The Effect of Size and Asymmetry at Birth on Brain Injury and Neurodevelopmental Outcomes in Congenital Heart Disease

AbstractPoor and asymmetric fetal growth have been associated with neonatal brain injury (BI) and worse neurodevelopmental outcomes (NDO) in the growth-restricted population due to placental insufficiency. We tested the hypothesis that postnatal markers of fetal growth (birthweight (BW), head circumference (HC), and head to body symmetry) are associated with preoperative white matter injury (WMI) and NDO in infants with single ventricle physiology (SVP) and d-transposition of great arteries (TGA). 173 term newborns (106 TGA; 67 SVP) at two sites had pre-operative brain MRI to assess for WMI and measures of microstructural brain development. NDO was assessed at 30 months with the Bayley Scale of Infant Development-II (n = 69). We tested the association between growth parameters at birth with the primary outcome of WMI on the pre-operative brain MRI. Secondary outcomes included measures of NDO. Newborns with TGA were more likely to have growth asymmetry with smaller heads relative to weight while SVP newborns were symmetrically small. There was no association between BW, HC or asymmetry and WMI on preoperative brain MRI or with measures of microstructural brain development. Similarly, growth parameters at birth were not associated with NDO at 30 months. In a multivariable model only cardiac lesion and site were associated with NDO. Unlike other high-risk infant populations, postnatal markers of fetal growth including head to body asymmetry that is common in TGA is not associated with brain injury or NDO. Lesion type appears to play a more important role in NDO in CHD.

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Impact of moderate and late preterm birth on neurodevelopment, brain development and respiratory health at school age: protocol for a longitudinal cohort study (LaPrem study)

BMJ Open ◽

10.1136/bmjopen-2020-044491 ◽

2021 ◽

Vol 11 (1) ◽

pp. e044491

Author(s):

Jeanie Cheong ◽

Kate Lillian Iona Cameron ◽

Deanne Thompson ◽

Peter J Anderson ◽

Sarath Ranganathan ◽

...

Keyword(s):

Cohort Study ◽

Brain Development ◽

Respiratory Health ◽

Brain Mri ◽

Late Preterm ◽

Longitudinal Cohort Study ◽

School Age ◽

Neurodevelopmental Outcomes ◽

Longitudinal Cohort ◽

Increased Risk

IntroductionChildren born moderate to late preterm (MLP, 32–36 weeks’ gestation) account for approximately 85% of all preterm births globally. Compared with children born at term, children born MLP are at increased risk of poor neurodevelopmental outcomes. Despite making up the largest group of preterm children, developmental outcomes of children born MLP are less well studied than in other preterm groups. This study aimed to (1) compare neurodevelopmental, respiratory health and brain magnetic resonance imaging (MRI) outcomes between children born MLP and term at 9 years of age; (2) examine the differences in brain growth trajectory from infancy to 9 years between children born MLP and term; and in children born MLP; (3) examine the relationship between brain development and neurodevelopment at 9 years; and (4) identify risk factors for poorer outcomes at 9 years.Methods and analysisThe ”LaPrem” (Late Preterm MRI Study) study is a longitudinal cohort study of children born MLP and term controls, born at the Royal Women’s Hospital in Melbourne, Australia, between 2010 and 2013. Participants were recruited in the neonatal period and were previously followed up at 2 and 5 years. This 9-year school-age follow-up includes neuropsychology, motor and physical activities, and lung function assessments, as well as brain MRI. Outcomes at 9 years will be compared between birth groups using linear and logistic regressions. Trajectories of brain development will be compared between birth groups using mixed effects models. The relationships between MRI and neurodevelopmental outcomes, as well as other early predictors of poor 9-year outcomes, will be explored using linear and logistic regression.Ethics and disseminationThis study was approved by the human research ethics committee at the Royal Children’s Hospital, Melbourne, Australia. Study outcomes will be disseminated through peer-reviewed publications, conference presentations and social media.

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Predicting developmental outcomes in preterm infants

Neurology ◽

10.1212/wnl.0000000000008172 ◽

2019 ◽

Vol 93 (13) ◽

pp. e1231-e1240 ◽

Cited By ~ 4

Author(s):

Dalit Cayam-Rand ◽

Ting Guo ◽

Ruth E. Grunau ◽

Isabel Benavente-Fernández ◽

Anne Synnes ◽

...

Keyword(s):

Characteristic Curve ◽

Brain Mri ◽

Adverse Outcomes ◽

Preschool Age ◽

Cognitive Outcomes ◽

White Matter Injury ◽

Preterm Neonates ◽

Posterior Commissure ◽

Neurodevelopmental Outcomes ◽

Motor Outcomes

ObjectiveTo develop a simple imaging rule to predict neurodevelopmental outcomes at 4.5 years in a cohort of preterm neonates with white matter injury (WMI) based on lesion location and examine whether clinical variables enhance prediction.MethodsSixty-eight preterm neonates born 24–32 weeks' gestation (median 27.7 weeks) were diagnosed with WMI on early brain MRI scans (median 32.3 weeks). 3D T1-weighted images of 60 neonates with 4.5-year outcomes were reformatted and aligned to the posterior commissure–eye plane and WMI was classified by location: anterior or posterior-only to the midventricle line on the reformatted axial plane. Adverse outcomes at 4.5 years were defined as Wechsler Preschool and Primary Scale of Intelligence full-scale IQ <85, cerebral palsy, or Movement Assessment Battery for Children, second edition percentile <5. The prediction of adverse outcome by WMI location, intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), and retinopathy of prematurity (ROP) was assessed using multivariable logistic regression.ResultsSix children had adverse cognitive outcomes and 17 had adverse motor outcomes. WMI location predicted cognitive outcomes in 90% (area under receiver operating characteristic curve [AUC] 0.80) and motor outcomes in 85% (AUC 0.75). Adding IVH, BPD, and ROP to the model enhances the predictive strength for cognitive and motor outcomes (AUC 0.83 and 0.88, respectively). Rule performance was confirmed in an independent cohort of children with WMI.ConclusionsWMI on early MRI can be classified by location to predict preschool age outcomes in children born preterm. The predictive value of this WMI classification is enhanced by considering clinical factors apparent by term-equivalent age.

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Early- versus Late-Onset Fetal Growth Restriction Differentially Affects the Development of the Fetal Sheep Brain

Developmental Neuroscience ◽

10.1159/000456542 ◽

2017 ◽

Vol 39 (1-4) ◽

pp. 141-155 ◽

Cited By ~ 21

Author(s):

Anna Karynna Alves de Alencar Rocha ◽

Beth J. Allison ◽

Tamara Yawno ◽

Graeme R. Polglase ◽

Amy E. Sutherland ◽

...

Keyword(s):

White Matter ◽

Brain Development ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Early Onset ◽

Late Onset ◽

Placental Insufficiency ◽

White Matter Injury ◽

Fetal Sheep ◽

Cell Counts

Fetal growth restriction (FGR) is a common complication of pregnancy, principally caused by suboptimal placental function, and is associated with high rates of perinatal mortality and morbidity. Clinical studies suggest that the time of onset of placental insufficiency is an important contributor towards the neurodevelopmental impairments that are evident in children who had FGR. It is however currently unknown how early-onset and late-onset FGR differentially affect brain development. The aim of this study was to examine neuropathology in early-onset and late-onset FGR fetal sheep and to determine whether they differentially alter brain development. We induced placental insufficiency and FGR via single umbilical artery ligation at either 88 days (early-onset) or 105 days (late-onset) of fetal sheep gestation (term is approx. 147 days), reflecting a period of rapid white matter brain development. Fetal blood samples were collected for the first 10 days after surgery, and all fetuses were sacrificed at 125 days' gestation for brain collection and subsequent histopathology. Our results show that early-onset FGR fetuses became progressively hypoxic over the first 10 days after onset of placental insufficiency, whereas late-onset FGR fetuses were significantly hypoxic compared to controls from day 1 after onset of placental insufficiency (SaO2 46.7 ± 7.4 vs. 65.7 ± 3.9%, respectively, p = 0.03). Compared to control brains, early-onset FGR brains showed widespread white matter injury, with a reduction in both CNPase-positive and MBP-positive density of staining in the periventricular white matter (PVWM), subcortical white matter, intragyral white matter (IGWM), subventricular zone (SVZ), and external capsule (p < 0.05 for all). Total oligodendrocyte lineage cell counts (Olig-2-positive) did not differ across groups, but mature oligodendrocytes (MBP-positive) were reduced, and neuroinflammation was evident in early-onset FGR brains with reactive astrogliosis (GFAP-positive) in the IGWM and cortex (p < 0.05), together with an increased number of Iba-1-positive activated microglia in the PVWM, SVZ, and cortex (p < 0.05). Late-onset FGR was associated with a widespread reduction of CNPase-positive myelin expression (p < 0.05) and a reduced number of mature oligodendrocytes in all white matter regions examined (p < 0.05). NeuN-positive neuronal cell counts in the cortex were not different across groups; however, the morphology of neuronal cells was different in response to placental insufficiency, most notable in the early-onset FGR fetuses, but it was late-onset FGR that induced caspase-3-positive apoptosis within the cortex. This study demonstrates that early-onset FGR is associated with more widespread white matter injury and neuroinflammation; however, both early- and late-onset FGR are associated with complex patterns of white and grey matter injury. These results indicate that it is the timing of the onset of fetal compromise relative to brain development that principally mediates altered brain development associated with FGR.

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Influence of timing of initiation of therapeutic hypothermia on brain MRI and neurodevelopment at 18 months in infants with HIE: a retrospective cohort study

BMJ Paediatrics Open ◽

10.1136/bmjpo-2019-000442 ◽

2019 ◽

Vol 3 (1) ◽

pp. e000442 ◽

Cited By ~ 2

Author(s):

Mireille Guillot ◽

Marissa Philippe ◽

Elka Miller ◽

Jorge Davila ◽

Nicholas James Barrowman ◽

...

Keyword(s):

Cohort Study ◽

Brain Injury ◽

Therapeutic Hypothermia ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Neonatal Intensive Care ◽

Brain Mri ◽

Whole Body ◽

Neurodevelopmental Outcomes ◽

Timing Of Initiation

ObjectiveTo examine the influence of timing of initiation of therapeutic hypothermia (TH) on brain injury on MRI and on neurodevelopmental outcomes at 18 months.DesignRetrospective cohort study.SettingTertiary neonatal intensive care unit in Ontario, Canada.PatientsNinety-one patients with hypoxic ischaemic encephalopathy (HIE) were included, 54 in the early TH group and 37 in the late TH group.InterventionWhole-body hypothermia administered for 72 hours, initiated either before 3 hours of life (early TH) or between 3 and 6 hours of life (late TH).Main outcome measuresBrain injury on MRI after TH (assessed by two neuroradiologists), and neurodevelopmental outcomes at 18 months old.ResultsTH was initiated at a median time of 1.4 hours (early TH) and 4.4 hours (late TH). Sixty-four neonates (early TH=36, late TH=28) survived and completed neurodevelopmental assessment at 18 months. Neonates in the early TH group received more extensive resuscitation than neonates in the late TH group (p=0.0008). No difference was observed between the two groups in the pattern or severity of brain injury on MRI, or in the neurodevelopmental outcomes at 18 months. The non-survivors (n=16) had lower Apgar scores at 10 min, more extensive resuscitation, suffered from more severe HIE and had significantly more abnormal cerebral function monitoring.ConclusionIn this retrospective cohort study, TH initiated early was associated neither with a difference in brain injury on MRI nor better neurodevelopmental outcomes at 18 months.

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Impact of Congenital Heart Disease on Brain Development and Neurodevelopmental Outcome

International Journal of Pediatrics ◽

10.1155/2010/359390 ◽

2010 ◽

Vol 2010 ◽

pp. 1-13 ◽

Cited By ~ 51

Author(s):

Mary T. Donofrio ◽

An N. Massaro

Keyword(s):

Congenital Heart Disease ◽

Heart Disease ◽

Brain Injury ◽

Brain Development ◽

Congenital Heart ◽

Neurodevelopmental Outcome ◽

Neurodevelopmental Outcomes ◽

Postnatal Brain ◽

Ongoing Research ◽

The Impact

Advances in cardiac surgical techniques and perioperative intensive care have led to improved survival in babies with congenital heart disease (CHD). While it is true that the majority of children with CHD today will survive, many will have impaired neurodevelopmental outcome across a wide spectrum of domains. While continuing to improve short-term morbidity and mortality is an important goal, recent and ongoing research has focused on defining the impact of CHD on brain development, minimizing postnatal brain injury, and improving long-term outcomes. This paper will review the impact that CHD has on the developing brain of the fetus and infant. Neurologic abnormalities detectable prior to surgery will be described. Potential etiologies of these findings will be discussed, including altered fetal intrauterine growth, cerebral blood flow and brain development, associated congenital brain abnormalities, and risk for postnatal brain injury. Finally, reported neurodevelopmental outcomes after surgical repair of CHD will be reviewed.

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Neurodevelopmental outcomes at five years after early-onset fetal growth restriction: Analyses in a Dutch subgroup participating in a European management trial

European Journal of Obstetrics & Gynecology and Reproductive Biology ◽

10.1016/j.ejogrb.2018.12.041 ◽

2019 ◽

Vol 234 ◽

pp. 63-70

Author(s):

A. Pels ◽

O.C. Knaven ◽

B.J. Wijnberg-Williams ◽

M.J.C. Eijsermans ◽

S.M. Mulder-de Tollenaer ◽

...

Keyword(s):

Fetal Growth ◽

Fetal Growth Restriction ◽

Early Onset ◽

Growth Restriction ◽

Neurodevelopmental Outcomes

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Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes

Pediatric Research ◽

10.1038/s41390-021-01521-7 ◽

2021 ◽

Author(s):

Rachel L. Leon ◽

Imran N. Mir ◽

Christina L. Herrera ◽

Kavita Sharma ◽

Catherine Y. Spong ◽

...

Keyword(s):

Brain Development ◽

Congenital Heart ◽

Fetal Brain ◽

In Utero ◽

Structure And Function ◽

Brain Growth ◽

Neurodevelopmental Outcomes ◽

Fetal Brain Development ◽

And Function

Abstract Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta–heart–brain connection. Impact Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD.

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Infant Gut Microbiota Associated with Fine Motor Skills

Nutrients ◽

10.3390/nu13051673 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1673

Author(s):

Inmaculada Acuña ◽

Tomás Cerdó ◽

Alicia Ruiz ◽

Francisco J. Torres-Espínola ◽

Ana López-Moreno ◽

...

Keyword(s):

Gut Microbiota ◽

Infant Development ◽

16S Rrna Gene Sequencing ◽

Fine Motor ◽

Rrna Gene ◽

Neurodevelopmental Outcomes ◽

Gut Colonization ◽

Healthy Infants ◽

Behavioural Characteristics ◽

Rrna Gene Sequencing

BACKGROUND: During early life, dynamic gut colonization and brain development co-occur with potential cross-talk mechanisms affecting behaviour. METHODS: We used 16S rRNA gene sequencing to examine the associations between gut microbiota and neurodevelopmental outcomes assessed by the Bayley Scales of Infant Development III in 71 full-term healthy infants at 18 months of age. We hypothesized that children would differ in gut microbial diversity, enterotypes obtained by Dirichlet multinomial mixture analysis and specific taxa based on their behavioural characteristics. RESULTS: In children dichotomized by behavioural trait performance in above- and below-median groups, weighted Unifrac b-diversity exhibited significant differences in fine motor (FM) activity. Dirichlet multinomial mixture modelling identified two enterotypes strongly associated with FM outcomes. When controlling for maternal pre-gestational BMI and breastfeeding for up to 3 months, the examination of signature taxa in FM groups showed that Turicibacter and Parabacteroides were highly abundant in the below-median FM group, while Collinsella, Coprococcus, Enterococcus, Fusobacterium, Holdemanella, Propionibacterium, Roseburia, Veillonella, an unassigned genus within Veillonellaceae and, interestingly, probiotic Bifidobacterium and Lactobacillus were more abundant in the above-median FM group. CONCLUSIONS: Our results suggest an association between enterotypes and specific genera with FM activity and may represent an opportunity for probiotic interventions relevant to treatment for motor disorders.

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Factors associated with neurodevelopment in preterm infants with systematic inflammation

BMC Pediatrics ◽

10.1186/s12887-021-02583-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Eun Sun Lee ◽

Ee-Kyung Kim ◽

Seung han Shin ◽

Young-Hun Choi ◽

Young Hwa Jung ◽

...

Keyword(s):

White Matter ◽

Preterm Infants ◽

Systemic Inflammation ◽

Head Circumference ◽

Brain Mri ◽

White Matter Injury ◽

Social Emotional ◽

Postmenstrual Age ◽

Neurodevelopmental Impairment ◽

Near Term

Abstract Background Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment. Methods This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months. Results The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months. Conclusions Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.

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