Prediction of Neurodevelopmental Outcome After Preterm Birth

doi:10.1016/j.pediatrneurol.2009.01.008

Pediatric Neurology

Volume 40, Issue 6, June 2009, Pages 413-419

https://doi.org/10.1016/j.pediatrneurol.2009.01.008 Get rights and content

Prediction of outcome after preterm birth is critical, but remains difficult, particularly in the early postnatal period. The ability to predict outcome improves parental counseling and selection of infants for early therapeutic strategies aiming at preventing or ameliorating cerebral injury. This review gives an overview of the spectrum and severity of neurodevelopmental, behavioral, and psychosocial outcomes, with discussion of predictors of outcome and, in particular, the clinical, electrophysiological, and imaging predictors. A detailed neurologic examination of infants is a valuable predictive tool in terms of later moderate to severe neurodevelopmental impairments; however, it may be limited in the immediate newborn period. Electrophysiological, neuroimaging, and clinical risk factors for adverse neurodevelopmental outcome have been identified. Good prediction is usually achieved for major functional disabilities in early childhood, but is poorer for moderate or mild long-term outcome. Future research should focus on the long-term quality of life, academic achievement, and the influence of the sociocultural environment. More emphasis should be placed on genetic diversity as a modifying factor for the large variability in outcome.

Introduction

Neurodevelopmental outcome after preterm birth varies widely and relates to time of onset, severity, and duration of injury, which result in different injury patterns [1]. Prediction of outcome remains difficult, particularly in the early postnatal period. The ability to better predict outcome in the infant period could substantially improve parental counseling and would also have the benefit of providing a better selection of infants for early therapeutic strategies. In addition, the efficacy of medical interventions and their potential negative effects on the central nervous system need to be identified. The spectrum and severity of deficits are underestimated when outcome is limited to early childhood examination.

Infants at highest risk for neurodevelopmental impairments are those born before 32 weeks of gestation. Infants who are born with a gestational age between 32 and 37 weeks have only a mildly increased risk for neurodevelopmental problems, unless there is cerebral injury, but they probably constitute a somewhat overlooked population.

Section snippets

Focus: Very Preterm Infants

Prematurity is usually defined by birth weight rather than by gestational age, due to uncertainty of obstetric estimation of gestational age and the lack of precision in postnatal gestational age assessment, particularly in very small infants [2]. Using birth weight as the defining factor for prematurity is problematic, however, because gestational age is the stronger determinant of biologic maturation and viability. Thus, outcome of premature infants born small for gestational age may be

Outcome

In principle, outcome can be categorized into severe and moderate-to-mild deficits. Severe deficits are summarized as functional disability, usually defined as an aggregate group comprising cerebral palsy, mental retardation (developmental or intellectual quotient of less than 70), and severe visual or hearing impairment [12]. Severe deficits can be detected by the age of 2 years. Moderate to mild deficits, however, are often not detected until school-age.

Prevalence rates differ considerably

Goal

Prediction of outcome is important, because knowledge of the spectrum and severity of neurodevelopmental sequelae is vital for decisions on withdrawal of support for neonates at the border of viability.

Prediction has been the focus of research for many decades. Biochemical markers such as pH, Apgar score, and base excess have been shown to be of little or no use for outcome prediction in term infants [48]. In preterm infants, these parameters play a secondary role. Thus, the focus has shifted

Perinatal Variables

A variety of prenatal and neonatal risk factors have been associated with adverse outcome for the preterm population. Gestational age or maturity at birth, along with birth weight, constitutes the strongest predictor of adverse neuromotor [22], [75], [76] and intellectual outcome [25], [77]. Other perinatal factors have also been related to adverse outcome, however, with a weaker association than maturity. Among those are preeclampsia [78], chorioamnionitis [22], [79], [80], sepsis [22], [70],

Conclusion and Future Directions

Children born prematurely are at risk for major and minor neurodevelopmental disabilities affecting long-term academic, behavioral, and social functioning. Prediction of outcome is of significance in the neonatal period, when new therapeutic interventions are introduced and decisions about withdrawal of support are made. Knowledge of the severity and spectrum of impairments is necessary for counseling parents, tailoring follow-up services, and allocating early intervention programs.

A detailed

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Despite advances in medical care and improved survival of extremely preterm infants, rates of neurodevelopmental impairment remain high. Outcomes are significantly improved with early intervention, but infants must be appropriately identified to facilitate services. Neuroimaging provides important information regarding neurodevelopmental outcomes but prognosticating and communicating risk remains challenging. Standardized neonatal neurodevelopmental assessments provide supplemental information to aid in the identification of high-risk infants and counseling for their families.
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It has been reported that chorioamnionitis (CA) could increase the risk of hearing impairment in premature infants, but results are inconsistent. A meta-analysis was performed to systematically evaluate the relationship between CA and hearing impairment in premature infants.
Search in PubMed, Embase, Cochrane Library from their inception to May 2020. We concluded all cohort and case-control studies which explored the associations between CA and hearing impairment in preterm infants. Pregnant women with other infections besides CA were excluded. PRISMA guidelines were followed. Fixed-and random-effects models were used, depending on heterogeneity. And we performed to calculate odds ratio (ORs), and 95% CIs using fixed-effects models.
Seven studies involving 4134 premature infants were included. There was non-significant association between CA and hearing impairment (adjusted OR 1.43, 95% CI 0.99 to 2.04, P = 0.05; heterogeneity: I² = 13%, P = 0.33).
This article concludes that CA is not a risk factor for hearing impairment in premature infants, but most of the current studies are retrospective studies with low intensity and lack of high-quality articles to discuss it.
Predictors of persistent and changing developmental problems of preterm children
2021, Early Human Development
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We included a total of 48 maternal, neonatal and social factors in our analyses, as shown in Table 1. We selected these factors because they were common in the preterm population during pregnancy and the neonatal period, or reported to be associated with developmental problems at follow-up in previous studies [7–12,17,18]. We collected the data of pre-existing maternal conditions, pregnancy-related factors, and neonatal factors from the hospital records of both mothers and children, and crosschecked these data with PCHC charts, and a parental general questionnaire filled out at the age of 4 years.
Accurate prediction of persistent and emerging developmental problems in preterm-born children may lead to targeted interventions.
To determine whether specific perinatal and social factors were associated with persistent, emerging, and resolving developmental problems of early-preterm (EPs) and moderately-and-late-preterm children (MLPs) from before to after school entry.
Observational longitudinal cohort study, part of the LOLLIPOP cohort-study.
341 EPs and 565 MLPs.
Developmental problems using the Ages and Stages Questionnaire at ages 4 and 5. We collected data on perinatal and social factors from medical records. Using logistic regression analyses we assessed associations between 48 factors and persistent, emerging, and resolving problems.
Of EPs, 8.7% had persistent and 5.1% emerging problems; this was 4.3% and 1.9% for MLPs, respectively. Predictors for persistent problems included chronic mental illness of the mother, odds ratio (95% confidence interval) 8.01 (1.85–34.60), male sex 4.96 (2.28–10.82), being born small-for-gestational age (SGA) 2.39 (1.15–4.99), and multiparity 3.56 (1.87–6.76). Predictors for emerging problems included MLP birth with prolonged premature rupture of membranes (PPROM) 5.01 (1.38–18.14). Including all predictors in a single prediction model, the explained variance (Nagelkerke R²) was 21.9%, whereas this was 3.0% with only EP/MLP birth as predictor.
Only few perinatal and social factors had associations with persistent and emerging developmental problems for both EPs and MLPs. For children with specific neonatal conditions such as SGA, and PPROM in MLPs, problems may persist. Insight in risk factors largely improved the prediction of developmental problems among preterm children.
Relationships between intelligence, executive function and academic achievement in children born very preterm
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Children born very preterm are at higher risk of adverse neurocognitive and educational outcomes. However, how low intelligence (IQ) and low executive function may each contribute to poorer academic outcomes at school age requires clarification.
To examine the associations between intelligence, executive function and academic achievement in children born very preterm.
This cohort study assessed children born <30 weeks' gestation or <1500 g at age 7 years using the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) for IQ, and the Test of Everyday Attention for Children (TEA-Ch) and Behavior Rating Inventory of Executive Function (BRIEF) for executive function. Academic achievement was rated by teachers against curriculum standards.
Of the 76 children (35 girls, 41 boys, mean age = 7.2 year), 22 (28%) were rated below expected level for reading, 32 (42%) for writing and 38 (50%) for mathematics. After adjustment for sex and socioeconomic status, low IQ (OR's 9.0–12.3) and most low executive function measures (OR's 4.1–9.3) were associated with below-expected achievement. After further adjustment for IQ, low cognitive flexibility (OR = 9.3, 95% CI = 1.2–71.5) and teacher ratings of executive function (OR = 5.3, 95% CI = 1.4–20.2) were associated with below-expected achievement. Mediation analysis showed IQ had indirect effects on writing (b = 1.5, 95% CI = 0.6–3.1) via attentional control; and on reading (b = 1.0, 95% CI = 0.2–3.2) and writing (b = 0.8, 95% CI = 0.1–2.5) via cognitive flexibility.
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Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm
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Together with the findings of the current study, this may suggest a specific misalignment between structure and function in conditions of impaired thalamocortical connectivity such as preterm birth, ASD or schizophrenia. Neurodevelopmental deficits including lower general cognitive abilities, executive dysfunctioning and poor academic abilities are frequent in very preterm children and adolescents even in the absence of major neurodevelopmental impairments (Aarnoudse et al., 2009; Brydges et al., 2018; Latal, 2009; Twilhaar et al., 2018). Importantly, intact thalamocortical connectivity has previously been shown to be essential for efficient cognitive functioning: For example, functional connectivity, particularly within the thalamus-salience network, predicted cognitive abilities at one year of age in healthy infants who underwent fMRI as neonates (Alcauter et al., 2014).
Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10–16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r = .53 ± .10; range = 0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 ± .06; 0.35 to 0.51 and 0.43 ± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r = .43 ± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r = −.53 ± .07; −.41 to −.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.
Specific cognitive deficits in preschool age correlated with qualitative and quantitative MRI parameters in prematurely born children
2020, Pediatrics and Neonatology
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Cognition is a complex range of processes, broader than the general ability usually measured by developmental or intelligence quotients. This quotient is not a criterion in assessing the cognitive consequences of perinatal lesion in preterm infants, especially due to the fact that there is a substantial number of children with mild cognitive impairment.12,13 In addition to evidence of global intellectual delay in children with more severe lesions, children with perinatal injury may have specific deficits in numerous areas: visuo-motor integration, visuo-spatial processing, verbal and language functions, learning, memory, executive functions and attention.13–16
Cognitive deficits after perinatal brain lesion in preterm infants are among the most common neurodevelopmental disturbances. The relationship between structural changes on at term magnetic resonance imaging (MRI) and cognitive deficits in the preschool age should be a special focus due to timely intervention. The aim of this study was to correlate qualitative and quantitative MRI parameters of perinatal brain lesion in preterm children, on early neonatal MRI and follow up MRI, with general and specific cognitive functions in the preschool age.
Twenty-one preterm infants with verified perinatal lesions based on clinical and ultrasound data underwent a brain MRI at term-equivalent age and a second MRI between 3 and 5 years of age. Qualitative and quantitative MRI analyses were done. All subjects underwent cognitive assessment (3–5 years) using Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Developmental Neuropsychological Assessment (NEPSY-II).
Results show that many structural changes on at term MRI and on follow up MRI in preterm born children moderately correlate with specific cognitive deficits in preschool age. At term equivalent MRI, white matter changes and cortical thickness correlate to general and specific cognitive functions in infants born preterm. By analyzing follow up MRI at preschool age, structural changes of different white matter segments, corpus callosum, cortical thickness and lobe volume correlate to some specific cognitive functions.
Besides general cognitive delay, specific cognitive deficits in preterm children should be targeted in research and intervention, optimally combined with MRI scanning, providing timely and early intervention of cognitive deficits after perinatal brain lesion. Our results, as well as previously published results, suggest the importance of detailed preschool neuropsychological assessment, prior to enrolment in the school system. Although preliminary, our results expand our understanding of the relationship between early brain developmental lesions and cognitive outcome following premature birth.

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Review ArticlePrediction of Neurodevelopmental Outcome After Preterm Birth

Introduction

Section snippets

Focus: Very Preterm Infants

Outcome

Goal

Perinatal Variables

Conclusion and Future Directions

Early Hum Dev

Early Hum Dev

J Pediatr

Lancet

Pediatr Neurol

J Pediatr

Lancet

Pediatr Neurol

J Pediatr

J Pediatr

Semin Perinatol

J Pediatr

J Pediatr

J Pediatr

Am J Obstet Gynecol

J Pediatr

Semin Neonatol

Semin Pediatr Neurol

Neonatal brain injury

N Engl J Med

Effects of gestation and birth weight on the growth and development of very low birthweight small for gestational age infants: a matched group comparison

Arch Dis Child Fetal Neonatal Ed

Impact of prenatal and/or postnatal growth problems in low birth weight preterm infants on school-age outcomes: an 8-year longitudinal evaluation

Pediatrics

Management and outcomes of very low birth weight

N Engl J Med

NICHD Neonatal Research Network. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996

Pediatrics

Declining severity adjusted mortality: evidence of improving neonatal intensive care

Pediatrics

Improved neurodevelopmental outcomes for extremely low birth weight infants in 2000-2002

Pediatrics

EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth

N Engl J Med

Neurocognitive outcome after very preterm birth

Arch Dis Child Fetal Neonatal Ed

Neurodevelopmental outcomes of infants born prematurely

J Dev Behav Pediatr

Outcome of extreme prematurity: as information increases so do the dilemmas

Arch Dis Child Fetal Neonatal Ed

Oxford Register of Early Childhood Impairments Management Group. Cerebral palsy rates among low-birthweight infants fell in the 1990s

Dev Med Child Neurol

Chronic conditions, functional limitations, and special health care needs of school-aged children born with extremely low-birth-weight in the 1990s

JAMA

Changes in the prevalence of cerebral palsy for children born very prematurely within a population-based program over 30 years

JAMA

EPICure Study Group. Neurologic and developmental disability after extremely preterm birth

N Engl J Med

Increasing rates of cerebral palsy across the severity spectrum in north-east England 1964-1993. The North of England Collaborative Cerebral Palsy Survey

Arch Dis Child Fetal Neonatal Ed

The changing epidemiology of cerebral palsy

Arch Dis Child Fetal Neonatal Ed

Perinatal correlates of cerebral palsy and other neurologic impairment among very low birth weight children

Pediatrics

Trends in the prevalence of cerebral palsy in a population-based study

Pediatrics

Cognitive and neuropsychological outcomes: more than IQ scores

Ment Retard Dev Disabil Res Rev

Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis

JAMA

Correlations between motor performance and cognitive functions in children born < 1250 g at school age

Neuropediatrics

Psychological development of prematurely born children

Arch Dis Child

Relation between visual perceptual impairment and neonatal ultrasound diagnosis of haemorrhagic-ischaemic brain lesions in 5-year-old children

Dev Med Child Neurol

Victorian Infant Collaborative Study Group. Executive functioning in school-aged children who were born very preterm or with extremely low birth weight in the 1990s

Pediatrics

Health, lifestyle, and quality of life for young adults born very preterm

Arch Dis Child

Health and school performance of teenagers born before 29 weeks gestation

Arch Dis Child Fetal Neonatal Ed

Review Article
Prediction of Neurodevelopmental Outcome After Preterm Birth