Divyen K. Shah

Impact Statement: What does this article add to the existing literature: This commentary highlights the significance of conducting prospective research in preterm populations as they age to characterize growth trajectories and links with metabolic profiles, supporting the concept of the developmental origins of health and disease (DOHaD). Significant gaps in foundational knowledge on physiological responses and optimal metabolic demands in preterm children exist and constrain the depth of current interpretations. Methodological challenges of different anthropometric and metabolic assessment methods must be carefully weighed to ensure reliable conclusions for future clinical application.

Improvements in treatment and survival of neonates with complex congenital heart disease have led to growing recognition of the associated neurodevelopmental impairments. In this review, we explore the possible antenatal mechanisms of altered brain development in these patients with particular focus on acquired and genetic risk factors. Hypoxia, placental pathology and maternal stress are acquired factors with therapeutic potential. Among the genetic and epigenetic mechanisms, we discuss the influences of angiogenic genes, chromatin modifiers, Wnt and Notch signalling pathways, chromosomal syndromes and apolipoprotein E alleles. Understanding these antenatal risk factors will allow for further development of currently experimental fetal therapies, such as maternal hyperoxygenation. Impact: Congenital heart disease has a substantial impact on neurodevelopmental outcome. This scoping review identifies and brings together overlapping genetic, environmental and hemodynamic antenatal mechanisms that impact on altered brain development. A better understanding of these mechanisms may lead to development of therapeutic potentials to improve neurodevelopment outcomes in this group.

Corrigendum on: Shah DK, Ponnusamy V, Evanson J,Kapellou O, Ekitzidou G, Gupta N,Clarke P, Michael-Titus AT and Yip PK(2018) Raised Plasma NeurofilamentLight Protein Levels Are Associatedwith Abnormal MRI Outcomesin Newborns Undergoing Therapeutic Hypothermia.Front. Neurol. 9:86.doi: 10.3389/fneur.2018.00086In the published article, there was an error in Table 2 as published. For patients 1 and 3, the cell for the column entitled "Neurologic exam prior to discharge" should read "Severe, died after 18 months" instead of "Severe, died". The corrected Table 2 and its caption "Patients arranged in descending rank order of neurofilament light levels at S3 in relation to MRI findings and neurological exam at discharge. The latter is classified primarily in terms of abnormality of tone" appear below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.

Background: Fetal growth restriction (FGR) corresponds to the fetus’s inability to achieve an adequate weight gain based on genetic potential and gestational age. It is an important cause of morbidity and mortality. Summary: In this review, we address the challenges of diagnosis and classification of FGR. We review how chronic fetal hypoxia impacts brain development. We describe recent advances on placental and fetal brain imaging using magnetic resonance imaging and how they offer new noninvasive means to study growth restriction in humans. We go on to review the impact of FGR on brain integrity in the neonatal period, later childhood, and adulthood and review available therapies. Key Messages: FGR consequences are not limited to the perinatal period. We hypothesize that impaired brain reserve, as defined by structure and size, may predict some concerning epidemiological data of impaired cognitive outcomes and dementia with aging in this group of patients.

Background: Effective seizure detection is important however, clinical signs of seizure activity may be subtle in neonates. This study aimed to systematically investigate SpO₂ and respiratory pattern changes associated with EEG seizures in term-born neonates. Method: An observational study in term neonates at risk of seizures admitted to a single tertiary level neonatal intensive care unit. Synchronised high-resolution physiological data (ECG, pulse oximetry, respiration) and EEG/amplitude-integrated EEG (aEEG) monitoring were recorded. Sections of traces with evidence of clear EEG seizure activity were compared with physiological data recorded at the same time. Results: 22/44 (50%) neonates who had aEEG monitoring were noted to have electrographic seizures. Physiologic download measurements were available for 11 of these neonates. In nine of these, an acute drop in oxygen saturation (SpO₂) of at least 5% was noted in at least one seizure. Accompanying apnoeas were noted in three neonates. Conclusion: Acute decreases in SpO₂ were seen in term neonates associated with seizures and these were not always accompanied by an apnoeic episode. Physiologic download in association with EEG monitoring may assist in improving seizure detection. Unexplained drops in SpO₂ could indicate further investigation for possible seizures in at-risk neonates. Impact: A decrease in blood oxygen saturation (SpO₂) associated with EEG seizures can occur in term infants with HIE or perinatal stroke. Drops in SpO₂ associated with EEG seizures in term infants with HIE or stroke may occur in the absence of apnoeas. Unexplained acute falls in SpO₂ in sick neonates may suggest possible seizures. Drops in SpO₂ associated with seizures in term infants can occur over less than 3 minutes. Physiological monitoring alongside EEG monitoring could help to improve seizure detection.

Hypoxic-ischaemic encephalopathy (HIE) is an important cause of morbidity and mortality globally. Although mild therapeutic hypothermia (TH) may improve outcomes in selected babies, the mechanism of action is not fully understood. A proteomics discovery study was carried out to analyse proteins in the plasma of newborns with HIE. Proteomic analysis of plasma from 22 newborns with moderate-severe HIE that had initially undergone TH, and relative controls including 10 newborns with mild HIE who did not warrant TH and also cord blood from 10 normal births (non-HIE) were carried out using the isobaric Tandem Mass Tag (TMT^®) 10plex^TM labelling with tandem mass spectrometry. A total of 7818 unique peptides were identified in all TMT10plex^TM samples, translating to 3457 peptides representing 405 proteins, after applying stringent filter criteria. Apart from the unique protein signature from normal cord blood, unsupervised analysis revealed several significantly regulated proteins in the TH-treated moderate-severe HIE group. GO annotation and functional clustering revealed various proteins associated with glucose metabolism: the enzymes fructose-bisphosphate aldolase A, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase 1, phosphoglycerate kinase 1, and pyruvate kinase PKM were upregulated in newborns with favourable (sHIE+) outcomes compared to newborns with unfavourable (sHIE−) outcomes. Those with favourable outcomes had normal MR imaging or mild abnormalities not predictive of adverse outcomes. However, in comparison to mild HIE and the sHIE− groups, the sHIE+ group had the additional glucose metabolism-related enzymes upregulated, including triosephosphate isomerase, α-enolase, 6-phosphogluconate dehydrogenase, transaldolase, and mitochondrial glutathione reductase. In conclusion, our plasma proteomic study demonstrates that TH-treated newborns with favourable outcomes have an upregulation in glucose metabolism. These findings may open new avenues for more effective neuroprotective therapy.

Introduction: In the event of fetal hypoxia-ischemia, circulation to the brain and central organs is thought to be preserved. The objective of the study was to explore the relationship between the presence of brain injury on MRI and multi-organ involvement, as reflected in routinely collected laboratory (lab) values in babies who have undergone therapeutic hypothermia (TH) after hypoxic-ischemic encephalopathy (HIE). Methods: Peak and trough values, and age at peak/trough, were obtained for 10 lab markers collected for clinical care, representing hematopoiesis, coagulation, inflammation, hepatic, and renal function, from 71 consecutively recruited newborns from four tertiary neonatal centers undergoing TH. Cerebral MR images obtained as part of clinical care were assessed by two raters with expertise, in a blinded fashion. Results: There was no significant association between the presence of cerebral injury on MRI and systems involvement in newborns who have undergone TH. However, the peak/trough platelet ratio was significantly associated with cerebral injury. Also, the peak platelet, lymphocyte, and urea counts occurred significantly later in babies with substantial brain injury compared to those without. Conclusion: Using a statistical approach, we demonstrate that there is no clear relationship between multi-organ involvement and cerebral injury in babies with HIE who have undergone TH. We infer that babies may have cerebral injury in the absence of involvement of other organ systems. The platelet count ratio as an independent biomarker of cerebral injury in this group requires further investigation. Reference ranges of lab values for term newborns undergoing TH are provided.

Background: Hypoxic-ischemic encephalopathy (HIE) is associated with brain injury in newborns and may lead to disability or death. Mild therapeutic hypothermia (TH) is an effective neuroprotective intervention and an established standard of care in western countries. The gut microbiome, the genomic and physicochemical contribution of the gut microbiota, serves important functions and is increasingly recognized as a major influencer on development. The impact of HIE and TH on the evolving gut microbiota of the newborn remains to be elucidated. Objective: The objective of this study was to carry out an exploratory study on the effects of HIE and TH on the gut microbiome in term neonates. Methods and Results: Stool samples were obtained from 28 newborns with HIE (median age 68 h) undergoing TH on the neonatal unit (HIE TH group), with a follow-on stool sample available for 20 of these babies (median age 151 h). For comparison, a single stool specimen was obtained from 19 healthy newborns on the postnatal ward (median age 34 h). The microbiota composition was determined using established microbial DNA extraction and 16S rRNA gene sequencing methodology. There was no difference in the mode of delivery or the method of feeding the newborns, once established, between the 2 groups. All the infants in the HIE TH group had received antibiotics compared to only one of the controls. A lower α-diversity, quantified by the Shannon diversity index, was noted in the microbiota of the HIE TH group in comparison to the control group. The HIE TH group had a higher mean relative abundance (MRA) of facultative anaerobes and aerobes such as Staphylococcus species and a lower MRA of strict anaerobes, such as members of the Bacteroides genus, compared to the control. Also, there was a significant reduction in the MRA of the genus Bifidobacterium in the HIE TH group. Although the mode of delivery exerts a profound influence on the gut microbiota of the newborn, distance-based redundancy analysis showed that TH may exert an independent influence. This study could not determine the independent contribution of the use of antibiotics or the neonatal intensive care unit environment. Conclusion: In this study, we demonstrate an alteration in the microbiota composition in newborns undergoing TH for HIE.

Hypoxic-ischemic encephalopathy (HIE) is associated with perinatal brain injury, which may lead to disability or death. As the brain is a lipid-rich organ, various lipid species can be significantly impacted by HIE and these correlate with specific changes to the lipidomic profile in the circulation. Objective: To investigate the peripheral blood lipidomic signature in dried blood spots (DBS) from newborns with HIE. Using univariate analysis, multivariate analysis and sPLS-DA modelling, we show that newborns with moderate–severe HIE (n = 46) who underwent therapeutic hypothermia (TH) displayed a robust peripheral blood lipidomic signature comprising 29 lipid species in four lipid classes; namely phosphatidylcholine (PC), lysophosphatidylcholine (LPC), triglyceride (TG) and sphingomyelin (SM) when compared with newborns with mild HIE (n = 18). In sPLS-DA modelling, the three most discriminant lipid species were TG 50:3, TG 54:5, and PC 36:5. We report a reduction in plasma TG and SM and an increase in plasma PC and LPC species during the course of TH in newborns with moderate–severe HIE, compared to a single specimen from newborns with mild HIE. These findings may guide the research in nutrition-based intervention strategies after HIE in synergy with TH to enhance neuroprotection.