Neurological outcomes in neonates treated with therapeutic hypothermia: challenges in a developing country

Abstract

Background Hypoxic-ischemic encephalopathy (HIE) affects 1.5 newborns per 1 thousand term live births. Therapeutic hypothermia (TH) does not prevent all adverse outcomes. The experience with TH is still limited in Latin America. In Rio de Janeiro, Hospital Universitário Pedro Ernesto treats neonates with HIE since 2017 using the servo-controlled system.

Objective To describe the frequency of epilepsy, altered neurological exam, and neurodevelopmental delay at 12 months of age in patients treated with TH in a reference hospital in Rio de Janeiro and to evaluate the possible risk associations with clinical data and data from complementary exams.

Methods We evaluated medical records from the Neonatal Intensive Care Unit hospitalization and from first evaluation recorded at 12 months of age in the High-Risk Neonate Follow-up Outpatient Sevice.

Results A total of 30 subjects were included in the study. We found epilepsy in 18.2% of the patients, altered neurological exam in 40.9%, and neurodevelopmental delay in 36.4%. We also found a significant relationship between altered magnetic resonance imaging scan and subsequent altered neurological exam. Our findings are in line with those of the international literature, which shows that adverse outcomes are still observed, even when TH is applied. Brazilian data shows our limited access to complementary exams. The rate of loss to follow-up was of 26.6%, probably due to the coronavirus disease 2019 (COVID-19) pandemic and to unfavorable socioeconomic conditions. More time for prospective follow-up and protocol adjustments should contribute to improve our data.

Conclusion High incidences of epilepsy, altered neurological exams, and neurodevelopmental delay were found, despite the use of TH. A more efficient use of resources is needed, as well as measures such as early intervention.

Resumo

Antecedentes A encefalopatia hipóxico-isquêmica (EHI) afeta 1,5 a cada mil nascidos vivos a termo. A hipotermia terapêutica (HT) não previne todos os desfechos negativos. A experiência com HT ainda é limitada na América Latina. No Rio de Janeiro, o Hospital Universitário Pedro Ernesto trata neonatos com EHI desde 2017 usando o sistema servo-controlado.

Objetivo Relatar a frequência de epilepsia, de alteração em exame neurológico e de atraso no desenvolvimento neuropsicomotor aos 12 meses de idade nos pacientes submetidos a HT em um hospital de referência no estado do Rio de Janeiro e avaliar as associações de risco com dados clínicos e de exames complementares.

Métodos Foi feita análise de dados do prontuário médico da internação na UTI Neonatal e da primeira avaliação registrada a partir de 12 meses completos de idade no Ambulatório de Seguimento de Recém-Nascido de Alto Risco.

Resultados Ao todo, 30 pacientes foram incluídos. As frequências de epilepsia, de alteração em exame neurológico e de atraso no desenvolvimento neuropsicomotor aos 12 meses de idade foram, respectivamente, de 18,2%, 40,9% e 36,4%. Observamos relação significativa entre alteração na ressonância magnética e posterior alteração no exame neurológico. Nossos achados corroboram a literatura internacional, em que desfechos desfavoráveis ocorrem mesmo aplicando-se HT. Dados brasileiros mostram a limitação da disponibilidade dos exames complementares. Houve perda de seguimento de 26,6%, provavelmente pela pandemia da doença do coronavírus 2019 (coronavirus disease 2019, COVID-19, em inglês) e condições socioeconômicas desfavoráveis. Mais tempo de seguimento e ajustes no protocolo devem contribuir para melhorar nossos dados.

Conclusão Foram encontradas elevadas incidências de epilepsia, de exame neurológico alterado e de atraso no neurodesenvolvimento, apesar da HT. Faz-se necessário uso mais eficiente dos recursos disponíveis, bem como de medidas como intervenção precoce.

Keywords

Hypoxia, Brain - Hypothermia, Induced - Neurologic Examination - Developmental Disabilities - Epilepsy

Palavras-chave

Hipóxia Encefálica - Hipotermia Induzida - Exame Neurológico - Deficiências do Desenvolvimento - Epilepsia

INTRODUCTION

Hypoxic-ischemic encephalopathy (HIE) affects 1.5 per 1 thousand term live births.[1] Its severity is associated with worse morbidity and mortality,[2] and it is also the first cause of neonatal seizures, despite therapeutic hypothermia (TH).[3]

The developmental delay indices in neonates treated with therapeutic hypothermia are of approximately 23%.[1] Before TH, the impairment rates were high, ranging from 42 to 100% in severe HIE.[4]

Unfortunately, TH still does not prevent all adverse outcomes, maybe due to delay in cooling, severe lesions, or incorrect diagnosis.[1] The risk of neonatal electroclinical or electrographic seizures varies from 50 to 83%, even in treated patients. The more antiseizure medicines (ASMs) needed, the worse the outcome.[5]

Experience with TH is still limited in Latin America, with very few Brazilian publications about the subject. In Rio de Janeiro, Hospital Universitário Pedro Ernesto treats neonates with HIE since 2017, using a servo-controlled system. Reporting experience is important to disseminate results, to look forward to local improvement and to encourage other institutions to engage in the cause.

The present study aimed to describe the frequency of epilepsy, altered neurological exam, and neurodevelopmental delay at 12 months of age in patients treated with TH at Hospital Universitário Pedro Ernesto, Rio de Janeiro.

We also aimed to evaluate possible associations involving the outcomes and blood pH at the first hour of life, number of ASMs needed to control the seizures, electroencephalographic (EEG) abnormalities and early changes in imaging, transfontanellar ultrasound (TFUS), and computed tomography (CT) or magnetic resonance (MRI) scans, when available.

METHODS

The present study was ethically approved under CAAE36862820.4.0000.5258 (Plataforma Brasil), and it was granted waiver of consent term due to its retrospective design.

Our sample included patients who were referred to the Neonatal Intensive Care Unit (NICU), underwent TH for HIE from March 2017 to July 2019, and were followed up in the High-Risk Neonate Follow-up Outpatient Service.

The institutional TH protocol was based essentially on a Portuguese consensus,[6] where the team was trained, and references are available in the same document.

The criteria for TH were:

• Thompson Encephalopathy Score[7] higher than 7, according to the trained NICU team, which included mild, moderate, and severe encephalopathy (the score is easy to fill out, and it is based on newborn tone, consciousness, fits, posture, the Moro, grasp, and suction reflexes, respiration, and fontanelle, as shown in [Table 1]);

• Acidosis (pH lower than 7.0 or base excess lower than -16 in the first hour of life), or minor acidosis (pH between 7.0 and 7.15, or base excess between -10 and -15) with a history of hipoxic-ischemic acute event and need of positive pressure ventilation by the tenth minute, or need of ventilation or Apgar Score lower than 6, or need of positive pressure ventilation by the tenth minute if there were no gasometer of first hour of life; and

• No exclusion criteria (gestational age < 35 weeks, birth weight < 1,800 g, congenital malformations incompatible with life, more than 24 hours of life).

Table 1 Thompson Encephalopathy Score

Sign	Score
	0	1	2	3
Tone	Normal	Hyper	Hypo	Flaccid
Level of consciousness	Normal	Hyperalert	Lethargic	Comatose
Fits	None	Infrequent < 3/day	Frequent > 2/day
Posture	Normal	Fisting/cycling	Strong distal flexion	Decerebrate
Moro reflex	Normal	Partial	Absent
Grasp	Normal	Poor	Absent
Sucking reflex	Normal	Poor	Absent ± bites
Respiration	Normal	Hyperventilation	Brief apnea	Intermittent positive pressure ventilation (apnea)
Fontanel	Normal	Full, not tense	Tense

Notes: 0–7 = no encephalopathy; 8–10 = mild encephalopathy; 11–14 = moderate encephalopathy; 15-22 = severe encephalopathy.

A servo-controlled whole-body cooling (WBC) technique was used to perform TH, to obtain 33.5°C ± 0.5°C, monitored by an esophageal and a rectal thermometer, and also by a cutaneous sensor. Continuous cardiorespiratory monitoring was employed, and TH was maintained for 72 hours, ideally started in the first 6 hours of life. Rewarming was of 0.2°C for each 30 minutes, until reaching temperatures ranging from 26.0 to 36.5°C.

The medical records were reviewed for: sex; gestational age; delivery method; weight for gestational age classification; Apgar score; clinical and laboratory evidence of HIE; Thompson Encephalopathy Score (mild, moderate, or severe encephalopathy); blood pH at the first hour; seizure occurrence during hospitalization; electroencephalogram (EEG) pattern; use of ASMs; and imaging reports.

For the purpose of statistical analysis, the EEG was classified by the authors as not specific if there was no epileptic activity; mildly abnormal, when focal epileptic activity was present; and severely abnormal, when there was multifocal epileptic activity, discontinuous trace or other critical findings, such as burst-suppression pattern or undifferentiated pattern.

The patients were categorized into a group that received up to one ASM and a group that received more than one ASM. The decision to prescribe ASMs was essentially based on clinical suspicion of seizure, since there was no continuous EEG monitoring available. The first ASM used was phenobarbital, and if there was no clinical improvement, the second-line options were phenytoin or midazolam (preferable if there was myocardial dysfunction). Other options included lidocaine, levetiracetam, and clonazepam, according to availability and seizure pattern.

The MRI scans were performed between the fifth and fourteenth days of birth. The results were classified as normal, mildly abnormal (if there were signs of hemorrhage and white matter or watershed lesions), and severely abnormal (if there were thalamus and basal ganglia lesions).

We also collected data from the follow-up at 12 months of age, including: history of seizures after the neonatal period; use of ASMs; EEG pattern; changes in standardized neurological exam according to the Amiel-Tison assessment;[8] [9] and neurodevelopmental delay according to Denver Developmental Screening Test II (domains: gross motor skills, language skills, fine motor skills and adaptative behavior, and personal-social skills).[10]

Through the Amiel-Tison assessment, physicians can easily evaluate the neuromotor behavior of term babies by describing developmental patterns from the 28th gestational week until the end of first year of extrauterine life, with an extension until 6 years. It includes observation of skull, tone, primary reflexes, posture, and movement. The child is classified as normal, abnormal or suspect, and the abnormality is classified as mild, moderate or severe.[8] [9] The Denver Developmental Screening Test II assesses the development of children between 0 to 6 years of age, and it presents good intra- and interexaminer reliability and fast application.[11] The Amiel-Tison assessment and the Denver Developmental Screening Test II were applied by the trained medical team at the High-Risk Neonate Follow-up Outpatient Service during the consultation at 12 months of age.

The outcomes studied were epilepsy following the International League Against Epilepsy (ILAE) 2017 criteria; altered neurological exam according to the systematic exam proposed by Amiel-Tison;[9] and neurodevelopmental delay in at least one domain of the Denver Developmental Screening Test II.[10]

The statistical analysis included the Fisher exact test and the Wilcoxon test. All analyses were conducted using the R (R Foundation for Statistical Computing, Vienna, Austria) software, version 2023.06.0, considering statistical significance of 5%.

RESULTS

In total, 30 (19 male and 11 female) patients were included in the study, and all of them were submitted to TH. Their clinical characteristics are summarized in [Table 2]. One patient (3.3%) did not have seizures and received no ASM; 15 patients (50%) needed only one ASM (phenobarbital); and 14 (46.7%) received 2 or 3 medications.

Table 2 Features of patients submitted to TH to treat HIE

Features		N (%)	Mean ± SD	Median (IQR)
Clinico-laboratory characteristics
Sex	Male	19 (63.3)
	Female	11 (36.7)
Route of delivery	Vaginal	18 (60.0)
	Cesarean	12 (40.0)
Weight for gestational age	Big	4 (13.3)
	Appropriate	24 (80.0)
	Small	2 (6.7)
Apgar 5th minute			3.6 ± 1.7	4.0 (3.0–4.0)
Thompson Encephalopathy Score	Mild	9 (30.0)
	Moderate	15 (50.0)
	Severe	6 (20.0)
First-hour pH			7.16 ± 0.2	7.18 (7–7.3)
Early seizure		29 (96.7)
Antiseizure drugs	None or one	16 (53.3)	1.5 ± 0.7	1.0 (1.0–2.0)
	Two or more	14 (46.7)
Complementary Exams
Electroencephalogram	Not specific	22 (75.9)
	Mildly abnormal	3 (10.3)
	Severely abnormal	4 (13.8)
Transfontanellar ultrasound	Normal	18 (64.3)
	Altered	10 (35.7)
Computed tomography	Normal	4 (36.4)
	Altered	7 (63.6)
Magnetic resonance imaging	Normal	7 (50.0)
	Mildly abnormal	4 (28.6)
	Severely abnormal	3 (21.4)

Abbreviations: HIE, hypoxic-ischemic encephalopathy; IQR, interquartile range; SD, standard deviation; TH, therapeutic hypothermia.

Most EEG records (n = 22; 75.9%) had no epileptogenic discharges; 3 patients (10.3%) had focal epileptic discharges (mildly abnormal); and 4 (13.8%) had multifocal epileptic activity or discontinuous trace (severely abnormal). One patient had no EEG record because of equipment unavailability. Amplitude-integrated electroencephalography (aEEG) monitoring was not available at that time.

Most TFUS (n = 18; 64.3%) were normal; the abnormal findings included hyperechogenicity, hemorrhage, or ventricular dilatation. Two patients were not submitted to TFUS because of staff unavailability, but they were submitted to a timely MRI scan.

Only 14 patients were submitted to an MRI scan, and half of them presented no lesions (n = 7; 50%). In total, 11 patients underwent a CT scan, mostly patients who were not submitted to MRI. Overall, imaging from 7 children showed no abnormalities.

The follow-up was completed by 22 patients. The outcomes in this group are listed in [Table 3]. We found epilepsy in 18.2% of the patients, altered neurological exam, in 40.9%, and neurodevelopmental delay, in 36.4%. The most affected developmental domains were gross motor and language skills, followed by fine motor skills and adaptative behavior, and then, personal-social skills.

Table 3 Neurological outcomes of patients submitted to TH to treat HIE, stratified by encephalopathy severity

Neurological outcomes: n (%)		N = 22	Thompson Encephalopathy Score
			Mild (N = 6)a	Moderate (N = 12)a	Severe (N = 4)a	p-valueb
Epilepsy	No	18 (82%)	5 (83%)	10 (83%)	3 (75%)	> 0.9
	Yes	4 (18%)	1 (17%)	2 (17%)	1 (25%)
Neurological exam	Normal	13 (59%)	4 (67%)	7 (58%)	2 (50%)	> 0.9
	Altered	9 (41%)	2 (33%)	5 (42%)	2 (50%)
Gross motor skills	Normal	15 (68%)	5 (83%)	8 (67%)	2 (50%)	0.6
	Altered	7 (32%)	1 (17%)	4 (33%)	2 (50%)
Language skills	Normal	15 (68%)	5 (83%)	8 (67%)	2 (50%)	0.6
	Altered	7 (32%)	1 (17%)	4 (33%)	2 (50%)
Fine motor skills and adaptative behavior	Normal	16 (73%)	5 (83%)	9 (75%)	2 (50%)	0.7
	Altered	6 (27%)	1 (17%)	3 (25%)	2 (50%)
Personal-social skills	Normal	17 (77%)	5 (83%)	10 (83%)	2 (50%)	0.4
	Altered	5 (23%)	1 (17%)	2 (17%)	2 (50%)
Delay in at least one domain of the Denver Developmental Screening Test II	No	14 (64%)	5 (83%)	7 (58%)	2 (50%)	0.6
	Yes	8 (36%)	1 (17%)	5 (42%)	2 (50%)

Abbreviations: HIE, hypoxic-ischemic encephalopathy; TH, therapeutic hypothermia.

Notes: ^aN (%); ^bFisher exact test.

We did not find associations regarding the outcomes and the Thompson Encephalopathy Score, even when stratified by gravity (mild, moderate and severe encephalopathy), as shown in [Table 3].

Neither were there associations involving the outcomes and the first-hour pH, electroencephalographic changes or the number of ASM needed. The radiological findings in the head CT and MRI scans were associated to future altered neurological exam. [Table 4] summarizes these results.

Table 4 Patient characteristics and outcomes after TH

		Epilepsy		p-value	Neurological exam		p-value	Neurodevelopment delay		p-value
		No (n = 18; 81.8%)	Yes (n = 4; 18.2%)		Normal (n = 13; 59.1%)	Altered (n = 9; 40.9%)		None (n = 14; 63.6%)	One or more domains (n = 8; 36.4%)
Clinico-laboratory characteristics
Sex: n (%)	Female	10 (55.6)	1 (25.0)		9 (69.2)	2 (22.2)	0.081	8 (57.1)	3 (37.5)	0.659
	Male	8 (44.4)	3 (75.0)		4 (30.8)	7 (77.8)		6 (42.9)	5 (62.5)
Route of birth: n (%)	Vaginal	8 (44.4)	2 (50.0)		6 (46.2)	6 (37.5)	0.415	7 (50.0)	5 (62.5)	0.675
	Cesarean	10 (55.6)	2 (50.0)		7 (53.8)	3 (66.6)		7 (50.0)	3 (37.5)
Thompson Encephalopathy Score: n (%)	Mild	5 (27.8)	1 (25.0)		4 (30.7)	2 (22.2)	1.000	5 (35.7)	1 (12.5)	0.588
	Moderate	10 (55.6)	2 (50.0)		7 (53.8)	5 (55.5)		7 (50.0)	5 (62.5)
	Severe	3 (16.7)	1 (25.0)		2 (15.4)	2 (.22.2)		2 (14.3)	2 (25.0)
1st hour pH*: mean ± SD		7.17 ± 0.1	7.04 ± 0.2	0.249	7.17 ± 0.1	7.10 ± 0.2	0.332	7.14 ± 0.2	7.16 ± 0.2	0.682
Seizure: n (%)	Yes	17 (94.4)	4 (100.0)		12 (92.3)	9 (100.0)	1.000	13 (92.9)	8 (100.0)	1.000
	No	1 (5.6)	0 (0.0)		1 (7.7)	0 (0.0)		1 (7.1)	0 (0.0)
ASM: n (%)	0–1	11 (61.1)	1 (25.0)		9 (69.2)	3 (33.3)	0.192	10 (71.4)	2 (25.0)	0.074
	2–3	7 (38.9)	3 (75.0)		4 (30.8)	6 (66.7)		4 (28.6)	6 (75.0)
Complementary exams
EEG: n (%)	Not specific	15 (88.2)	2 (50.0)		11 (91.7)	6 (66.7)	0.404	12 (85.7)	5 (71.4)	0.194
	Mildly abnormal	2 (11.8)	0 (0.0)		1 (8.3)	1 (11.1)		2 (14.3)	1 (14.3)
	Severely abnormal	0 (0.0)	2 (50.0)		0 (0.0)	2 (22.2)		0 (0.0)	1 (14.3)
TFUS: n (%)	Normal	12 (66.7)	1 (33.3)		5 (38.5)	3 (37.5)	1.000	6 (42.9)	2 (28.6)	0.656
	Altered	6 (33.3)	2 (66.7)		8 (61.5)	5 (62.5)		8 (57.1)	5 (71.4)
Head CT: n (%)	Normal	4 (57.1)	0 (0.0)		2 (50.0)	2 (33.3)	0.048	2 (66.7)	2 (28.6)	0.500
	Altered	3 (42.9)	3 (100.0)		2 (50.0)	4 (66.7)		1 (33.3)	5 (71.4)
MRI: n (%)	Normal	5 (62.5)	0 (0.0)		5 (83.3)	0 (0.0)	0.047	5 (62.5)	0 (0.0)	0.444
	Mildly abnormal	2 (25.0)	0 (0.0)		1 (16.7)	1 (33.3)		2 (25.0)	0 (0.0)
	Severely abnormal	1 (12.5)	1 (100.0)		0 (0.0)	2 (66.7)		1 (12.5)	1 (100.0)

Abbreviations: ASM, antiserizure medication; CT, computed tomography; EEG, electreoencephalogram; MRI, magnetic resonance imaging; SD, standard deviation; TFUS, trasnsfontenellar ultrasound; TH, therapeutic hypothermia.

Note: *Wilcoxon test.

In the sample of the present study, 10 patients presented at least 1 unfavorable outcome at 12 months of age.

DISCUSSION

Despite our limited number of cases and all of the challenges regarding the follow-up in our population, our main findings show that, unfortunately, adverse outcomes are still observed, even when TH is applied, which is in accordance with the international literature.[1] [3] [4]

We observed that almost every patient in our case series had seizures, which shows the severity of the hypoxic-ischemic damage, but also points out the need for staff training and early treatment, as well as adequate EEG monitoring to optimize management.

We found a higher incidence of symptomatic seizures when compared to other studies that have reported seizures in 50 to 83% of asphyxic children.[1] [5] [12] This number might be overestimated, since we only had clinical suspicion in most cases. Unfortunately, continuous EEG monitoring was not available for our patients. Previous works[1] show that clinical evaluation alone without neuromonitoring can both overestimate and underestimate the burden of seizures.

Still, seizures in the neonatal period are not related to epilepsy in the first year of life, but they reflect the acute injury to these newborns. In contrast, requiring more ASMs to control seizures has been previously described as associated to poor outcomes.[1] We did not find an association, probably due to the small size of sample and to our limited evaluation to diagnose seizures, since we only used clinical parameters.

The EEG also has prognostic value. Normal pattern or early normalization suggests a good outcome. More severe and persistent changes are associated with moderate-to-severe lesions, death, and disability.[1] [13] Maybe with aEEG available and a bigger sample, we can better study this association.

Approximately 15 to 16% of treated children have a diagnosis of epilepsy at 18 months of age. Small studies[5] have suggested that this incidence might be higher at school age. According to the literature,[14] blood acidity, burst suppression on the fourth day of life and gray matter lesion on MRI on the seventh day of life seem to be associated with epilepsy.

Magnetic resonance imaging is indicated in all children to confirm the diagnosis of HIE and to assess prognosis.[1] [15] Unfortunately, routine MRI is not yet readily available in Brazil. Barkovich et al.[16] proposed a classification based in lesion pattern, in which basal ganglia and thalamus lesions are associated with cerebral palsy. Watershed lesions have a better prognosis.[1] Still, normal MRI is not exclusively associated with normal cognitive functions at 24 months of age.[17]

We point out that only 14 out of our 30 patients underwent an MRI scan and that, among these, the outcomes of only 9 children are known. Thus, we should cautiously analyze our finding of altered MRI associated with future altered exam. Even though CT is not as sensitive as MRI, when some degree of lesion is visible on CT, we expected to find an altered neurological exam.

All patients diagnosed with epilepsy at 12 months of age also presented alterations in the neurological examination and neuropsychomotor developmental delay. It might be interesting to include the neurological examination after reheating or predischarge from the NICU and analyze its power as a prognostic factor.

In a Brazilian cohort study[18] that followed 72 patients with neonatal HIE treated by TH, neuropsychomotor development delay at 12 months was found in 45% of the patients, according to the Bayley scale. The most affected domain was language (37%), followed by the cognitive (32.5%) and motor (20%) domains.[18] Although it is not possible to compare those results with ours, because we used a screening test (Denver Developmental Screening Test II) and not a diagnostic test (such as the Bayley scale), we found delays in 38.1% of the patients, predominantly in language and gross motor skills (33.3% each). These differences may be explained by the smaller sample size and different method, but they agree with international data,[19] in which 40 to 50% of the patients may present some degree of impairment, despite TH.

Additionally, we should point out that most patients treated had been referred from other hospitals in the state of Rio de Janeiro, which could have delayed the start of servo-controlled HT for a few hours in some patients. Even though they all received passive hypothermia[20] at their hospital of origin and during transportation, it is difficult to assess if this could affect prognosis.

The main limitation to the present study is the small number of cases. Furthermore, a remarkable number of patients (n = 8; 26%) were lost to follow-up. This may be due to difficulties in access due to socioeconomic conditions and to the isolation measures enforced during the COVID-19 pandemic. Most of these patients came from other cities in the state of Rio de Janeiro; distance and displacement costs probably influenced the discontinuation of follow-up.

It is crucial to reduce the loss to follow-up to compare our data to international statistics and to adjust our protocols. It might be interesting to establish partnerships with other institutions in the state of Rio de Janeiro and to train professionals to be able to care for these patients in other units. Still, our current health system is not favorable to an integrated network, due to ever-changing health teams, temporary contracts, and little investment on the training of these professionals.

It also became clear in the present study that we have a deficient access to complementary exams. Thus, to estimate prognosis, we might need better clinical parameters.

A recent survey[21] conducted through social media with health professionals in Brazil showed that TH was implemented in Brazil in a very heterogeneous manner, which can impair its safety and efficacy. There were many variations in the cooling method, as well as availability of aEEG, MRI (only in 19%), and specialized follow-up.[21] This reinforces the need for reference centers, specialized assistance, and “state-of-the-art” knowledge replicability. This also reaffirms the need for strong clinical parameters to make decisions and to correlate with outcomes.

Finally, more time for prospective follow-up and protocol adjustments should contribute to improve our data. The current study is a part of our initial work, and we plan to improve it based on our first observations. We are also working to ensure fast and safe transportation of newborns, full access to MRI and continuous aEGG monitoring, as well as better monitoring of child neurodevelopment, applying other scales, such as the General Movement Assessment[22] and Bayley III.[23]

In conclusion, high incidences of epilepsy, altered neurological exams and neurodevelopmental delay were found despite the use of TH. We look forward to a more efficient use of resources, to provide more answers to staff and families. This is expected to better guide acute management and early intervention in neurodevelopment.

As new treatments for HIE are being studied, prevention is still the best way to avoid all the human and economic costs of neonatal asphyxia. In Brazil, we need better assistance to pregnancy and labor.

Conflict of Interest

The authors have no conflict of interest to declare.

Authors' Contributions

RFO: conceptualization, data curation, formal analysis, project administration, investigation, methodology, visualization, and writing – original draft; LHW: data curation, methodology, and validation; ASS: formal analysis, methodology, and writing – review and editing; MCCR: conceptualization, data curation, methodology, supervision, validation, and writing – review and editing; GCBL: conceptualization, data curation, formal analysis, methodology, supervision, validation, and writing – review and editing.

Editor-in-Chief

Hélio A. G. Teive.

Associate Editor

Alexandra Prufer de Queiroz Campos Araújo.

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Publication History

Received: 01 February 2024

Accepted: 15 June 2024

Article published online:
28 September 2024