Table 2.
Included studies for preterm born children.
| References | Study type | Definition of fetal growth | Participants | Neurology/neuromotor function | Cognitive/behavior Outcome measure | Cognitive/behavior findings | Conclusion |
|---|---|---|---|---|---|---|---|
| Franz (58) | Single center study (Level 3 Neonatal Unit) | IUGR defined as BW < −2 SD according to British Growth Reference (59) expressed as SDS | Born < 30 wGA and BW <1,500 g BY 1996–1999 N = 297 preterms admitted to neonatal unit Age at assessment: 5.4 y Those with neuromotor and sensory impairment included | Neurological examination: normal, mildly abnormal (minor neurologic signs such as broad gait, dysdiadochokinesis, or dysmetria), severely abnormal (any paresis with or without spasticity, cerebral nerve palsy, or ataxia) GMFCS for level of motor function Findings: Neuromotor outcome associated with post-natal growth, not IUGR |
K-ABC (Mental Processing Composite, MPC) Analyses adjusted for GA, sex, multiple birth, ICH > Grade 3; PVL, ROP > Grade 3, ventilation > 7 days, language, maternal education |
MPC associated with IUGR (BW), early neonatal weight gain, head growth post-discharge | Intrauterine growth (weight) and in-hospital weight gain predictor of cognitive outcome Post-natal weight gain but not IUGR associated with CP HC growth but not weight gain from discharge to follow-up predictor of cognitive outcome Combined contribution of IVH and prolonged mechanical ventilation greater than the combined contribution of growth |
| Guellec (7) | Population based; EPIPAGE study, 9 regions in France |
N = 2,846 SGA = <10th centile (9.2%) Mildly SGA (MSGA) = 10th– <20th centile (9.6%) AGA = >20th centile Neonatal internal reference to approach in utero growth restriction, similar to Mamelle et al. (60) 2 preterm groups: <28 weeks GA (n = 828) 28–32 weeks GA (n = 2018) Term born (39/40 wGA) reference group (666 children) included at birth in the same regions |
All live borns 24–32 weeks GA, born 1997 in 9 regions in France n = 2,846 Age at assessment: 5 y: 77% neurology; 65% cognitive assessment;71% behavior questionnaires 8 y: 61% |
Categorized into presence of absence of cerebral palsy (SCPE criteria for CP used) Findings: 29-32 weeks GA group: Cerebral Palsy: AGA 7.7%; MSGA 4.6%; SGA 3.2% <28 weeks GA group: Cerebral Palsy: AGA 14%; MSGA 11.1%; SGA 18.2% |
At age 5 years: K-ABC: Mental processing composite score (IQ equivalent). Moderate cognitive deficiency: score between 70 and 84; severe cognitive deficiency: score <70 Behavioral problems: SDQ: inattention-hyperactivity, conduct, emotional, peer problems; total behavioral difficulties score At age 8 years: School questionnaire (school difficulties: special schooling institution or special school, special class in mainstream school, mainstream class) or low grades Analyses adjusted for sex, GA |
29–32 weeks GA group: Cognitive deficit: AGA 28.7%; MSGA 41.8%; SGA 40.6% Behavioral problems: AGA 19.4%; MSGA 15.7%; SGA 23.5% School difficulties: AGA 18.4%; MSGA 32.18%; SGA 28 % <28 weeks GA group: Cognitive deficit: AGA 38.3%; MSGA 32.1%; SGA 37.5% Behavioral problems: AGA 23.7%; MSGA 27.3%; SGA 33.3% School difficulties: AGA 33.2%; MSGA 44.8%; SGA 35.3% Analyses controlled for socio-economic factors and sex |
Growth restriction associated with adverse neurodevelopmental outcomes only in the 29- to 32-week GA group; both SGA and MSGA associated with an increase of cognitive deficiency, behavioral problems, and school difficulties. CP not associated with SGA |
| Guellec (61) | Population based; EPIPAGE study, 9 regions in France | 4 categories: Symmetric growth restriction (SGR): HC and BW <20th centile and in the same percentile range; asymmetric growth restriction (AGR): at least 1 of HC and BW <20th centile and the other in a higher decile range. Two forms of AGR: head growth restriction (HGR), weight growth restriction (WGR). AGA: both BW and HC >20th centile |
All live borns 26–32 wGA BY 1997 Age at assessment: 5 y (school performance at 8 y) |
Categorized into presence of absence of cerebral palsy (SCPE criteria for CP used) Findings: No difference between groups for CP |
K-ABC: Mental processing composite score (IQ equivalent), Moderate cognitive deficiency: score between 70 and 84; severe cognitive deficiency: score <70 Behavioral problems: SDQ: inattention-hyperactivity, conduct, emotional, peer problems; total behavioral difficulties score |
SGR: higher risks of both moderate and severe cognitive deficiency. HGR: only higher risk for severe cognitive deficiency No difference between groups for behavior SGR: higher rate of school difficulties than AGA children Discussion |
SGR associated with impaired cognitive and school performance Outcome of AGR differed according to HC: HGR associated with impaired cognitive function; WGR not associated with cognitive outcome No higher risk for CP in SGR |
| Kallankari (62) | Population based (regional cohort, Finland) | FGR defined as BW < −2 SD from mean of gestation-adjusted birth weight; documented FGR due to placental insufficiency by Doppler ultrasound and histological placental perfusion defect and lack of congenital infections or malformations | Born <32 wGA (n = 154); term born controls (n = 90) BY 1998–2002 Age at assessment: 9 y n = 77 preterms; n = 18 (23% FGR), n = 27 term controls Only preterms without CP and without cognitive impairment included |
N/A | 14 subtests from NEPSY II 6 subtests from WISC-III Mean scores for 5 domains calculated: visuospatial–sensorimotor processing, attention–executive functions, language, memory–learning and social perception Analyses controlled for GA, sex, maternal education |
FGR only identified risk factor for impairment in language and memory learning skills in the preterm group; no difference between preterm AGA and FGR group for attention, executive functions, visuo-spatial, sensorimotor function | FGR independently predicts poor language, memory and learning skills |
| Kan (63) | Population based; Victorian Infant Collaborative Study | IUGR defined as BW < −2 SD according to British Growth Reference (59); expresses as Z-score | Born <28 wGA BY 1991–1992 n = 179 (2.2% IUGR); Age at assessment: 8 y Those with neurosensory impairment excluded |
M-ABC 2 for assessment of motor skills (dexterity, ball skills, balance) Findings: HC or BW, or weight catch up in early childhood not associated with outcome, but, HC age 2 y and age 8 y associated with motor outcome |
WISC-III for IQ WRAT-II for educational skills (reading, spelling, arithmetic) Analyses adjusted for potential biological and environmental risk factors (IVH grade 3 or 4, cystic PVL, surgery, post-natal steroids; maternal education, social class, other languages than English) |
IUGR not associated with outcome at age 8 years HC or weight at birth, or weight catch up in early childhood not associated with outcome, but HC age 2 y and age 8 y associated with cognitive outcome |
Intrauterine growth mostly unrelated to cognitive and other outcomes in preterm children without neurosensory impairment, but events between post-birth and age 2 years have an effect on brain growth and function, over and above effects of prematurity |
| Korzeniewski (64) | Multicenter, prospective, observational study (Extremely Low Gestational Age Newborns, ELGAN) | 3 groups according to BW z-score (65) Severe FGR: <−2, Less severe FGR: ≥−2 and <−1 No FGR: ≥−1 |
Born <28 w GA N = 889 (93%) of original cohort BY 2002–2004 n = 52 severe FGR n = 113 less severe FGR Age at assessment: 10 y |
GMFCS for gross motor function MACS for hand function Findings: FGR not associated with poorer motor function |
DAS-II, NEPSY-II for general and specific cognitive functions (including executive function, memory, attention, verbal reasoning, visuo-motor precision etc.) WIAT-III for academic achievements (reading, spelling, numerical operations) OWLS for language (oral and written), Communication Function Classification Scale, and CCC-2 for communication skills SRS for social abilities, SCQ for screen for autism; ADOS-2 for autism diagnosis Analyses adjusted for sex and racial identity |
Both severe and less severe FGR similar in having lower scores than no FGR peers in verbal reasoning, listening, comprehension, visuomotor precision, word reading, working memory, pseudoword decoding, and spelling subtests; more problems with social awareness and social cognition Severe FGR group lower scores than less severe FGR group for measures of auditory attention and response as well as inhibition switching, inhibition naming, as well as having higher scores on autism screen, and a variety of communication problems |
Severe FGR poses increased risk of multiple cognitive and behavioral dysfunctions There is a positive relationship between severity of FGR and severity of cognitive impairment and behavior FGR not associated with poorer motor function |
| Morsing (66) | Single center study, Sweden | BW < −2 SD from mean of Swedish growth standards (53) | 46 fetuses with IUGR and ARED umbilical artery blood flow; delivered <30 wGA at level III perinatal center BY 1998–2004 Follow-up: n = 34 preterm SGA with IUGR, ARED on umbilical arterial flow antenatally n = 34 preterm AGA (matched for sex, GA, BY) n = 34 term AGA Age at assessment: 5–8 y Those with CP not excluded |
Information on diagnosis of CP and GMFCS level, hearing and visual function collected at time of cognitive assessment Findings: No difference in CP frequency |
WPPSI-III; WISC-III (IQ) SDQ, Brown ADD Scale (total scores) for socio-emotional functioning and attention difficulties Analyses controlled for parental education, neonatal septicaemia, CLD, ICH>grade 3, PVL, post-natal steroids, ROP grade 3–5 |
FSIQ and VIQ lower in SGA/IUGR preterms than AGA preterms; PIQ not different; this was driven by poorer performance of male preterm SGA/IUGR children No difference in SDQ and ADD scores |
Male preterm SGA children with IUGR and ARED blood flow in utero have poorer cognitive outcome than female preterms with IUGR and AERD No higher risk for CP |
| Raz (67) | Single center study | IUGR defined as BW <10th centile; Z-score computed as the deviation of BW from the mean BW gestational age group, at delivery | Born 23–34+6 wGA (mean 28.6) BY 1991–2000 n = 25 IUGR n = 118 AG (appropriate growth) Age at assessment: 3–6 y Those with CP and ICH excluded |
PDMS-2 for gross and fine motor skills Findings: Difference in gross and fine motor scores with IUGR having poorer motor skills |
WPPSI-R for IQ scores PLS-3 for language skills (auditory comprehension and expressive communication) Analyses adjusted for sex, no significant difference in socio-economic class between groups |
Full Scale IQ poorer in IUGR group; driven by difference in Performance IQ scores | Association between intrauterine growth and cognitive and motor outcome even within the population of preterm children who had adequate standardized birth weight |
| Tanis (44) | Population based regional cohort—subgroup (Longitudinal Preterm Outcome Project study), Netherlands | BW < −1 SD and birth weight > −1 SD according to GA; Dutch Kloosterman curve (45). Cut-off for SGA (> 1 SD, below the 16th percentile) according to Etude Epidemiologique sur les Petits Ages Gestationnels study |
Born 31–41 wGA. AGA = 336; 216/336 moderately preterm SGA = 42; 216 32/42 moderately preterm BY 2002–2003 Age at assessment: 7 y |
M-ABC 2 for assessment of motor skills (dexterity, ball skills, balance) Findings: No significant difference between groups |
WISC III (Full Scale IQ) TEA-Ch: selective attention and Attention control RAVLT: Verbal memory NEPSY-II: Visuomotor integration BRIEF: Executive functioning in daily life Analyses adjusted for GA and sex |
SGA children poorer attentional control, irrespective of GA No significant difference in other outcome measures |
SGA children higher risk for difficulties with attentional control, irrespective of GA at birth. General cognitive, executive function, and motor skills not different between AGA and SGA |
AGA, appropriate for gestational age; ARED, absent or reversed end-diastolic blood flow; AGR, asymmetric growth restriction; BW, birth weight; CLD, chronic lung disease; FGR, fetal growth restriction; GA, gestational age; HGR, head growth restriction; ICH, intracranial hemorrhage; IUGR, intrauterine growth restriction; PVL, periventricular leukomalacia; ROP, retinopathy of prematurity; SGA, small for gestational age; SGR, symmetric growth restriction; w, week; WGR, weight growth restriction; y, year. ADOS, Autism Diagnostic Observation Schedule; CCL, Children's Communication Scale; CP, Cerebral Palsy; CSI, Child Symptom Inventory; Brown ADD, Brown Attention-Deficit Disorder Scales; BRIEF, Behavior Rating Inventory of Executive Function; CBCL, Child Behavior Checklist;; DAS, Differential Ability Scales; GMFCS, Gross Motor Function Classification Scale; K-ABC, Kaufmann Assessment Battery for Children; MACS, Manual Ability Classification Scale; M-ABC, Movement ABC for Children; MPC, Mental Processing Composite; NEPSY, A Developmental NEuroPSYchological Assessment; OWLS, Oral and Written Language Scales; PDMS, Peabody Developmental Motor Scales; PLS, Preschool Language Scale; RAVLT, Rey's Auditory Verbal Learning Test; SCQ, Social Communication Questionnaire; SDQ, Strengths and Difficulties Questionnaire; TeaCH, Test of Everyday Attention in Children; WIAT, Wechsler Individual Achievement Test; WISC, Wechsler Intelligence Scales for Children; WPPSI, Wechsler Preschool and Primary Scale of Intelligence; WRAT, Wide Range Achievement Test. The terms SGA, IUGR, FGR were used as in the study that is described.