Imperial College London

ProfessorSudhinThayyil

Faculty of MedicineDepartment of Brain Sciences

Professor of Perinatal Neuroscience
 
 
 
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Contact

 

+44 (0)20 3313 8515s.thayyil

 
 
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Location

 

529Hammersmith HouseHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

146 results found

Thayyil S, 2024, Sequential levetiracetam and phenytoin in electroencephalographic neonatal seizures unresponsive to phenobarbital: a multicenter prospective observational study in India, The Lancet Regional Health — Southeast Asia

Journal article

Montaldo P, Burgod C, Herberg JA, Kaforou M, Cunnington AJ, Mejias A, Cirillo G, Miraglia Del Giudice E, Capristo C, Bandiya P, Kamalarathnam CN, Chandramohan R, Manerkar S, Rodrigo R, Sumanasena S, Krishnan V, Pant S, Shankaran S, Thayyil Set al., 2024, Whole-blood gene expression profile after hypoxic-ischemic encephalopathy, JAMA Network Open, Vol: 7, ISSN: 2574-3805

Importance Induced hypothermia, the standard treatment for hypoxic-ischemic encephalopathy (HIE) in high-income countries (HICs), is less effective in the low-income populations in South Asia, who have the highest disease burden.Objective To investigate the differences in blood genome expression profiles of neonates with HIE from an HIC vs neonates with HIE from South Asia.Design, Setting, and Participants This case-control study analyzed data from (1) a prospective observational study involving neonates with moderate or severe HIE who underwent whole-body hypothermia between January 2017 and June 2019 and age-matched term healthy controls in Italy and (2) a randomized clinical trial involving neonates with moderate or severe HIE in India, Sri Lanka, and Bangladesh recruited between August 2015 and February 2019. Data were analyzed between October 2020 and August 2023.Exposure Whole-blood RNA that underwent next-generation sequencing.Main Outcome and Measures The primary outcomes were whole-blood genome expression profile at birth associated with adverse outcome (death or disability at 18 months) after HIE in the HIC and South Asia cohorts and changes in whole-genome expression profile during the first 72 hours after birth in neonates with HIE and healthy controls from the HIC cohort. Blood samples for RNA extraction were collected before whole-body hypothermia at 4 time points (6, 24, 48, and 72 hours after birth) for the HIC cohort. Only 1 blood sample was drawn within 6 hours after birth for the South Asia cohort.Results The HIC cohort was composed of 35 neonates (21 females [60.0%]) with a median (IQR) birth weight of 3.3 (3.0-3.6) kg and gestational age of 40.0 (39.0-40.6) weeks. The South Asia cohort consisted of 99 neonates (57 males [57.6%]) with a median (IQR) birth weight of 2.9 (2.7-3.3) kg and gestational age of 39.0 (38.0-40.0) weeks. Healthy controls included 14 neonates (9 females [64.3%]) with a median (IQR) birth weight of 3.4 (3.2-3.7) kg and

Journal article

Burgod C, Mazlan M, Pant S, Krishnan V, Garegrat R, Montaldo P, Muraleedharan P, Bandiya P, Kamalaratnam CN, Chandramohan R, Manerkar S, Jahan I, Moni SC, Shahidullah M, Rodrigo R, Sumanasena S, Sujatha R, Sathyanathan BP, Joshi AR, Pressler RR, Bassett P, Shankaran S, Thayyil Set al., 2024, Duration of birth depression and neurodevelopmental outcomes after whole-body hypothermia for hypoxic ischemic encephalopathy in India, Sri Lanka and Bangladesh – an exploratory analysis of the HELIX trial, Lancet Regional Health - Southeast Asia, Vol: 20, ISSN: 2772-3682

Background:Effect of duration of birth depression on neurodevelopmental outcomes in low- and middle-income countries (LMICs) is not known. We examined the association of birth depression with brain injury, neurodevelopmental outcomes, and hypothermia after hypoxic ischemic encephalopathy (HIE) in south Asia.Methods:We compared cerebral magnetic resonance (MR) at 2 weeks, and adverse outcomes (death or moderate or severe disability) at 18 months in 408 babies with moderate or severe HIE who had long birth depression (positive pressure ventilation (PPV) >10 min or Apgar score<6 at 10 min or cord pH < 7.0) and short birth depression (PPV for 5–10 min or Apgar score<6 at 5 min, but ≥6 at 10 min).Findings:Long depression group (n = 201) had more severe HIE (32.8% versus 6.8%), mortality (47.5% versus 26.4%), death or disability at 18 months (62.2% versus 35.4%) (all p < 0.001), MR injury (Odds ratio; 95% CI) to basal ganglia (2.4 (1.3, 4.1); p = 0.003), posterior limb of internal capsule (2.3 (1.3, 4.3); p < 0.001) and white matter (1.7 (1.1, 2.7); p = 0.021), and lower thalamic N-acetylaspartate levels (7.69 ± 1.84 versus 8.29 ± 1.60); p = 0.031) than short depression group (n = 207). Three babies had no heartbeat at 5 min, of which 1 died and 2 survived with severe disability. No significant interaction between the duration of birth depression and whole-body hypothermia was seen for any of the MR biomarker or clinical outcomes.Interpretation:Long birth depression was associated with more brain injury and adverse outcomes than short depression. Effect of hypothermia was not modified by duration of birth depression.

Journal article

Thayyil S, Montaldo P, Krishnan V, Ivain P, Pant S, Lally PJ, Bandiya P, Benkappa N, Kamalaratnam CN, Chandramohan R, Manerkar S, Mondkar J, Jahan I, Moni SC, Shahidullah M, Rodrigo R, Sumanasena S, Sujatha R, Burgod C, Garegrat R, Mazlan M, Chettri I, Babu Peter S, Joshi AR, Swamy R, Chong K, Pressler RR, Bassett P, Shankaran Set al., 2023, Whole-body hypothermia, cerebral magnetic resonance biomarkers, and outcomes in neonates with moderate or severe hypoxic-ischemic encephalopathy born at tertiary care centers vs other facilities: a nested study within a randomized clinical trial, JAMA Network Open, Vol: 6, Pages: 1-16, ISSN: 2574-3805

Importance The association between place of birth and hypothermic neuroprotection after hypoxic-ischemic encephalopathy (HIE) in low- and middle-income countries (LMICs) is unknown.Objective To ascertain the association between place of birth and the efficacy of whole-body hypothermia for protection against brain injury measured by magnetic resonance (MR) biomarkers among neonates born at a tertiary care center (inborn) or other facilities (outborn).Design, Setting, and Participants This nested cohort study within a randomized clinical trial involved neonates at 7 tertiary neonatal intensive care units in India, Sri Lanka, and Bangladesh between August 15, 2015, and February 15, 2019. A total of 408 neonates born at or after 36 weeks’ gestation with moderate or severe HIE were randomized to receive whole-body hypothermia (reduction of rectal temperatures to between 33.0 °C and 34.0 °C; hypothermia group) for 72 hours or no whole-body hypothermia (rectal temperatures maintained between 36.0 °C and 37.0 °C; control group) within 6 hours of birth, with follow-up until September 27, 2020.Exposure 3T MR imaging, MR spectroscopy, and diffusion tensor imaging.Main Outcomes and Measures Thalamic N-acetyl aspartate (NAA) mmol/kg wet weight, thalamic lactate to NAA peak area ratios, brain injury scores, and white matter fractional anisotropy at 1 to 2 weeks and death or moderate or severe disability at 18 to 22 months.Results Among 408 neonates, the mean (SD) gestational age was 38.7 (1.3) weeks; 267 (65.4%) were male. A total of 123 neonates were inborn and 285 were outborn. Inborn neonates were smaller (mean [SD], 2.8 [0.5] kg vs 2.9 [0.4] kg; P = .02), more likely to have instrumental or cesarean deliveries (43.1% vs 24.7%; P = .01), and more likely to be intubated at birth (78.9% vs 29.1%; P = .001) than outborn neonates, although the rate of severe HIE was not different (23.6% vs 17.9%; P =&thin

Journal article

Montaldo P, Thayyil S, 2023, Hippocampus and hypothermia: a missing link, Developmental Medicine and Child Neurology, Vol: 65, Pages: 303-304, ISSN: 0012-1622

Journal article

Krishnan V, Kumar V, Vegda H, Ujjanappa V, Manari A, Vellani Thamunni A, Thottoli Puthiyapurayil A, Devadas S, Fattepur S, Basett P, Thayyil Set al., 2022, Development and validation of a neonatal physical maturity score for low- and middle- income countries., American Journal of Perinatology: neonatal and maternal-fetal medicine, ISSN: 0735-1631

Currently available gestational age scoring systems are complex and inaccurate for wider use in low and middle-income countries(LMIC), particularly in infants with neonatal encephalopathy. Here we developed a scoring system based on physical characteristics for identifying late preterm infants from term infants. In the first phase, we examined the accuracy of 10 objective physical characteristics in a prospective cohort of 1006 babies recruited from three hospitals in South India. A weighted scoring system and a photo card were then developed based on the six best performing characteristics, which was validated in another prospective cohort of 1004 babies. The final score had a sensitivity of 66.0%, (95% Confidence intervals (CI), 58.4%-73.8%), specificity of 80.0%, (95% CI, 77.2%-82.7%) and a negative predictive value of 93.0%, (95%CI, 90.5%-94.5%). This scoring system may have wider applications in low and middle-income countries, particularly in community settings and in infants with neonatal encephalopathy.

Journal article

Thayyil S, Shankaran S, 2022, Rise and fall of therapeutic hypothermia in low-resource settings: lessons from the HELIX trial: authors’ reply, Indian Journal of Pediatrics, Vol: 89, Pages: 311-313, ISSN: 0019-5456

Journal article

Song Y, Lally PJ, Lopez MY, Oeltzschner G, Nebel MB, Gagoski B, Kecskemeti S, Hui SCN, Zollner HJ, Shukla D, Arichi T, De Vita E, Yedavalli V, Thayyil S, Fallin D, Dean DC, Grant PE, Wisnowski JL, Edden RAEet al., 2022, Edited magnetic resonance spectroscopy in the neonatal brain, NEURORADIOLOGY, Vol: 64, Pages: 217-232, ISSN: 0028-3940

Journal article

Shankaran S, Laptook A, Thayyil S, 2022, Hypothermia for neonatal encephalopathy: how do we move forward?, ARCHIVES OF DISEASE IN CHILDHOOD-FETAL AND NEONATAL EDITION, Vol: 107, Pages: 4-5, ISSN: 1359-2998

Journal article

Thayyil S, Shankaran S, 2022, From Therapeutic Hypothermia to Targeted Temperature Management in Low-Resource Settings, INDIAN PEDIATRICS, Vol: 59, Pages: 9-10, ISSN: 0019-6061

Journal article

Thayyil S, Bassett P, Shankaran S, 2021, Questions about the HELIX trial, LANCET GLOBAL HEALTH, Vol: 9, Pages: E1654-E1655, ISSN: 2214-109X

Journal article

Burgod C, Pant S, Morales MM, Montaldo P, Ivain P, Elangovan R, Bassett P, Thayyil Set al., 2021, Effect of intra-partum Oxytocin on neonatal encephalopathy: a systematic review and meta-analysis, BMC Pregnancy and Childbirth, Vol: 21, Pages: 1-7, ISSN: 1471-2393

BackgroundOxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy.MethodsThe protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (≥36 weeks’ gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals.ResultsWe included data from seven studies (6 Case-control studies, 1 cluster-randomised trial) of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36 weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; p < 0.00001).ConclusionsIntra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.

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, Vol: 106, Pages: 669-672, 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

Thayyil S, Pant S, Montaldo P, 2021, Hypothermia for moderate or severe neonatal encephalopathy in low-income and middle-income countries (HELIX): a randomised controlled trial in India, Sri Lanka, and Bangladesh (vol 9, pg e1273, 2021), LANCET GLOBAL HEALTH, Vol: 9, Pages: E1371-E1371, ISSN: 2214-109X

Journal article

Jenkins DD, Moss HG, Brown TR, Yazdani M, Thayyil S, Montaldo P, Vento M, Kuligowski J, Wagner C, Hollis BW, Wiest DBet al., 2021, Nac and vitamin d improve cns and plasma oxidative stress in neonatal hie and are associated with favorable long-term outcomes, Antioxidants, Vol: 10, Pages: 1-21, ISSN: 2076-3921

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal mod-els of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

Journal article

Pant S, Elias MA, Woolfall K, Thayyil Set al., 2021, OP23 Parental consent for time-critical neonatal trials in low and middle-income countries: is it truly informed? FREE, SSM Annual Scientific Meeting, Publisher: BMJ Publishing Group, Pages: A11-A11, ISSN: 0143-005X

Background Parental consent rates for neonatal interventional trials are significantly higher in Low and middle-income countries (LMIC) than in high-income countries, raising concerns about the credibility of the consent processes (Patterson et al PLOS One 2021). We conducted a mixed-methods study to understand the informed consent process in a neonatal cooling trial [Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial] conducted in India, Sri Lanka and Bangladesh.Methods Term infants with neonatal encephalopathy, aged less than six hours were randomly allocated to cooling therapy or usual care, following informed parental consent. The consenting process was audio-video (A-V) recorded in all cases. We analysed the A-V records of the consent process using a 5-point Likert scale on three parameters – Empathy, Information, Autonomy. Additionally, we used exploratory observation method to capture relevant aspects of consent process and discussions between parents and professionals. Finally, we conducted in-depth interviews with a subgroup of 20 parents and 15 health care professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts.Results In HELIX trial, a total of 475 parents were approached, of which 408 (86%) consented. Of these, 294 A-V records were analysed. Median (Interquartile range) score for empathy, information, autonomy was 5 (0), 5 (1) and 5 (1) respectively. However, thematic analysis suggested that the parental decision to participate was based on a unreserved trust in the treating doctors, therapeutic misconception, and access to an expensive treatment free of cost. Most parents did not understand the concept of a clinical trial, nor the nature of the intervention. Lower levels of parental education and misinformation further convoluted the voluntary informed consent process. Parents were visibly incapacitated, and many told the doctor to do whatever is best for the

Conference paper

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

Krishnan V, Kumar V, Variane GFT, Carlo WA, Bhutta ZA, Sizonenko S, Hansen A, Shankaran S, Thayyil S, Newborn Brain Society Guidelines and Publications Committeeet al., 2021, Need for more evidence in the prevention and management of perinatal asphyxia and neonatal encephalopathy in low and middle-income countries: A call for action., Seminars in Fetal and Neonatal Medicine, Vol: 26, Pages: 101271-101271, ISSN: 1084-2756

Although low- and middle-income countries (LMICs) shoulder 90 % of the neonatal encephalopathy (NE) burden, there is very little evidence base for prevention or management of this condition in these settings. A variety of antenatal factors including socio-economic deprivation, undernutrition and sub optimal antenatal and intrapartum care increase the risk of NE, although little is known about the underlying mechanisms. Implementing interventions based on the evidence from high-income countries to LMICs, may cause more harm than benefit as shown by the increased mortality and lack of neuroprotection with cooling therapy in the hypothermia for moderate or severe NE in low and middle-income countries (HELIX) trial. Pooled data from pilot trials suggest that erythropoietin monotherapy reduces death and disability in LMICs, but this needs further evaluation in clinical trials. Careful attention to supportive care, including avoiding hyperoxia, hypocarbia, hypoglycemia, and hyperthermia, are likely to improve outcomes until specific neuroprotective or neurorestorative therapies available.

Journal article

Krishnan V, Kumar V, Shankaran S, Thayyil Set al., 2021, Rise and fall of therapeutic hypothermia in low resource settings: Lessons from the HELIX trial, Indian Journal of Pediatrics, ISSN: 0019-5456

In the past decade, therapeutic hypothermia using a variety of low-cost devices has been widely implemented in India and other low-and middle-income countries (LMIC) without adequate evidence of either safety or efficacy. The recently reported data from the world’s largest cooling trial (HELIX - hypothermia for encephalopathy in low- and middle-income countries) in LMIC provides definitive evidence of harm of cooling therapy with increase in mortality (number to harm 9) and lack of neuroprotection. Although the HELIX participating centers were highly selected tertiary neonatal intensive care units in South Asia with facilities for invasive ventilation, cardiovascular support, and 3 Tesla magnetic resonance imaging (MRI), and the trial used state-of-the-art automated servo-controlled cooling devices, a therapy that is harmful under such optimal conditions cannot be safe in low-resource settings that cannot even afford servo-controlled cooling devices.The HELIX trial has set a new benchmark for conducting high quality randomized controlled trials in terms of research governance, consent, ethics, follow-up rates, and involvement of parents. The standard care for neonatal encephalopathy in LMIC should remain normothermia, with close attention to prevention of hyperthermia. There is no role for therapeutic hypothermia in LMIC as the efficacy of hypothermia is dependent on the population, and not merely on the level of neonatal intensive care facilities. Future research should explore timings and origins of brain injury and prevention of brain injury in LMIC, with a strong emphasis on academic research capacity building and patient and public engagement.

Journal article

Kumar V, Singla M, Thayyil S, 2021, Cooling in mild encephalopathy: Costs and perils of therapeutic creep, Seminars in Fetal and Neonatal Medicine, Vol: 26, ISSN: 1084-2756

Increasing confidence in therapeutic hypothermia and ambiguity of cooling guidelines has led to many clinicians extending its use to untested populations like mild encephalopathy, or even no encephalopathy. Poor quality clinical neurological examination for encephalopathy staging coupled with a fear of litigation if a baby with mild encephalopathy progress to moderate or severe encephalopathy appears to be the primary driver for this therapeutic creep. Recent data suggesting increased apoptosis with cooling uninjured brains, and lack of hypothermic neuroprotection in partial prolonged hypoxia, implies that such therapeutic creeps may cause more harm than benefit. Currently available preclinical and clinical data do not support the clinical use of therapeutic hypothermia for mild encephalopathy, although phase II clinical trials are ongoing. We recommend that until further evidence from adequately powered randomised controlled trials are available, cooling in mild encephalopathy need to be considered experimental and parental consent should be obtained before providing this therapy.

Journal article

Pant S, 2021, Parental and professional perceptions of informed consent and participation in a time-critical neonatal trial in Low and Middle-income countries: A mixed methods study, BMJ Global Health, Vol: 6, Pages: 1-9, ISSN: 2059-7908

Introduction Time-critical neonatal trials in low-and-middle-income countries (LMICs) raise several ethical issues. Using a qualitative-dominant mixed-methods design, we explored informed consent process in Hypothermia for encephalopathy in low and middle-income countries (HELIX) trial conducted in India, Sri Lanka and Bangladesh.Methods Term infants with neonatal encephalopathy, aged less than 6 hours, were randomly allocated to cooling therapy or usual care, following informed parental consent. The consenting process was audio-video (A-V) recorded in all cases. We analysed A-V records of the consent process using a 5-point Likert scale on three parameters—empathy, information and autonomy. In addition, we used exploratory observation method to capture relevant aspects of consent process and discussions between parents and professionals. Finally, we conducted in-depth interviews with a subgroup of 20 parents and 15 healthcare professionals. A thematic analysis was performed on the observations of A-V records and on the interview transcripts.Results A total of 294 A-V records of the HELIX trial were analysed. Median (IQR) score for empathy, information and autonomy was 5 (0), 5 (1) and 5 (1), respectively. However, thematic analysis suggested that the consenting was a ceremonial process; and parental decision to participate was based on unreserved trust in the treating doctors, therapeutic misconception and access to an expensive treatment free of cost. Most parents did not understand the concept of a clinical trial nor the nature of the intervention. Professionals showed a strong bias towards cooling therapy and reported time constraints and explaining to multiple family members as key challenges.Conclusion Despite rigorous research governance and consent process, parental decisions were heavily influenced by situational incapacity and a trust in doctors to make the right decision on their behalf. Further research is required to identify culturally and

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

Jones D, Taha S, Jones MS, Bauserman M, Pant S, Bose C, Thayyil S, Patterson JK, Montaldo Pet al., 2021, Informed Consent Rates For Neonatal Randomized Controlled Trials In Low And Lower-Middle Income Countries Versus High-Income Countries: A Systematic Review, Publisher: AMER ACAD PEDIATRICS, ISSN: 0031-4005

Conference paper

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

Cartwright JH, Aziz Q, Harmer SC, Thayyil S, Tinker A, Munroe PBet al., 2020, Genetic variants in TRPM7 associated with unexplained stillbirth modify ion channel function, Human Molecular Genetics, Vol: 29, Pages: 1797-1807, ISSN: 0964-6906

INTRODUCTION: Stillbirth is the loss of a foetus after 22 weeks of gestation, of which almost half go completely unexplained despite post-mortem. We recently sequenced 35 arrhythmia-associated genes from 70 unexplained stillbirth cases. Our hypothesis was that deleterious mutations in channelopathy genes may have a functional effect in utero that may be pro-arrhythmic in the developing foetus. We observed four heterozygous, nonsynonymous variants in TRPM7, a ubiquitously expressed ion channel known to regulate cardiac development and repolarisation in mice. METHODS: We used site-directed mutagenesis and single-cell patch-clamp to analyse the functional effect of the four stillbirth mutants on TRPM7 ion channel function in heterologous cells. We also used cardiomyocytes derived from human pluripotent stem cells to model the contribution of TRPM7 to action potential morphology. RESULTS: Our results show that two TRPM7 variants, p.G179V and p.T860M lead to a marked reduction in ion channel conductance. This observation was underpinned by a lack of measurable TRPM7 protein expression, which in the case of p.T860M was due to rapid proteasomal degradation. We also report that human hiPSC-derived cardiomyocytes possess measurable TRPM7 currents, however siRNA knockdown did not directly affect action potential morphology. CONCLUSION: TRPM7 variants found in the unexplained stillbirth population adversely affect ion channel function and this may precipitate fatal arrhythmia in utero.

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

Thayyil S, 2019, Cooling therapy for the management of hypoxic-ischaemic encephalopathy in middle-income countries: we can, but should we?, Paediatrics and International Child Health, Vol: 39, Pages: 231-233, ISSN: 2046-9047

In the past decade a large number of studies of cooling for the treatment of hypoxic-ischaemic encephalopathy have been reported from middleincome countries (MIC), yet credible evidence of its safety and efficacy is still lacking. Although cooling therapy should not be considered in settings which lack basic neonatal care, many neonatal units in India and other MIC have excellent tertiary neonatal intensive care facilities. Most of these centres now routinely offer cooling therapy in clinical practice using a wide range of devices including ice and phase-change material (PCM). A large trial (HELIX: Hypothermia for Encephalopathy in Low- and Middle-Income Countries) involving 408 infants with moderate and severe encephalopathy in seven tertiary academic neonatal units in India, Sri Lanka and Bangladesh recently completed recruitment, and assessment of the neurodevelopmental outcome is ongoing. Considering the differences in population co-morbidities and the strong association between increased neonatal mortality and hypothermia, it would be prudent for clinicians in tertiary neonatal units in MIC to await the results of the HELIX trial before offering cooling therapy as standard care.

Journal article

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