesions or other neurosensory impairments, and rarely including late preterm children (33-37 weeks GA), whocomprise over 70% of all preterm births. Compared with their term-born peers, the late preterm exhibit a high prevalenceof low severity motor, cognitive, and behavioral impairments.2-6 They account for up to 74% of the total burden of dysfunc-tion because of preterm birth,7 a greater need for special education,2,8,9 lower net income, and a reduced likelihood ofcompleting a university education.7 These outcomes are not explained by perinatal brain lesions that affect <1% of children(<10% in those born <32 weeks GA), but more likely by microstructural brain abnormalities not readily detected with stan-dard magnetic resonance imaging (MRI).10-13
Using transcranial magnetic stimulation (TMS), we previously showed relationships between preterm birth and reduced cor-ticomotor excitability, neuroplasticity, and functional motor development in early adolescence.4,14 The motor cortex (M1)contributes to at least some cognitive functions15,16 and a basic TMS measure of corticomotor excitability, the resting motorthreshold (rMT), also correlates with cortical white matter maturation and integrity.17 Here, we investigated if there are alsolinks between GA, corticomotor excitability, and cognitive abilities, in adolescents born across a range of GAs but without
known brain lesions or neurosensory disabilities. We hypothesized that increasedFrom the 1Research Center for Early Origins of Healthand Disease, Robinson Institute, School of Pediatricsand Reproductive Health, 2School of Psychology, and3Discipline of Public Health, University of Adelaide,Adelaide, Australia
Supported by the National Health and Medical ResearchCouncil of Australia (565344 and 299087 both to J.P.), theSouth Australian Channel 7 Children’s Research Foun-dation, the Women’s and Children’s Hospital ResearchFoundation, and the Faculty of Health Sciences, Univer-sity of Adelaide. The authors declare no conflicts ofinterest.
0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc.
All rights reserved.
http://dx.doi.org/10.1016/j.jpeds.2014.03.030
BW% Birthweight percentile
GA Gestational age
GIA General intellectual ability
IRSD Index of relative socioeconomic disadvantage
M1 Motor cortex
MRI Magnetic resonance imaging
rMT Resting motor threshold
SES Socioeconomic status
TMS Transcranial magnetic stimulation
WCH Women’s and Children’s Hospital
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cortical excitability is associated with increased cognitive per-formance. To better characterize any associations, we alsoexamined the influence of a range of pre- and postnatal vari-ables known to influence cognitive abilities, including fetalgrowth18 and socioeconomic factors.19 Preliminary resultshave been presented in abstract.20
Methods
Stratified recruitment was used to recruit 145 early adoles-cents (78 males) with parent/primary caregiver writteninformed consent (Table). GAs ranged from 25-41 weeks(34.5 � 3.5 weeks) and the mean uncorrected age atassessment was 148.7 � 9.3 months (ie, 12 years and5 months, range: 128-168 months). All preterm adolescents(N = 101) were born between January 1996 and December1997 at the Women’s and Children’s Hospital (WCH),Adelaide, Australia. Term-born adolescents (N = 44) wererecruited from the preterm children’s schools and fromcommunity newspaper advertisements. Exclusion criteriawere any abnormality on perinatal cranial ultrasound (noMRI available), any genetic or chromosomal disorder, anidentifiable syndrome, or physical or intellectual disabilitythat rendered participants unable to follow simpleinstructions, in addition to the exclusion criteriarecommended for the safe use of TMS.21 Ineligible childrenwere screened and removed from the database lists prior torecruitment. Ethical approval was provided by local WCH,university, government, and Catholic education humanresearch ethics committees. All procedures were performedin accordance with the Declaration of Helsinki (2008revision).
Table. Characteristics and cognitive abilities of the participan
Early preterm, £32 wk GA(N = 38)
Late
GA (wk) 29.7 � 2.2*,†
BW% 37.7 � 33.0*SexMales 19 (50%)Females 19 (50%)
Parity 0.8 � 1.3Birth head circumference (cm) 27.8 � 2.3*,†
Birth length (cm) 39.0 � 3.4*,†
Apgar score 1 min 6.6 � 1.8*,†
Apgar score 5 min 8.6 � 1.4*,†
Child weight at assessment (kg) 40.8 � 11Child height at assessment (m) 1.5 � 0.1*,†
Child % body fat at assessment 20.6 � 8.8IRSD score birth 996.2 � 109.3IRSD score current 1006.5 � 76GIA 93.8 � 13†
Verbal ability 97.3 � 10.3Thinking ability 99.8 � 14.1Cognitive efficiency 89 � 13.9†
Auditory processing 106.3 � 14.5Phonemic awareness 102.5 � 16.2Working memory 94.8 � 13.4*,†
Data are mean � SD for each GA group, except for sex N (%) of sample in each GA group.*Denotes P < .05 compared with the term-born group.†Denotes P < .05 compared with the late preterm group.
2
As this study was part of the broader Preterm Motor andCognitive Development study,14 all data collection was per-formed by investigators blinded to GA, BW%, etc. Each child’scurrent height, weight, and percentage of body fat, determinedusing bio-impedance scales (body composition analyzer, Ta-nita, Kewdale, Australia) were recorded. Characteristics per-taining to each preterm (and some term) participant’s birthwere obtained from WCH Perinatal Statistics collection withparental written consent. Gestation Related Optimal Weightsoftware22 was used to calculate each child’s actual birthweightrelative to their predicted optimal term weight adjusted forGA, sex, maternal size, ethnicity, and parity. This BW% is amarker of fetal growth. The Australian Bureau of Statistics’ in-dex of relative socioeconomic disadvantage (IRSD) was calcu-lated for the address each child went home to following theirbirth (1996 National Census; IRSDbirth) and for their currentaddress (2006 National Census; IRSDcurrent). This compositemeasure, which includes educational attainment, occupation,employment, and income, is a summary of economic and so-cial conditions of people and households within smallgeographic areas (ie, census districts).
Cognitive Abilities AssessmentThe age-normed Woodcock-Johnson III Tests of CognitiveAbilities23 were administered to each participant accordingto standardized procedures.24 The Woodcock-Johnson IIITests of Cognitive Abilities is explicitly linked to theCattell-Horn-Carroll theory, which provide a model of thestructure of cognitive abilities.25 We included tests 1-9from the standard and test 14 from the extended batteries(see www.assess.nelson.com/pdf/asb-7.pdf for more specifictest details). Combinations of the subtests contribute to
ts by GA group
preterm, 33-36 wk GA(N = 63)
Term, 37-41 wk GA(N = 44) Total (N = 145)
34.8 � 1.1* 38.1 � 1.5 34.5 � 3.537.1 � 31.5* 56.2 � 30.0 43.3 � 32.4
36 (57%) 23 (52%) 78 (54%)27 (43%) 21 (48%) 67 (46%)0.8 � 0.9 1 � 1 0.8 � 132.4 � 1.9* 34.8 � 3.5 31.8 � 3.745.9 � 2.6* 48.5 � 4.5 44.8 � 57.9 � 1.5 8.1 � 1.1 7.6 � 1.79.1 � 0.7 9.2 � 0.6 9 � 144.6 � 10.4 45.8 � 11.4 44 � 111.5 � 0.1 1.5 � 0.1 1.5 � 0.120.4 � 6.6 21.2 � 7.9 20.7 � 7.6960.8 � 109.3 995.7 � 88.5 980 � 104.81007.1 � 88.5 993.0 � 91.6 1002.7 � 86.1100.7 � 14.2 99.3 � 11.2 98.5 � 13.299.5 � 9.9 97.0 � 11.9 98.2 � 10.6104.8 � 14 104.3 � 12.2 103.3 � 13.698.1 � 15.6 94.7 � 16.8 94.7 � 15.9110.7 � 13.4 111.2 � 16 109.7 � 14.6106.3 � 18.4 107.1 � 17.6 105.5 � 17.6102.3 � 15.2 102.5 � 12.7 100.4 � 14.3
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cluster scores for 6 broad cognitive abilities: verbal ability,thinking ability, cognitive efficiency, auditory processing,phonemic awareness, and working memory; and a global in-telligence score, general intellectual ability (GIA). GIA is acomposite score derived from principal component analysisof the narrow cognitive abilities to provide a single “best”predictor of cognitive ability, academic performance, careersuccess, and exceptional achievement.25
TMSCorticomotor excitability was assessed prior to the cognitiveassessment. Participants were seated in an arm chair withtheir hands and forearms supported. Adhesive silver–silverchloride electrodes were applied over the first dorsal inteross-eous muscles of both hands using a muscle belly-tendonmontage. Electromyogram signals were amplified (�1000)and band-pass filtered (20 Hz-1 kHz) (D360; Digitimer,Welwyn Garden City, United Kingdom) then digitized at5.1 kHz with a laboratory interface (CED 1401; CambridgeElectronic Design, Cambridge, United Kingdom). Theoptimal M1 scalp site for TMS was determined for bothhemispheres separately using a ‘hunting’ procedure.26 Thecoil was oriented so that the current induced in the cortexflowed in a plane perpendicular to the estimated alignmentof the central sulcus in a posterior-to-anterior direction.Single pulse TMS was used to determine rMT and wasapplied with a 70 mm figure-of-eight stimulating coil con-nected to a monophasic Magstim 2002 magnetic stimulator(Magstim Co, Whitland, United Kingdom). The rMT wasdetermined as the lowest TMS intensity that evoked motorevoked potentials of at least 50 mV peak-to-peak amplitudein the resting first dorsal interosseous in 5 of 10 trials.
Statistical AnalysesData were analysed using R statistical analysis freeware(v 2.13.1; http://www.r-project.org/). Statistical significancewas accepted at a # 0.05. Cognitive outcome variableswere included in the analyses as standard scores based onage-norms. In separate analyses, we considered weeks GAas a continuous variable and as a categorical variable (GAgroup). For the latter, we used the World Health Organiza-tion definitions (ie, 37-41 weeks GA: term-born;33-36 weeks GA: late preterm; 28-32 weeks GA: very preterm;#27 weeks GA: extremely preterm). GA group comparisonswere made using 1-way ANOVA with polynomial contrastsand post hoc tests adjusted for multiple comparisons.
Explanatory variables were included in the main analysis ifthey correlated with the broad cognitive ability cluster scoreof interest and included head circumference and body lengthat birth, Apgar score at 1/5 minutes, singleton or multiplebirth, parity, maternal age at child’s birth, maternal bodymass index at first antenatal visit, the IRSDbirth and IRSDcur-
rent, the child’s current height, weight and percentage of bodyfat, laterality quotient (Edinburgh Handedness Inventory27),and the rMT for both hands. The influence of the explanatoryvariables on each of the cognitive cluster scores was assessedwith relative importance regression modeling. We averaged
Cognitive Abilities in Preterm and Term-Born Adolescents
over all orderings of regressors in the model, facilitating theinterpretation of the variance allocations of each regressorto the total R2.28,29
Results
As there were only 7 extremely preterm children, the very(ie, 28-32 weeks GA) and extremely (#27 weeks GA) pretermgroups were combined into an early preterm group(#32 weeks). However, it should be noted that the meanBW% in the extremely preterm group was 83.7% � 8.2%(range: 72.9%-93.1%) compared with 26.8% � 27.0%(0.05%-84.0%) in the very preterm; that is, the onlyextremely preterm children who fulfilled the criteria forinclusion in the study were those with good fetal growth atthe time of their preterm birth (relative to their individualpredicted potential). Thus, the sample is not representativeof all preterm children, only the most neurologically normal(ie, those with no known brain lesions or neurosensory dis-abilities). BW% data are missing for 22 participants forwhom all data necessary for the calculation were not avail-able. Thirty-three children were excluded; 29 on the basisof the TMS safety screen and 4 because of ipsilateralresponses to TMS (indicating a possible corticospinal tractlesion).
GA Group Comparison of Cognitive Abilities andCorticomotor ExcitabilityGIA (F[1,142] = 3.49, P = .03), cognitive efficiency(F[1,142] = 4.12, P = .02), and corticomotor excitability(rMT-right hand; F[1,135] = 4.24, P = .02) (rMT-left hand;F[1,129] = 3.17, P = .05) were lower in the early pretermcompared with the late preterm group, but not the term-born group. They had poorer working memory(F[1,142] = 4.13, P = .02) than both the late preterm(P = .03) and term-born (P = .04) children. There were nodifferences between any of the groups in verbal ability,thinking ability, auditory processing, or phonemic aware-ness. There were no differences between late preterm andterm-born groups in any cognitive domain or in corticomo-tor excitability. Combining these groups did not alter the dif-ferences found for the early preterm group.
Relationships between GA, BW%, CorticomotorExcitability, and Cognitive Abilities ScoresPositive linear relationships were evident between GIA andGA (R2 = 0.03, F[1,143] = 4.2, P = .04), and also betweenGIA and BW% (R2 = 0.05, F[1,121] = 6.2, P = .01), althoughGA and BW% explained only a limited amount of the vari-ability (Figure 1, A and B). An rMT could be obtainedfrom the left hemisphere (right hand) of 133, and the righthemisphere (left hand) of 128 participants. The lower theGA, the higher the stimulus intensity required to obtainrMT in the left (R2 = 0.06, F[1,126] = 8.1, P = .005) andright hands (R2 = 0.09, F[1,131] = 13.0, P # .001). BW%explained a proportion of the variance in rMT of the left(R2 = 0.05, F[1,105] = 5.5, P = .02), but not the right hand.14
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Figure 1. Individual relationships between GIA, and A, GA, B, BW%, and rMT in the C, left and D, right hands. Data points areindividual subject results. Dotted lines are 95% CIs.
Figure 2. Relative importance regression model of explana-tory variables contributing toGIA. TheP value is given for eachindividual regressor in the model. The relative importance ofregressors sums to 100% of the total variance accounted forby the best regression model.
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Individuals with greater corticomotor excitability (ie, lowerrMT) had better GIA, and this was evident for both the left(R2 = 0.04, F[1,126] = 4.7, P = .03) and right (R2 = 0.06,F[1,131] = 8.2, P = .005) rMTs. Lower rMTs were alsoassociated with better verbal ability (right hand only,R2 = 0.04, F[1,131] = 4.9, P = .03), thinking ability (righthand, R2 = 0.06, F[1,131] = 7.6, P = .006; left hand,R2 = 0.04, F[1,126] = 4.8, P = .03), and cognitive efficiency(right hand only, R2 = 0.03, F[1,131] = 4.7, P = .03) but notauditory processing, phonemic awareness, or workingmemory (Figure 1, C and D).
Factors Influencing GIAThe best model for GIA (R2 = 0.18, F[3,124] = 9.4, P < .001)(Figure 2) indicated higher GIA scores in those childrenwho went home to less social disadvantage after birth(IRSDbirth = 59.4%, b = 0.04, P < .001), who had a lowerright hand rMT (rMT-right hand = 21.2%, b = �0.18,P = .05), and who were taller at assessment(height = 19.4%, b = 26.99, P = .03).
Factors Influencing Broad Cognitive AbilitiesVerbal ability (R2 = 0.17, F[3,135] = 9.4, P # .001) (Figure 3,A) was better in taller children (height = 36.3%, b = 28.30,P = .001), who, at birth, went home to less socialdisadvantage (IRSDbirth = 36.1%, b = 0.02, P = .004), witha mother who had given birth to fewer children previously
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(parity = 27.6%, b = �2.05, P = .01). Thinking ability(R2 = 0.20, F[3,114] = 9.3, P < .001) was better in childrenwho went home to less social disadvantage after birth(38.3%, b = 0.04, P = .002), were taller at assessment
Schneider et al
Figure 3. Relative importance regression models for explanatory variables contributing to A, verbal ability, B, thinking ability,C, cognitive efficiency, D, auditory processing, E, phonemic awareness, and F, working memory. The P value is given for indi-vidual regressors in each model. The relative importance of regressors sums to 100% of the total variance accounted for by thebest regression model for each cognitive ability.
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(height = 32.1%, b = 34.00, P = .008), and had a higher BW%(BW% = 29.6%, b = 0.09, P = .01) (Figure 3, B). Cognitiveefficiency (R2 = 0.16, F[3,135] = 8.6, P < .001) (Figure 3, C)was highest in females (sex = 33.6%, b = 6.94, P = .004),with less social disadvantage at birth (IRSD birth = 38.4%,b = 0.03, P = .004) and greater length at birth(length = 28.0%, b = 0.65, P = .007). Taller adolescents(height = 66.1%, b = 41.89, P = .002) with a higher BW%(BW% = 33.9%, b = 0.08, P = .03) had the best auditoryprocessing abilities (R2 = 0.12, F[2,120] = 8.5, P < .001)(Figure 3, D). Phonemic awareness (R2 = 0.20,F[3,119] = 10.1, P < .001) (Figure 3, E) was better in talleradolescents (height = 62.3%, b = 65.82, P < .001), with agreater BW% (BW% = 21.3%, b = 0.10, P = .02), whowere born to a mother who had given birth to fewerchildren previously (parity = 16.4%, b = �3.60, P = .01).
Cognitive Abilities in Preterm and Term-Born Adolescents
Working memory was influenced by IRSDbirth, headcircumference at birth, and sex (R2 = 0.17, F[3,135] = 9.5,P < .001) (Figure 3, F) and was highest in children whowent home to less social disadvantage after birth(IRSDbirth = 57.4%, b = 0.04, P < .001), had a greater headcircumference at birth (head circumference = 23.2%,b = 0.85, P = .006), and were female (sex = 19.4%,b = 5.19, P = .02).
Influence of Social Disadvantage at Birth vs atAssessmentGAdidnot correlatewith IRSDbirth (r= 0.015,P= .86,N=143)asmight have been expected.30 IRSDbirth and IRSDcurrent corre-lated (r = 0.633, P # .0001). Although IRSDcurrent was higher(ie, less disadvantage) (mean � SD = 1002.7 � 86.0) thanIRSDbirth (980.0 � 104.8) (t(142) = �3.61, P # .0001), both
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scores lie within the fifth percentile for national IRSD scores(1996 and 2006). Even though statistically different, this is un-likely to indicate a tangible shift in overall disadvantage.
Discussion
In individuals born preterm but with no clinical history ofbrain lesions or neurosensory disability, corticomotor excit-ability and a number of other factors, most notably relativesocial disadvantage at birth, BW%, and height, are strongerpredictors of cognitive abilities than GA, when assessed inearly adolescence.
As we reported previously, corticomotor excitability wasreduced in preterm adolescents14 and this correlated withtheir GIA, as well as a number of more specific cognitiveabilities. Taken together with other imaging evidence,17,31
this suggests that these adolescents may have reducedcortical thickness and/or reduced white matter maturation,integrity, and/or connectivity in cortical regions associatedwith M1. However, there is also limited evidence that reduc-tions in M1 gray matter are associated with concurrent in-creases in rMT.32 Many children for whom we report dataparticipated in both studies, and readers are referred toPitcher et al14 for more detailed interpretation. Whetheror not reduced corticomotor excitability contributes directlyto reduced cognitive abilities in preterm adolescents, or issimply a marker of overall cortical development is unknown.Impairments in motor and cognitive function commonlyco-occur in preterm children,33 suggesting that cortical def-icits because of preterm birth are global rather than confinedto discrete cortical regions. However, white matter andcortical excitability are “plastic,” particularly in childhood,and can be modulated by factors associated with environ-mental enrichment, such as learning to play a musical in-strument.34 A postnatal environment that promotescortical development (eg, good nutrition, stimulating, lowpsychosocial stress) may ameliorate some of the effects ofa low GA on corticomotor excitability. This may alsoexplain, at least in part, why corticomotor excitability andIRSDbirth, but not GA, consistently featured in our modelsof cognitive abilities. The relationship between corticomotorexcitability and GIA may also be partly explained by geneticvariability. Increased cortical thickness is associated withincreased corticomotor excitability,31 and there is an overlapin the genes that influence intelligence and cortical thick-ness, such that greater cortical thickness is associated withhigher IQ.35 Regardless, real-time neurophysiologic TMSmeasures of corticomotor excitability would appear to bea useful addition to assessment of these individuals, at leastin early adolescence.
Increased height at the time of assessment was a consistentpredictor of cognitive scores, in accord with the existing largeliterature indicating height correlating with IQ, health, andeconomic status in adulthood.36 However, the mechanismsunderlying this association are still poorly understood. Adultheight is determined by a combination of genetics, environ-ment (including fetal and postnatal nutrition and psychoso-
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cial stress), and gene-environment interactions, although thevariance explained by the latter is unknown.36 In our sample,BW% correlated with length at birth but not current height(absolute and z-scores). Neither birth length nor currentheight correlated with IRSD at any age. However, we hadno accurate data for postnatal growth rate, nor of the timingandmagnitude of growth spurts at 0-3 years and early adoles-cence, both of which have been implicated in mediating theassociation between height and cognitive ability.36 Eluci-dating these mechanisms will require prospective, fetal, andlong-term postnatal growth evaluation studies.It is well-known that socioeconomic status (SES) has ef-
fects on cognitive development and on the risk of pretermbirth, even in developed countries like Australia.30 AlthoughIRSDbirth did not correlate with GA in our sample, it was astrong predictor of poorer cognitive abilities, particularlyworking memory and GIA. Conversely, IRSDcurrent had noinfluence, suggesting that cognitive development is more sus-ceptible to perturbation by disadvantage in infancy, a periodduring which gray matter volume increases exponentially,rather than in later childhood. This is supported by MRIstudies comparing gray matter development in childrenfrom low, mid, and high SES groups.37 In infancy, gray mat-ter volumes were similar across all SES groups, but by age4 years, children with low SES had lower frontal and parietalgray matter volumes then children with either middle or highSES.37 These differences were not explained by differences inweight or head circumference at birth, or infant health. Thefrontal lobes are believed to mediate high level cognitivefunctions including working memory,38 and the parietallobes play a variety of roles, particularly in sensory integra-tion, spatial perception, and visuospatial aspects of attentionand working memory.39 Others have also reported associa-tions between low SES, cognitive abilities, and gray mattervolumes in older children,40 but interestingly, neither of thesestudies found effects on white matter volumes.37,40 Eventhough the underlying mechanisms are not clear, our find-ings indicate that the associations between low SES at birthon cognitive abilities are still evident in early adolescence.Rather than standardized birthweight charts, we used a
customized BW% calculator based on each individual’soptimal fetal growth potential. This varies with maternaland pregnancy characteristics, is different for each infant,and is not taken into account in standardized population-based charts. A low BW% was associated with poorerthinking ability, auditory processing, and phonemic aware-ness, consistent with the well-documented effects of subopti-mal fetal growth on neurodevelopment, even in childrenborn at term.41 The thinking ability cluster includes tasksthat call upon spatial abilities, which are known to beimpaired in growth restricted children.42 Critically, BW% ap-pears to exert influences on cognitive outcomes that aredistinct from, and in some domains stronger than, the effectsof GA, highlighting the need to differentiate GA from BW%in outcome studies. The serendipitous observation that onlychildren born <27 weeks GA with high BW% (ie, the lowestwas 72.9%) were neurologically-healthy enough for inclusion
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in the study, may suggest a protective effect of good fetalgrowth in this GA group. However, we did not have BW%or neurologic details of those infants excluded.
Greater head circumference at birth was associated withimproved working memory. This finding is potentiallyinteresting; although head circumference is commonly asso-ciated with degree of intrauterine growth restriction andbrain volume, it is less frequently directly associated withneurodevelopmental outcome.43-45 However, when utilizedas a measure of postnatal growth, changes in head circum-ference across early life are highly predictive of cognitiveoutcome.44-47 Unfortunately, we did not have data pertain-ing to early postnatal changes in head circumference toinvestigate this finding further. Moreover, the birth mea-surements (length, head circumference, ponderal index)were not collected under research conditions, and thisobservation requires more rigorous investigation beforevalid conclusions can be drawn.
Females had better cognitive efficiency and working mem-ory scores than males. Previous findings indicate that femalestend to perform better than males on tasks involving cogni-tive processing speed, and this is further modulated by pu-bertal stage, which we did not assess.48 Previous findingsregarding sex differences in working memory are inconsis-tent, with reports of no differences,49 or a slight male advan-tage.50 However, Kaufman51 noted a male advantage inworking memory only when the task involved spatial stimuli,but not when the task was verbal, suggesting that the natureof the task determines if sex differences are evident.
There is an intricate and changing balance between geneticand environmental influences on cognitive abilitiesthroughout life, whereby the role of genetics increases acrossthe lifespan, while the role of environmental factors becomesless important.35 That people essentially move toward theirgenetic potential suggests that, in the absence of brain lesions,the consequences of a reduced GA may diminish over child-hood, potentially explaining our finding that GA has onlylimited effects on cognitive outcomes when assessed in earlyadolescence. Arguing against this is the weight of evidenceindicating that most preterm children do not catch up totheir peers,2,7,52,53 although this evidence may reflect age atassessment and sample characteristics, particularly relatedto perinatal neurological history.
There are some limitations to our findings. We did nothave access to MRI facilities to confirm the lesion-free statusof our participants, or to detect possible gray and white mat-ter abnormalities. However, no participants had any historyof abnormal cranial ultrasounds, or had been diagnosedwith, or suspected of having, cerebral palsy.14 In addition,up to 25% of preterm children with normal imaging go onto exhibit later dysfunction.13 Many of the participants arelikely to have entered puberty. We did not determine puber-tal stage and did not control for hormonal statuses, whichmay have influenced our corticomotor data, as it is knownthat sex steroid levels affect cortical excitability.54 Finally,identifying which specific aspects of social disadvantagemediate cognitive development will require more direct
Cognitive Abilities in Preterm and Term-Born Adolescents
measures of individual social and psychosocial disadvantagethan used here.In summary, in individuals born preterm but with no his-
tory of brain lesion or neurosensory disability, GA appears tohave limited direct influence on their cognitive abilities inearly adolescence. Of greatest importance is the degree ofsocial disadvantage experienced in their home environmentat birth and in early infancy. Taken together with the findingsof others, the strong influence of current height, but not ofbirth length and head circumference on cognitive abilitiesin adolescence, supports the notion that growth rates (andpresumably nutrition) in early childhood have an importantmediating effect on cognitive development, although pro-spective studies are required to confirm this in preterm chil-dren. The association between corticomotor excitability andcognitive performance suggests that reduced connectivity,potentially associated with brain microstructural abnormal-ities, may contribute to cognitive deficits in preterm children.What is not clear is whether the effects of lowGA on cognitiveoutcomes attenuate over childhood in favor of a concomitantincrease in the relative importance of heritability, or whethercognitive development trajectories are more heavily influ-enced by the quality of the postnatal environment. n
Submitted for publication Sep 17, 2013; last revision received Jan 30, 2014;
accepted Mar 13, 2014.
Reprint requests: Julia B. Pitcher, PhD, Research Center for Early Origins of
Health and Disease, DX 640-517 Robinson Institute, School of Pediatrics and
Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia.
E-mail: [email protected]
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