Imperial College London


Faculty of MedicineDepartment of Brain Sciences

Honorary Research Fellow







Commonwealth BuildingHammersmith Campus





Publication Type

31 results found

Thayyil S, Pant S, Montaldo P, Shukla D, Oliveira V, Ivain P, Bassett P, Swami R, Mendoza J, Moreno-Morales M, Lally PJ, Benakappa N, Bandiya P, Shivarudhrappa I, Somanna J, Kantharajanna UB, Rajvanshi A, Krishnappa S, Joby PK, Jayaraman K, Chandramohan R, Kamalarathnam CN, Sebastian M, Tamilselvam I, Rajendran U, Soundrarajan R, Kumar V, Sudarsanan Het al., 2021, Hypothermia for moderate or severe neonatal encephalopathy in low and middle-income countries (HELIX): a randomised control trial in India, Sri Lanka and Bangladesh, The Lancet Global Health, Vol: 9, Pages: e1273-e1285, ISSN: 2214-109X

Background: Although therapeutic hypothermia reduces death or disability after neonatal encephalopathy in high-income countries, its safety and efficacy in low- and middle-income countries (LMICs) remains unclear. We examined if therapeutic hypothermia alongside optimal supportive intensive care reduces death or disability after neonatal encephalopathy in South Asia. Methods: We conducted a multi-country open label randomised controlled trial involving seven tertiary neonatal intensive care units in India, Sri Lanka and Bangladesh, between August 2015 and September 2020. We allocated infants born at or after 36 weeks of gestation with moderate or severe neonatal encephalopathy into whole body hypothermia (33·5 0 C) for 72 hours using a servo-controlled cooling device, or usual care (control group), within six hours of birth. All recruiting sites had facilities for invasive ventilation, cardiovascular support and access to 3 Telsa magnetic resonance imaging and spectroscopy. The primary outcome was a combined end point of death or moderate or severe disability at 18 to 22 months of age, assessed by Bayley scales of infant development (Version III).Findings: Of 576 eligible infants, we assigned 202 to hypothermia and 206 to control group. Primary outcome data were available for 394 (96·5%) infants, and occurred in 98(50·3%) of the hypothermia and 94 (47·2%) of the control group (Risk Ratio (RR) 1·06;95% confidence intervals (CI) 0·87 to 1·30 (p = 0·55). Eighty-four infants (42·4%) in the hypothermia group and 63 (31·3%) (p = 0·02) infants in the control group died, of whom 72 (35·6%) and 49 (23·8%) (p = 0·009) died during neonatal hospitalisation. Interpretation: Therapeutic hypothermia did not reduce the combined outcome of death or disability at18 months after neonatal encephalopathy in LMICs, but significantly increased mortality. Therapeutic hypothermia should not

Journal article

Moreno Morales M, Montaldo P, Ivain P, Pant S, Kumar V, Krishnan V, Shankaran S, Thayyil Set al., 2021, Association of Total Sarnat Score with brain injury and neurodevelopmental outcomes after neonatal encephalopathy, Archives of Disease in Childhood: Fetal and Neonatal Edition, ISSN: 1359-2998

We examined the association of Total Sarnat Score (TSS) with brain injury on neonatal magnetic resonance (MR) and adverse neurodevelopmental outcome (NDO) (death or moderate or severe disability) at 2 years of age in 145 infants undergoing therapeutic hypothermia for neonatal encephalopathy. TSS was associated with basal ganglia/thalamic injury on conventional MR (p=0.03) and thalamic N-acetyl aspartate on MR spectroscopy (R2=0.16, p=0.004) at 2 weeks of age, and Bayley Composite Cognitive (R2=0.18, p=0.01), Motor (R2=0.15, p=0.02) and Language (R2=0.11, p=0.01) Scores at 2 years of age after adjustment for seizures at the time of neurological assessment. The accuracy of TSS (area under the curve (AUC)=0.71) for predicting adverse NDO was similar to the modified Sarnat staging (AUC=0.72). TSS of >12 within 6 hours of birth indicated high risk of adverse NDO, while TSS of <4 indicated intact survival and was reassuring of a good outcome among cooled infants.

Journal article

Ivain P, Montaldo P, Khan A, Elagovan R, Burgod C, Moreno Morales M, Pant S, Thayyil Set al., 2021, Erythropoietin monotherapy for neuroprotection after neonatal encephalopathy in low 2 to-middle income countries: A systematic review and meta-analysis, Journal of Perinatology, ISSN: 0743-8346

Objective: We examined whether erythropoietin monotherapy improves neurodevelopmental outcomes in near-term and term infants with neonatal encephalopathy (NE) in low-middle income countries (LMICs). Methods: We searched Pubmed, Embase, and Web of Science databases to identify studies that used erythropoietin (1,500 to 12,500 units/kg/dose) or a derivative to treat NE. Results: Five studies, with a total of 348 infants in LMICs, were retrieved. However, only three of the five studies met the primary outcome of death or neuro-disability at 18 months of age or later. Erythropoietin reduced the risk of death (during neonatal period and at follow55 up) or neuro-disability at 18 months or later (p<0.05). Death or neuro-disability occurred in 27.6% of the erythropoietin group and 49.7% of the comparison group (Risk Ratio 0.56 (95% CI: 0.42 to 0.75). Conclusion: The pooled data suggests that erythropoietin monotherapy may improve outcomes after NE in LMICs where therapeutic hypothermia is not available.

Journal article

Patterson JK, Pant S, Jones DF, Taha S, Jones MS, Bauserman MS, Montaldo P, Bose CL, Thayyil Set al., 2021, Informed consent rates for neonatal randomized controlled trials in low- and lower middle-income versus high-income countries: a systematic review, PLoS One, Vol: 16, Pages: 1-14, ISSN: 1932-6203

Objective: Legal, ethical, and regulatory requirements of medical research uniformly call for informed consent. We aimed to characterize and compare consent rates for neonatal randomized controlled trials in low- and lower middle-income countries versus high-income countries, and to evaluate the influence of study characteristics on consent rates.Methods: In this systematic review, we searched MEDLINE, EMBASE and Cochrane for randomized controlled trials of neonatal interventions in low- and lower middle-income countries or high-income countries published 01/01/2013 to 01/04/2018. Our primary outcome was consent rate, the proportion of eligible participants who consented amongst those approached, extracted from the article or email with the author. Using a generalised linear model for fractional dependent variables, we analysed the odds of consenting in low- and lower middle-income countries versus high-income countries across control types and interventions.Findings: We screened 3523 articles, yielding 300 eligible randomized controlled trials with consent rates available for 135 low- and lower middle-income country trials and 65 high-income country trials. Median consent rates were higher for low- and lower middle-income countries (95.6%; interquartile range (IQR) 88.2–98.9) than high-income countries (82.7%; IQR 68.6–93.0; p<0.001). In adjusted regression analysis comparing low- and lower middle-income countries to high-income countries, the odds of consent for no placebo-drug/nutrition trials was 3.67 (95% Confidence Interval (CI) 1.87–7.19; p = 0.0002) and 6.40 (95%CI 3.32–12.34; p<0.0001) for placebo-drug/nutrition trials.Conclusion: Neonatal randomized controlled trials in low- and lower middle-income countries report consistently higher consent rates compared to high-income country trials. Our study is limited by the overrepresentation of India among randomized controlled trials in low- and lower middle-income countries. This st

Journal article

Montaldo P, Cunnington A, Oliveira V, Swamy R, Bandya P, Pant S, Lally P, Ivain P, Mendoza J, Atreja G, Padmesh V, Baburaj M, Sebastian M, Yasashwi I, Kamalarathnam C, Chandramohan R, Mangalabharathi S, Kumaraswami K, Kumar S, Benakappa N, Manerkar S, Mondhkar J, Prakash V, Sajjid M, Seeralar A, Jahan I, Choudhury Moni S, Shahidullah M, Sujatha R, Chandrasekaran M, Ramji S, Shankaran S, Kaforou M, Herberg J, Thayyil Set al., 2020, Transcriptomic profile of adverse neurodevelopmental outcomes after neonatal encephalopathy, Scientific Reports, Vol: 10, Pages: 1-7, ISSN: 2045-2322

A rapid and early diagnostic test to identify the encephalopathic babies at risk of adverse outcome may accelerate the development of neuroprotectants. We examined if a whole blood transcriptomic signature measured soon after birth,predicts adverse neurodevelopmental outcomeeighteenmonths after neonatal encephalopathy.We performed next generation sequencing on whole blood ribonucleic acid obtained within sixhours of birth from the first 47encephalopathic babies recruited to the Hypothermia for Encephalopathy in Low and middle-income countries (HELIX)trial. Two infants with blood culture positive sepsis were excluded, and the data from remaining 45 were analysed. A total of 855genes were significantly differentially expressed between the good and adverse outcome groups, of which RGS1and SMC4 werethe most significant. Biological pathway analysis adjusted for gender, trial randomisation allocation (cooling therapy versus usual care) and estimated blood leukocyte proportions revealed over-representation of genes from pathways related to melatoninand polo-like kinase in babieswith adverse outcome. These preliminary data suggest that transcriptomic profiling may be a promising tool for rapid risk stratification in neonatal encephalopathy. It may provide insights into biological mechanismsand identify novel therapeutic targetsfor neuroprotection.

Journal article

Burgod C, Thayyil S, Montaldo P, 2020, The use of gene expression as a disease stratification tool of neonatal encephalopathy, Pediatric Research, Vol: 89, Pages: 12-13, ISSN: 0031-3998

Journal article

Kariholu U, Montaldo P, Markati T, Lally PJ, Teiserskas J, Liow N, Oliveira V, Soe A, Shankaran S, Thayyil Set al., 2020, Therapeutic hypothermia for mild neonatal encephalopathy: A systematic review and meta-analysis, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 105, Pages: 225-228, ISSN: 1359-2998

Objectives To examine if therapeutic hypothermia reduces the composite outcome of death, moderate or severe disability at 18 months or more after mild neonatal encephalopathy (NE).Data source MEDLINE, Cochrane database, Scopus and ISI Web of Knowledge databases, using ‘hypoxic ischaemic encephalopathy’, ‘newborn’ and ‘hypothermia’, and ‘clinical trials’ as medical subject headings and terms. Manual search of the reference lists of all eligible articles and major review articles and additional data from the corresponding authors of selected articles.Study selection Randomised and quasirandomised controlled trials comparing therapeutic hypothermia with usual care.Data extraction Safety and efficacy data extracted independently by two reviewers and analysed.Results We included the data on 117 babies with mild NE inadvertently recruited to five cooling trials (two whole-body cooling and three selective head cooling) of moderate and severe NE, in the meta-analysis. Adverse outcomes occurred in 11/56 (19.6%) of the cooled babies and 12/61 (19.7%) of the usual care babies (risk ratio 1.11 (95% CIs 0.55 to 2.25)).Conclusions Current evidence is insufficient to recommend routine therapeutic hypothermia for babies with mild encephalopathy and significant benefits or harm cannot be excluded.

Journal article

Montaldo P, Ivain P, Lally P, Bassett P, Pant S, Oliveira V, Mendoza J, Morales M, Swamy R, Shankaran S, Thayyil Set al., 2020, White matter injury after neonatal encephalopathy is associated with thalamic metabolite perturbations, EBioMedicine, Vol: 52, ISSN: 2352-3964

BackgroundAlthough thalamic magnetic resonance (MR) spectroscopy (MRS) accurately predicts adverse outcomes after neonatal encephalopathy, its utility in infants without MR visible deep brain nuclei injury is not known. We examined thalamic MRS metabolite perturbations in encephalopathic infants with white matter (WM) injury with or without cortical injury and its associations with adverse outcomes.MethodsWe performed a subgroup analysis of all infants recruited to the MARBLE study with isolated WM or mixed WM/cortical injury, but no visible injury to the basal ganglia/thalamus (BGT) or posterior limb of the internal capsule (PLIC). We used binary logistic regression to examine the association of MRS biomarkers with three outcomes (i) WM injury score (1 vs. 2/3); (ii) cortical injury scores (0/1 vs. 2/3); and (iii) adverse outcomes (defined as death, moderate/severe disability) at two years (yes/no). We also assessed the accuracy of MRS for predicting adverse outcome.FindingsOf the 107 infants included in the analysis, five had adverse outcome. Reduced thalamic N-acetylaspartate concentration [NAA] (odds ratio 0.4 (95% CI 0.18–0.93)) and elevated thalamic Lactate/NAA peak area ratio (odds ratio 3.37 (95% CI 1.45–7.82)) were significantly associated with higher WM injury scores, but not with cortical injury. Thalamic [NAA] (≤5.6 mmol/kg/wet weight) had the best accuracy for predicting adverse outcomes (sensitivity 1.00 (95% CI 0.16–1.00); specificity 0.95 (95% CI 0.84–0.99)).InterpretationThalamic NAA is reduced in encephalopathic infants without MR visible deep brain nuclei injury and may be a useful predictor of adverse outcomes.FundingThe National Institute for Health Research (NIHR).

Journal article

Montaldo P, Vakharia A, Ivain P, Mendoza J, Oliveira V, Markati T, Shankaran S, Thayyil Set al., 2020, Pre-emptive opioid sedation during therapeutic hypothermia, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 105, Pages: 108-109, ISSN: 1359-2998

Journal article

Montaldo P, Lally P, Oliveira V, Swamy R, Mendoza J, Atreja G, Kariholu U, Shivamurthappa V, Liow N, Teiserskas J, Pryce R, Soe A, Shankaran S, Thayyil Set al., 2019, Therapeutic hypothermia initiated within 6 hours of birth is associated with reduced brain injury on MR biomarkers in mild hypoxic ischemic encephalopathy: a non-randomised cohort study, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 104, Pages: F515-F520, ISSN: 1359-2998

Objective To examine the effect of therapeutic hypothermia on MR biomarkers and neurodevelopmental outcomes in babies with mild hypoxic-ischaemic encephalopathy (HIE).Design Non-randomised cohort study.Setting Eight tertiary neonatal units in the UK and the USA.Patients 47 babies with mild HIE on NICHD neurological examination performed within 6 hours after birth.Interventions Whole-body cooling for 72 hours (n=32) or usual care (n=15; of these 5 were cooled for <12 hours).Main outcome measures MRI and MR spectroscopy (MRS) within 2 weeks after birth, and a neurodevelopmental outcome assessment at 2 years.Results The baseline characteristics in both groups were similar except for lower 10 min Apgar scores (p=0.02) in the cooled babies. Despite this, the mean (SD) thalamic NAA/Cr (1.4 (0.1) vs 1.6 (0.2); p<0.001) and NAA/Cho (0.67 (0.08) vs 0.89 (0.11); p<0.001) ratios from MRS were significantly higher in the cooled group. Cooled babies had lower white matter injury scores than non-cooled babies (p=0.02). Four (27%) non-cooled babies with mild HIE developed seizures after 6 hours of age, while none of the cooled babies developed seizures (p=0.008). Neurodevelopmental outcomes at 2 years were available in 40 (85%) of the babies. Adverse outcomes were seen in 2 (14.3%) non-cooled babies, and none of the cooled babies (p=0.09).Conclusions Therapeutic hypothermia may have a neuroprotective effect in babies with mild HIE, as demonstrated by improved MRS biomarkers and reduced white matter injury on MRI. This may warrant further evaluation in adequately powered randomised controlled trials.

Journal article

Oliveira V, von Rosenberg W, Montaldo P, Adjei T, Mendoza J, Shivamurthappa V, Mandic D, Thayyil Set al., 2019, Early postnatal heart rate variability in healthy newborn infants, Frontiers in Physiology, Vol: 10, Pages: 1-12, ISSN: 1664-042X

Background: Despite the increasing interest in fetal and neonatal heart rate variability (HRV) analysis and its potential use as a tool for early disease stratification, no studies have previously described the normal trends of HRV in healthy babies during the first hours of postnatal life.Methods: We prospectively recruited 150 healthy babies from the postnatal ward and continuously recorded their electrocardiogram during the first 24 h after birth. Babies were included if born in good condition and stayed with their mother. Babies requiring any medication or treatment were excluded. Five-minute segments of the electrocardiogram (non-overlapping time-windows) with more than 90% consecutive good quality beats were included in the calculation of hourly medians and interquartile ranges to describe HRV trends over the first 24 h. We used multilevel mixed effects regression with auto-regressive covariance structure for all repeated measures analysis and t-tests to compare group differences. Non-normally distributed variables were log-transformed.Results: Nine out of 16 HRV metrics (including heart rate) changed significantly over the 24 h [Heart rate p < 0.01; Standard deviation of the NN intervals p = 0.01; Standard deviation of the Poincaré plot lengthwise p < 0.01; Cardiac sympathetic index (CSI) p < 0.01; Normalized high frequency power p = 0.03; Normalized low frequency power p < 0.01; Total power p < 0.01; HRV index p = 0.01; Parseval index p = 0.03], adjusted for relevant clinical variables. We observed an increase in several HRV metrics during the first 6 h followed by a gradual normalization by approximately 12 h of age. Between 6 and 12 h of age, only heart rate and the normalized low frequency power changed significantly, while between 12 and 18 h no metric, other than heart rate, changed significantly. Analysis with multilevel mixed effects regression analysis (multivariable) revealed that gestational age, reduced fetal movements, cardi

Journal article

Montaldo P, Swamy R, Bassett P, Lally PJ, Shankaran S, Thayyil Set al., 2019, Pitfalls in using neonatal brain NAA to predict infant development - Authors' reply., The Lancet Neurology, Vol: 18, Pages: 423-424, ISSN: 1474-4422

Journal article

Thayyil S, Liow N, Montaldo P, Lally P, Teiserskas J, Bassett P, Oliveira V, Mendoza J, Slater R, Shankaran Set al., 2019, Pre-emptive morphine during therapeutic hypothermia after neonatal encephalopathy: a secondary analysis, Therapeutic Hypothermia and Temperature Management, Vol: 10, Pages: 45-52, ISSN: 2153-7658

Although therapeutic hypothermia (TH) improves outcomes after neonatal encephalopathy (NE), the safety and efficacy of preemptive opioid sedation during cooling therapy is unclear. We performed a secondary analysis of the data from a large multicountry prospective observational study (Magnetic Resonance Biomarkers in Neonatal Encephalopathy [MARBLE]) to examine the association of preemptive morphine infusion during TH on brain injury and neurodevelopmental outcomes after NE. All recruited infants had 3.0 Tesla magnetic resonance imaging and spectroscopy at 1 week, and neurodevelopmental outcome assessments at 22 months. Of 223 babies recruited to the MARBLE study, the data on sedation were available from 169 babies with moderate (n = 150) or severe NE (n = 19). Although the baseline characteristics and admission status were similar, the babies who received morphine infusion (n = 141) were more hypotensive (49% vs. 25%, p = 0.02) and had a significantly longer hospital stay (12 days vs. 9 days, p = 0.009) than those who did not (n = 28). Basal ganglia/thalamic injury (score ≥1) and cortical injury (score ≥1) was seen in 34/141 (24%) and 37/141 (26%), respectively, of the morphine group and 4/28 (14%) and 3/28 (11%) of the nonmorphine group (p > 0.05). On regression modeling adjusted for potential confounders, preemptive morphine was not associated with mean (standard deviation [SD]) thalamic N-acetylaspartate (NAA) concentration (6.9 ± 0.9 vs. 6.5 ± 1.5; p = 0.97), and median (interquartile range) lactate/NAA peak area ratios (0.16 [0.12–0.21] vs. 0.13 [0.11–0.18]; p = 0.20) at 1 week, and mean (SD) Bayley-III composite motor (92 ± 23 vs. 94 ± 10; p = 0.98), language (89 ± 22 vs. 93 ± 

Journal article

Montaldo P, Kaforou M, Pollara G, Hervás-Maríne D, Calabria I, Panadero J, Pedrola L, Lally PJ, Oliveira V, Kage A, Atreja G, Mendoza J, Soe A, Pattnayak S, Shankaranh S, Vento M, Herberg J, Thayyil Set al., 2019, Whole blood gene expression reveals specific transcriptome changes in neonatal encephalopathy, Neonatology, Vol: 115, Pages: 68-76, ISSN: 1661-7800

BackgroundVariable responses to hypothermic neuroprotection are related to the clinical heterogeneity of encephalopathic babies, hence better disease stratification may facilitate the development of individualized neuroprotective therapies.ObjectivesWe examined if whole blood gene expression analysis can identify specific transcriptome profiles in neonatal encephalopathy. Material and MethodsWe performed next generation sequencing on whole blood RNA from twelve babies with neonatal encephalopathy, and six time-matched healthy term babies. The significantly differentially expressed genes between encephalopathic and control babies were identified. This set of genes was then compared to the host RNA response in septic neonates and subjected to pathway analysis. ResultsWe identified 950 statistically significant genes discriminating perfectly between the healthy controls and neonatal encephalopathy. The major pathways in neonatal encephalopathy were axonal guidance signaling (p =0.0009), granulocyte adhesion and diapedesis (p = 0.003), IL-12 Signaling and Production in Macrophages (p= 0.003) and hypoxia-inducible factor 1α signaling (p = 0.004). There were only 137 genes in common between neonatal encephalopathy and bacterial sepsis sets. ConclusionBabies with neonatal encephalopathy have striking differences in gene expression profiles compared with healthy control and septic babies. Gene expression profile may be useful for disease stratification based and for developing personalized neuroprotective therapies.

Journal article

Lally PJ, Montaldo P, Oliveira V, Soe A, Swamy R, Bassett P, Mendoza J, Atreja G, Kariholu U, Pattnayak S, Sashikumar P, Harizaj H, Mitchell M, Ganesh V, Harigopal S, Dixon J, English P, Clarke P, Muthukumar P, Satodia P, Wayte S, Abernethy LJ, Yajamanyam K, Bainbridge A, Price D, Huertas A, Sharp DJ, Kalra V, Chawla S, Shankaran S, Thayyil Set al., 2019, Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study, Lancet Neurology, Vol: 18, Pages: 35-45, ISSN: 1474-4422

BackgroundIn neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.MethodsWe conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was anabnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.FindingsWe recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independentlyassociated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).InterpretationThalamic 1H MRS measures acquired soon after

Journal article

Montaldo P, Lally PJ, Oliveira V, Thayyil Set al., 2018, Hypothermic neuroprotection for neonatal encephalopathy in low-and middle-income countries: a new approach to an old problem,, Vol: 19, Pages: e735-e741, ISSN: 1526-9906

Little progress has been made over the past decade in improving the outcomes of infants with neonatal encephalopathy in low-and middle-income countries (LMICs), and millions of infants still die or sustain permanent neurodisability every year. One of the key reasons for this lack of progress is a disconnect between encephalopathy research in high-income countries and LMICs. The majority of the neonatal encephalopathy research has been conducted in high-income countries with a low disease burden, without the involvement of LMICs. Here we discuss how a collaborative approach—particularly between middle-income countries and high-income countries—enables the use of state-of-the-art magnetic resonance biomarkers and host gene expression profiling for effective disease stratification. Using the example of the Hypothermia for Encephalopathy in Low-and middle-Income countries (HELIX) trial, we describe how this approach may result in a paradigm shift in global perinatal brain research over the next decade.

Journal article

Chalak LF, Nguyen K-A, Prempunpong C, Heyne R, Thayyil S, Shankaran S, Laptook AR, Rollins N, Pappas A, Koclas L, Shah B, Montaldo P, Techasaensiri B, Sánchez PJ, Sant'Anna Get al., 2018, Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18-22 months, Pediatric Research, Vol: 84, Pages: 861-868, ISSN: 0031-3998

BACKGROUND: Studies of early childhood outcomes of mild hypoxic-ischemic encephalopathy (HIE) identified in the first 6 h of life are lacking. OBJECTIVE: To evaluate neurodevelopmental outcomes at 18-22 months of PRIME study. STUDY DESIGN: Multicenter, prospective study of mild HIE defined as ≥1 abnormality using the modified Sarnat within 6 h of birth and not meeting cooling criteria. Primary outcome was disability with mild: Bayley III cognitive 70-84 or ≥85 and either Gross Motor Function Classification System (GMFCS) 1 or 2, seizures, or hearing deficit; moderate: cognitive 70-84 and either GMFCS 2, seizures, or hearing deficit; severe: cognitive <70, GMFCS 3-5. RESULTS: Of the 63 infants enrolled, 51 (81%) were evaluated at 19 ± 2 months and 43 (68%) completed Bayley III. Of the 43 infants, 7 (16%) were diagnosed with disability, including 1 cerebral palsy and 2 autism. Bayley scores < 85 in either cognition, motor, or language were detected in 17 (40%): 14 (32%) language, 7 (16%) cognitive, and 6 (14%) motor domain. Infants with disability had more abnormalities on discharge examination and brain MRI, with longer hospital stay (p < 0.001). CONCLUSIONS: In this contemporary untreated cohort of mild HIE, disability occurred in 16% of infants at 18-22 months.

Journal article

Oliveira V, Kumutha JR E N, Somanna J, Benkappa N, Bandya P, Chandrasekeran M, Swamy R, Mondkar J, Dewang K, Manerkar S, Sundaram M, Chinathambi K, Bharadwaj S, Bhat V, Madhava V, Nair M, Lally PJ, Montaldo P, Atreja G, Mendoza J, Bassett P, Ramji S, Shankaran S, Thayyil Set al., 2018, Hypothermia for encephalopathy in low-income and middle-income countries: feasibility of whole-body cooling using a low-cost servo-controlled device, BMJ Paediatrics Open, Vol: 2, ISSN: 2399-9772

Although therapeutic hypothermia (TH) is the standard of care for hypoxic ischaemic encephalopathy in high-income countries, the safety and efficacy of this therapy in low-income and middle-income countries (LMICs) is unknown. We aimed to describe the feasibility of TH using a low-cost servo-controlled cooling device and the short-term outcomes of the cooled babies in LMIC. Design: We recruited babies with moderate or severe hypoxic ischaemic encephalopathy (aged <6 hours) admitted to public sector tertiary neonatal units in India over a 28-month period. We administered whole-body cooling (set core temperature 33.5°C) using a servo-controlled device for 72 hours, followed by passive rewarming. We collected the data on short-term neonatal outcomes prior to hospital discharge. Results: Eighty-two babies were included-61 (74%) had moderate and 21 (26%) had severe encephalopathy. Mean (SD) hypothermia cooling induction time was 1.7 hour (1.5) and the effective cooling time 95% (0.08). The mean (SD) hypothermia induction time was 1.7 hour (1.5 hour), core temperature during cooling was 33.4°C (0.2), rewarming rate was 0.34°C (0.16°C) per hour and the effective cooling time was 95% (8%). Twenty-five (51%) babies had gastric bleeds, 6 (12%) had pulmonary bleeds and 21 (27%) had meconium on delivery. Fifteen (18%) babies died before discharge from hospital. Heart rate more than 120 bpm during cooling (P=0.01) and gastric bleeds (P<0.001) were associated with neonatal mortality. Conclusions: The low-cost servo-controlled cooling device maintained the core temperature well within the target range. Adequately powered clinical trials are required to establish the safety and efficacy of TH in LMICs. Clinical trial registration number: NCT01760629.

Journal article

Prempunpong C, Chalak LF, Garfinkle J, Shah B, Kalra V, Rollins N, Boyle R, Nguyen K-A, Mir I, Pappas A, Montaldo P, Thayyil S, Sánchez PJ, Shankaran S, Laptook AR, Sant'Anna Get al., 2017, Prospective research on infants with mild encephalopathy: the PRIME study., Journal of Perinatology, Vol: 38, Pages: 80-85, ISSN: 0743-8346

OBJECTIVE: To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age. STUDY DESIGN: Prospective multicenter study. Mild NE was defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge. RESULTS: A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing. CONCLUSIONS: A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.Journal of Perinatology advance online publication, 2 November 2017; doi:10.1038/jp.2017.164.

Journal article

Lally PJ, Montaldo P, Oliveira V, Swamy RS, Soe A, Shankaran S, Thayyil Set al., 2017, Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F383-F387, ISSN: 1359-2998

We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage).

Journal article

Sánchez-Illana Á, Thayyil S, Montaldo P, Jenkins D, Quintás G, Oger C, Galano J-M, Vigor C, Durand T, Vento M, Kuligowski Jet al., 2017, Novel free-radical mediated lipid peroxidation biomarkers in newborn plasma., Analytica Chimica Acta, Vol: 996, Pages: 88-97, ISSN: 0003-2670

Oxidative stress derived from perinatal asphyxia appears to be closely linked to neonatal brain damage and lipid peroxidation biomarkers have shown to provide predictive power of oxidative stress related pathologies in situations of hypoxia and reoxygenation in the newborn. The objective of this work was to develop and validate of a comprehensive liquid chromatography tandem mass spectrometry approach for the quantitative profiling of 28 isoprostanoids in newborn plasma samples covering a broad range of lipid peroxidation product classes. The method was developed taking into account the specific requirements for its use in neonatology (i.e. limited sample volumes, straightforward sample processing and high analytical throughput). The method was validated following stringent FDA guidelines and was then applied to the analysis of 150 plasma samples collected from newborns. Information obtained from the quantitative analysis of isoprostanoids was critically compared to that provided by a previously developed approach aiming at the semi-quantitative detection of total parameters of fatty acid derived lipid peroxidation biomarkers.

Journal article

Oliveira V, Singhvi DP, Montaldo P, Lally PJ, Mendoza J, Manerkar S, Shankaran S, Thayyil Set al., 2017, Therapeutic hypothermia in mild neonatal encephalopathy: a national survey of practice in the UK, Archives of Disease in Childhood. Fetal and Neonatal Edition, Vol: 103, Pages: F388-F390, ISSN: 1359-2998

Although major cooling trials (and subsequent guidelines) excluded babies with mild encephalopathy, anecdotal evidence suggests that cooling is often offered to these infants. We report a national survey on current cooling practices for babies with mild encephalopathy in the UK. From 74 neonatal units contacted, 68 were cooling centres. We received 54 responses (79%) and included 48 (five excluded due to incomplete data and one found later not to offer cooling). Of these, 36 centres (75%) offered cooling to infants with mild encephalopathy. Although most of the participating units reported targeting 33-34°C core temperature, seven (19%) considered initiating cooling beyond 6 hours of age and 13 (36%) discontinued cooling prior to 72 hours. Babies were ventilated for cooling in two (6%) units and 13 (36%) sedated all cooled babies. Enteral feeding was withheld in 15 (42%) units and reduced below 25% of requirements in eight (22%) units. MRI and neurodevelopmental outcome evaluation were offered to all cooled babies in 29 (80%) and 27 (75%) units, respectively. Further research is necessary to ensure optimal neuroprotection in mild encephalopathy.

Journal article

Thayyil S, Oliveira V, Lally PJ, Swamy R, Bassett P, Chandrasekaran M, Mondkar J, Mangalabharathi S, Benkappa N, Seeralar A, Shahidullah M, Montaldo P, Herberg J, Manerkar S, Kumaraswami K, Kamalaratnam C, Prakash V, Chandramohan R, Bandya P, Mannan MA, Rodrigo R, Nair M, Ramji S, Shankaran S, HELIX Trial groupet al., 2017, Hypothermia for encephalopathy in low and middle-income countries (HELIX): study protocol for a randomised controlled trial., Trials, Vol: 18, ISSN: 1745-6215

BACKGROUND: Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as standard therapy in these settings. However, the safety and efficacy of cooling therapy in low- and middle-income countries (LMICs), where 99% of the disease burden occurs, remains unclear. We will examine whether whole body cooling reduces death or neurodisability at 18-22 months after neonatal encephalopathy, in LMICs. METHODS: We will randomly allocate 408 term or near-term babies (aged ≤ 6 h) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries (India, Bangladesh or Sri Lanka), to either usual care alone or whole-body cooling with usual care. Babies allocated to the cooling arm will have core body temperature maintained at 33.5 °C using a servo-controlled cooling device for 72 h, followed by re-warming at 0.5 °C per hour. All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1-2 weeks after birth. Our primary endpoint is death or moderate or severe disability at the age of 18 months. DISCUSSION: Upon completion, HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs. The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection. TRIAL REGISTRATION:, NCT02387385 . Registered on 27 February 2015.

Journal article

Chalak LF, Prempunpong C, Garfinkle J, Rollins N, Nguyen K-A, Pappas A, Montaldo P, Thayyil S, Sanchez PJ, Shankaran S, Laptook AR, Sant'Anna Get al., 2017, PROSPECTIVE STUDY OF INFANTS WITH MILD ENCEPHALOPATHY: PRIME STUDY, XXV Biennial Meeting of the International Perinatal Collegium, Publisher: WILEY, Pages: 9-9, ISSN: 0803-5253

Conference paper

Chandrasekaran M, Chaban B, Montaldo P, Thayyil Set al., 2017, Predictive value of amplitude-integrated EEG (aEEG) after rescue hypothermic neuroprotection for hypoxic ischemic encephalopathy: a meta-analysis, Journal of Perinatology, Vol: 37, Pages: 684-689, ISSN: 0743-8346

Objective:Amplitude-integrated electroencephalography (aEEG) is a useful bedside tool in predicting the neurodevelopmental outcome after neonatal encephalopathy; however, the prognostic accuracy may be altered by rescue hypothermic neuroprotection. The objective of this study is to examine the prognostic accuracy of aEEG for predicting long-term neurodevelopmental outcomes in term newborn infants undergoing therapeutic hypothermia for neonatal encephalopathy.Study Design:We examined all studies (Medline, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library; 2000 to 2014) comparing aEEG (6, 24, 48 or 72 h) in term encephalopathic babies undergoing therapeutic hypothermia, with neurodevelopmental outcome at 1 year or more. We extracted individual patient data from the eligible studies to calculate prognostic indices with exact confidence intervals (CIs). We considered continuous normal voltage as normal aEEG pattern and discontinuous normal voltage, burst suppression, flat trace and persistently low voltage as abnormal, and defined adverse outcome as death or moderate/severe disability at 1 year.Results:We reviewed a total of 70 articles, 17 of which met the inclusion criteria. Eight studies were excluded and 9 studies (N=520) were included in the meta-analysis. The pooled sensitivity and specificity for an abnormal trace at 6 h of age to predict adverse outcome were 96% (95% CI 91 to 98%) and 39% (95% CI 32 to 46%). The diagnostic odds ratio of an abnormal trace was highest at 48 h (66.9 (95% CI 19.7, 227.2)).Conclusions:A persistantly abnormal aEEG at 48 h or more is associated with an adverse neurodevelopmal outcome. The positive prognostic value of 6 h aEEG is poor and good outcome may occur despite abnormal aEEG. Conversely, a normal 6 h aEEG has a good negative predictive value although do not exclude adverse outcomes.

Journal article

Montaldo P, Oliveira V, Lally PJ, Chaban B, Atreja G, Kirmi O, Thayyil Set al., 2016, Therapeutic hypothermia in neonatal cervical spine injury, Archives of Disease in Childhood: Fetal & Neonatal Edition, Vol: 101, Pages: F468-F468, ISSN: 1468-2052

Journal article

Montaldo P, Addison S, Oliveira V, Lally PJ, Taylor AM, Sebire NJ, Thayyil S, Arthurs OJet al., 2016, Quantification of Maceration Changes using Post Mortem MRI in Fetuses, BMC MEDICAL IMAGING, Vol: 16, ISSN: 1471-2342

BackgroundPost mortem imaging is playing an increasingly important role in perinatal autopsy, andcorrect interpretation of imaging changes is paramount. This is particularly importantfollowing intra-uterine fetal death, where there may be fetal maceration. The aim of thisstudy was to investigate whether any changes seen on a whole body fetal post mortemmagnetic resonance imaging (PMMR) correspond to maceration at conventionalautopsy.Methods: We performed pre-autopsy PMMR in 75 fetuses using a 1.5 Tesla SiemensAvanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to theclinical history and autopsy data using a numerical severity scale (0 = no macerationchanges to 2 = severe maceration changes) for 6 different visceral organs (total 12).The degree of maceration at autopsy was categorized according to severity on anumerical scale (1 = no maceration to 4 = severe maceration). We also generatedquantitative maps to measure the liver and lung T2.Results: The mean PMMR maceration score correlated well with the autopsymaceration score (R2=0.93). A PMMR score of ≥ 4.5 had a sensitivity of 91%,specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver andlung T2 were increased in fetuses with maceration scores of 3-4 in comparison tothose with 1-2 (liver p=0.03, lung p=0.02).Conclusions: There was a good correlation between PMMR maceration score and theextent of maceration seen at conventional autopsy. This score may be useful ininterpretation of fetal PMMR.

Journal article

Lally P, PAULIAH S, MONTALDO P, CHABAN B, Oliveira V, Bainbridge A, Soe A, Pattnayak S, Clarke P, Satodia P, Harigopal S, Abernethy LJ, Turner MA, Huertas Ceballos A, Shankaran S, THAYYIL Set al., 2015, Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): A Prospective Multi-Country Study, BMJ Open, Vol: 5, ISSN: 2044-6055

Despite cooling adverse outcomes are seen in upto half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Riggorous evaluation of these therapies in phase II trials using surrogate magnetic resonance biomarkers may speed up thier bench to bedside translation. A recent systematic review of single centres studies have suggested that Magnetic resonance spectroscopy biomarkers offers the best promise, however the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makes is not known.

Journal article

Montaldo P, Chaban B, Lally PJ, Sebire NJ, Taylor AM, Thayyil Set al., 2015, Quantification of ante-mortem hypoxic ischemic brain injury by post-mortem cerebral magnetic resonance imaging in neonatal encephalopathy, European Journal of Paediatric Neurology, Vol: 19, Pages: 665-671, ISSN: 1090-3798

Post-mortem (PM) magnetic resonance imaging (MRI) is increasingly used as an alternative to conventional autopsy in babies dying from neonatal encephalopathy. However, the confounding effect of post-mortem changes on the detection of ante-mortem ischemic injury is unclear. We examined whether quantitative MR measurements can accurately distinguish ante-mortem ischemic brain injury from artifacts using post-mortem MRI.Methods:We compared PM brain MRI (1.5 T Siemens, Avanto) in 7 infants who died with neonatal encephalopathy (NE) of presumed hypoxic-ischemic origin with 7 newborn infants who had sudden unexplained neonatal death (SUND controls) without evidence of hypoxic-ischemic brain injury at autopsy. We measured apparent diffusion coefficients (ADCs), T1-weighted signal intensity ratios (SIRs) compared to vitreous humor and T2 relaxation times from 19 predefined brain areas typically involved in neonatal encephalopathy.Results:There were no differences in mean ADC values, SIRs on T1-weighted images or T2 relaxation times in any of the 19 predefined brain areas between NE and SUND infants. All MRI images showed loss of cortical gray/white matter differentiation, loss of the normal high signal intensity (SI) in the posterior limb of the internal capsule on T1-weighted images, and high white matter SI on T2-weighted images.Conclusion:Normal post-mortem changes may be easily mistaken for ante-mortem ischemic injury, and current PM MRI quantitative assessment cannot reliably distinguish these. These findings may have important implications for appropriate interpretation of PM imaging findings, especially in medico-legal practice.

Journal article

Montaldo P, Montaldo L, Chaban B, Thayyil Set al., 2015, Perinatal infection as risk factor of neonatal encephalopathy, Asphyxia: Risk Factors, Prevalence and Neurological Impacts, Pages: 55-72, ISBN: 9781634822251

Fetal exposure to inflammation and infection has been shown to increase brain vulnerability to hypoxia-ischemia via stimulation of immune and inflammatory responses, chemotaxis, toll-like receptors and cell death. Perinatal infection is a potentially modifiable, risk factor for encephalopathy that has been linked to adverse outcomes. Nevertheless, the exact role of perinatal infection among neonates with a history of encephalopathy, is not yet completely understood. Emerging experimental data suggest that hypothermia may not be neuroprotective after a bacterial lipopolysaccharide-sensitized encephalopathy brain injury whereas it can be neuroprotective if a bacterial lipopolysaccharide-sensitized encephalopathy is not present. Hence, therapeutic hypothermia in the presence of infection might even be deleterious as hypothermia may impair innate immune function, including neutrophil migration and function. This chapter aims to discuss how an infective insult can affect the vulnerability of the neonatal brain to the hypoxic damage. We review whether newborns with encephalopathy and signs of neonatal sepsis are associated with a higher risk of neonatal brain injury and worse long-term neurodevelopmental outcome. Finally, we highlight new therapeutic strategies in this scenario.

Book chapter

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