Neonatal stress and behavior problems in preschool children born preterm

Abstract

The aim of the present longitudinal study was to examine the effect of preterm childbirth, acute neonatal stress, and child behavior at 18–36 months of age on later behavior outcomes in 4-5-year-old children. The sample comprised of 70 children who were born preterm. The neonatal characteristics of children were assessed during hospitalization by reviewing their medical records and utilizing the Neonatal Infant Stressor Scale. Behavior problems were evaluated by the maternal-report in the Child Behavior Checklist 1½-5 years. A multiple linear regression analysis was conducted. Also, the repeated measures analysis of variance and the McNemar test for paired samples were performed. Daily exposure of the infants to high neonatal acute stress during NICU hospitalization and more behavior problems at 18–36 months of age was associated with more total and externalizing behavior problems at 4–5 years of age. Lower gestational age at childbirth and more internalizing behavior problems at 18–36 months was associated with more internalizing problems at 4–5 years old. The present study showed the combination of predictors of neonatal conditions and behavioral problems at childhood, highlighting the relevance of the implementation of developmental care in the NICU and follow-up the preterm infants after discharge programs.

Keywords

Preterm birth neonatal stress behavior problems

Introduction

The estimated global rate of preterm births was 10.6% (Chawanpaiboon et al., 2019). Clinical complications of preterm childbirth are responsible for 15% of deaths in newborns, and this proportion is expected to grow to 18% by 2030 (Liu et al., 2015). The low- and middle-income countries account for most of the world’s preterm birth rates (Blencowe et al., 2012). Thus, it highlighted the importance of studies in these countries to investigate the development trajectory of children born preterm.

The immaturity of infants born preterm makes hospitalization in the Neonatal Intensive Care Unit (NICU) necessary after childbirth to offer the best medical support for survival. However, the NICU presents many stressful and discomforting factors, such as neonatal pain-related stress experiences (Valeri et al., 2015), loud sounds (Lahav & Skoe, 2014), and high luminosity (Morag & Ohlsson, 2016). Each of these events could harm the development of the child. The period of stay in the NICU showed to be one of the most crucial risk factors for neurodevelopmental and health outcomes of children born preterm (Field, 2017). More significant numbers of painful procedures at NICU were directly correlated to decreases in head growth and brain function in very preterm infants. Repeated pain during a vulnerable period may activate a cascade of stress signaling that affects later growth (Vinall et al., 2012). A meta-analysis study found that 39.4% of infants admitted to NICU after preterm birth or neonatal insult had at least one neurodevelopmental deficit (Mwaniki et al., 2012). In this study, the most common sequelae were learning difficulties, cognition, or developmental delay, cerebral palsy, hearing impairment, and visual impairment.

According to Cong et al. (2017), preterm infants experienced a total of 643 acute procedures (23 daily) and 1193 hours of chronic events (43 hours daily) cumulatively (chronic stressors accruing simultaneously) during their first 4 weeks of NICU hospitalization. Considering that the cumulative infant pain/stress procedures in NICU have a high impact on the neurodevelopment of infants born pretem, it is fundamental to quantify and analyze these impacts on a critical period of development (Field, 2017). The more painful and stressful procedures experienced in early life, the more stress signs and worse habituation behavior demonstrated in preterm infants (Cong et al., 2017). Premature childbirth and acute stressful events were associated with worse motor development and vigor, and alertness and orientation in preterm infants (Gorzilio et al., 2015).

The cumulative infant pain stressful procedures in NICU still impact preterm development (Valeri et al., 2015). High neonatal pain-related stress total index, associated with toddler’s temperament with less effortful control, and mother’s temperament with high surgency predicted attention problems in toddlers born preterm (Gaspardo et al., 2018). However, the impact of cumulative neonatal acute pain and stress on child development is still poorly investigated.

Previous studies have investigated the prevalence of behavior problems in children born preterm (Bora et al., 2014; Mathewson et al., 2017; Ross et al., 2020). However, few studies have investigated the developmental of behavior problems in different phases, examining predictors of neonatal stress experiences. As far as we know, no studies have been investigated with the effect of the immaturity of tiny infants and the stressful contextual experience of NICU on child behavior outcomes at different ages.

The present study aimed to examine the effect of preterm childbirth, acute neonatal stress, and child behavior at 18–36 months of age on later behavior outcomes in 4-5-year-old children. The secondary aim of the study was to examine the proportion of behavior problems in children born preterm and their potential stability from toddlerhood to preschool age.

Method

Participants

The sample was composed of 70 children born preterm (<37 weeks of gestational age) at 4–5 years old, that is a sub-sample of a large longitudinal study (Cassiano et al., 2019). These children were born in a public university tertiary hospital in Southeastern Brazil, and enrolled in a follow-up preventive multidisciplinary intervention program in the same hospital. In this program, the children undergo medical and psychological consultations to monitor the child’s health and developmental evolution and provide a psychoeducational orientation for parents about the stimulation of child development and positive parenting practices. The inclusion criteria were as follows: < 37 weeks of gestational age, birth weight ≤1500 grams, and admission to a neonatal intensive care unit (NICU) after birth. The following were excluded from the study: children with congenital malformations, intracranial hemorrhage (III and IV levels), and those who were on oxygen at 18–36 months of age, as well as mothers and children with apparent cognitive impairments or those who were taking medications which could alter their levels of consciousness.

During data collection, 139 children born prematurely with a birth weight ≤1500 grams attended the follow-up preventive intervention program. Among these children, 33 (24%) were excluded for the following reasons: 18 children presented intracranial hemorrhage grade III or IV, two were on oxygen at 18–36 months of age, and 13 mothers showed apparent cognitive impairments that could negatively impact the quality of the report data. Of the eligible sample of 106 toddlers at 18–36 months of age, only one mother refused to participate in the study. Therefore, the sample consisted of 105 toddlers at 18–36 months of age. Of these, 10 (9.5%) did not reach 4 years of age by the end of data collection. Therefore, 95 children who were 4–5 years old were eligible for the study. A total of 25 children (26%) missed outpatient visits in the follow-up program. Thus, the final sample consisted of 70 children who were born preterm.

No statistically significant differences were found between the sample out of the study (i.e., Out-sample) and the final sample in the study (i.e., In-sample) for the following variables: prematurity level (In-sample, very preterm [ < 32 weeks] = 79%; Out-sample, very preterm [ < 32 weeks] = 74%; p = 0.63), childbirth weight (In-sample, mean = 1136 ± 243 grams; Out-sample, mean = 1043 ± 250 grams; p = 0.11), length of stay in NICU (In-sample, mean = 21 ± 20 days; Out-sample, mean = 33 [± 31] days; p = 0.07), total length of stay in hospital (In-sample, mean = 52 ± 26 days; Out-sample, mean = 69 [± 38] days; p = 0.06), Apgar score at the 5^th minute (In- sample, mean = 8 ± 2; Out-sample, mean = 9 [± 1]; p = 0.28), Clinical Risk Index for Babies (CRIB) score (In-sample, mean = 3 [± 2.5]; Out-sample, mean = 3 [± 3.5]; p = 0.53), and socioeconomic score (In-sample, mean = 21 [± 5.5]; Out-sample, mean = 20.5 [± 4.7]; p = 0.73).

Instruments and measures

Neonatal phase

Neonatal Infant Stressor Scale - NISS (Newnham et al., 2009) (Gorzilio et al., 2015 Brazilian version). The NISS evaluates the amount and the intensity of stressful procedures that infants suffer during their stay in the NICU. This instrument comprises a list of acute events and chronic conditions that could be assessed retrospectively using medical and nursing charts. The stressful procedures are classified according to the intensity of stress as the following: extremely stressful (e.g., intubation and chest drain insertion), very stressful (e.g., endotracheal aspiration and nasal CPAP insertion), moderately stressful (e.g., nasogastric tube insertion), and slightly stressful (collection of arteria blood and catheter removal). In this study, only the acute stressful events in the NICU were assessed. The acute and total NISS scores were associated with salivary cortisol levels in hospitalized moderately preterm infants, showing clinical validation of the instrument ((Pourkavian et al., 2020).

Medical chart

A retrospective review of medical chart was conducted independently by two medical students blinded to the developmental assessments. The children were characterized according to the following neonatal clinical variables: sex, gestational age (evaluated by the New Ballard score), childbirth weight, Apgar score at 5^th minute, CRIB score (Cockburn et al., 1993), length of stay in the NICU, the total length of stay in the hospital, and diseases in the neonatal phase.

Todlerhood and preschool phases

Child Behavior Checklist 1½-5y (CBCL1½-5; Achenbach & Rescorla, 2000), (Linhares, Santa Maria-Mengel, Silvares & Rocha, 2010) Brazilian version. The tool evaluates behavioral and emotional problems in children 18 months to 5 years of age by parental reports. The CBCL comprises 99 items and includes two axes (externalizing and internalizing problems) and seven scales (emotionally reactive, anxious/depressed, somatic complaints, withdrawn, attention problems, aggressive behavior, and sleep problems). The total behavior problems score is obtained by summing the two axes. The results are expressed as normalized T-scores, with classifications of normal (T < 65), borderline (T = 65-69), and clinical (T ≥ 70). High scores indicate more disruptive behavior. The internal consistencies that were obtained in the present sample of the study were the following: total behavior problem (0.93), internalizing behavior problems (0.81), and externalizing behavior problems (0.88).

Criteria for Economic Classification in Brazil (Critério de Classificação Econômica Brasil of the Brazilian Association of Market Research Companies) (Associação Brasileira de Empresas de Pesquisa, 2014). The Criteria for Economic Classification in Brazil (Critério de Classificação Econômica Brasil [CCEB]) questionnaire assesses the socioeconomic status (SES) of Brazilian families in terms of household resources, such as ownership of electronic equipment, cars, whether the family has a housekeeper and the educational level of the head of the family. The sum of the items is classified according to SES levels. The families were classified on an ordinal scale as follows: A1 (score = 42-46), A2 (score = 35-41), B1 (score = 29-34), B2 (score = 23-28), C1 (score = 18-22), C2 (score = 14-17), D (score = 8-13), and E (score = 0-7). The SES status was classified as very low (D/E), low (C), medium (B), or high (A). The A represented the highest socioeconomic level, and E presented the lowest.

Procedures

Data collection

This study was approved by the Ethical Committe of Clinical Hospital, Faculty of Medicine of Ribeirão Preto, University of São Paulo. The mothers were invited to participate in the study and signed the free informed consent form before data collection when their toddlers reached 18–36 months of age. They participated in one individual face-to-face interview, during which the sample characteristics questionnaire, CBCL1½-5, and CCEB were applied. Afterward, when the children were in the age range of 4–5 years, the mothers participated in another single face-to-face interview, during which the same instruments were administered. The data were collected in the hospital setting in the premature outpatient clinic. Two specialized psychologists who were trained experts in psychological assessment performed the data collection. Medical charts were reviewed to obtain the neonatal clinical data by two medical students trained by an expert neonatologist and blinded by behavior assessments. The NISS scores were calculated through the data obtained in the medical chart review, focusing on the items of the scale.

Data analysis

A descriptive statistical analysis was performed using frequencies and percentages for categorical variables and means, standard deviations, and range for continuous variables. To examine the prediction of behavior problems in children born preterm at 4–5 years of age, a correlation analysis was performed between potential predictor variables and the main outcomes (total, internalizing, and externalizing behavior problems). The potential predictor variables examined were gestational age, level of prematurity at birth, sex, NISS rate score, and behavior scores at 18-to-36 months of age. The association between continuous variables was examined by Pearson’s correlation coefficient, and the association between categorical and continuous variables was performed by Student’s t-test. Finally, the regression models were constructed considering statistical and theoretical reasons. The multicollinearity accepted in the analyses was VIF ≤2. The highest explanatory power (R²) and the statistical significance of the predictor variables were examined to identify the best regression models to explain the main outcomes of the study.

To examine the profile of the behavior problems between the two ages, a repeated-measures analysis of variance (ANOVA) was performed for CBCL1½-5 scores, followed by the Bonferroni post hoc test. Classifications of behavior problems at 18–36 months and 4–5 years of age were compared using the McNemar test for paired samples. According to the manual of the CBCL1½-5y (Achenbach & Rescorla, 2000), borderline and clinical classifications of behavior problems were taken together to avoid false-positive cases in the clinical classification comparisons. The clinical and borderline classifications were used separately only in the descriptive analyses.

The level of significance adopted for all of the statistical analyses was 5% (p ≤ 0.05). The effect size (partial eta-square effect [η_p²]) was calculated to assess the magnitude and practical relevance of the results (Portney & Watkins, 2008). According to Cohen (1992), the effect size was considered small (≤0.01), moderate (≤0.06), or large (≤0.14).

Results

As noted in the Table 1, the majority of children born preterm were very preterm, with a very low birth weight. The children had a mean Apgar at a 5^th-minute a mean CRIB score that indicating good vitality birth and a potentially good clinical prognosis. Concerning the clinical complications of prematurity, most of the sample presented retinopathy of prematurity.

Table 1.

Characteristics of the sample (n = 70).

Characteristics of sample	Values
Sex - Male f (%)	36(51)
Gestational age (weeks) – mean (SD; min - max)	30 (±2; 24 - 34)
Birthweight (grams) – mean (SD; min - max)	1136 (±243; 560 - 1500)
Apgar at 5^th min (score) - mean (SD; min - max)	8(±2; 2 - 10)
CRIB - mean (SD; min - max)	3(±2.5; 0 - 6)
Length of stay in NICU (days) - mean (SD; min - max)	21(±20; 2 - 92)
Total length of stay in the hospital - mean (SD; min - max)	52(±26; 16 - 129)
Retinopathy of prematurity- f (%)	46(66)
Bronchopulmonary dysplasia - f (%)	24(34)
NISS - total acute stress - mean (SD; min - max)	359(±393; 17 - 1711)
NISS- Acute stress rate per day of stay - mean (SD; min - max)	15(±4; 8 - 26)
Toddlers’ age at the date of first evaluation (months) – mean (SD; min - max)	26(±2; 18 – 36)
Toddlers’ age at the date of second evaluation (months) – mean (SD; min - max)	52 (±5; 48 – 71)
Mother’s age at child’s birth (years) - mean (SD; min - max)	29 (±6; 17 – 42)
Mother’s education (years) – mean ((SD; min - max)	10 (±4; 1 - 17)
Socioeconomic level* - f (%)
C	39(56%)
B	23(33%)
D	6(9%)
A	1(2%)

f = frequency; min = minimum values; max = maximum values; NICU = Neonatal intensive care unit; SD = standard deviation.

*Socioeconomic level is representative for the following scores: A (score = 46 - 35), B (score = 34 - 23), C1 (score = 14 - 22), D (score = 8-13), and E (score = 0-7).

The sample had a similar distribution of boys and girls. The mothers were young adults at the time of childbirth and studied until high school. The majority of the sample was low-to-average medium-income families.

Table 2 shows the predictive models of behavior problems at 4–5 years of age. Daily exposure of the infants to high neonatal acute stress during NICU hospitalization was associated with more total behavior problems at 18–36 months of age. This also explained 40% of the variability of the total behavior problems later at 4–5 years old. High neonatal acute stress at NICU that the infants were exposed to per day was associated with more externalizing behavior problems at 18–36 months of age. This explained 33% of the variability of externalizing problems later at 4–5 years old. Finally, lower gestational age at childbirth was associated with more internalizing behavior problems at 18–36 months. This explained 21% of the variability of internalizing problems at 4–5 years old. In all three models, the behavior problems at toddlerhood had a greater degree of explanation than the neonatal variables in predicting the later behavior problems at preschool age.

Table 2.

Prediction models of behavior problems (Total, Internalizing, and Externalizing) in children born preterm at 4–5 years of age (n = 70).

Behavior problems 4–5 years (predicted variable)	Neonatal indicators and behavior problems 18–36 months (predictor variables)	R² adjusted	β	t	p	95% CI
Behavior problems 4–5 years (predicted variable)		R² adjusted	β	t	p	Min	Max
Total behavior problems	Total behavior problems (score)	0.40	0.63	6.72	<0.0001	0.40	0.74
Total behavior problems	Neonatal stress (rate score^a)		0.21	2.23	0.03	0.06	1.13
Externalizing behaviors	Externalizing behaviors (score)	0.33	0.56	5.68	<0.0001	0.34	0.70
Externalizing behaviors	Neonatal stress (rate score^a)		0.21	2.19	0.03	0.05	1.13
Internalizing behaviors	Internalizing behaviors (score)	0.21	0.41	3.86	<0.0001	0.18	0.56
Internalizing behaviors	Gestational age (weeks)		- 0.21	- 1.95	0.05	- 2.05	0.02

R² adjusted = squared correlation coefficient adjusted for sample size; β = standardized coefficient; CI = Confidence Interval; Min = minimum value; Max = maximum value; NICU = Neonatal Intensive Care Unit.

^arate score was calculated dividing the total number of stressful events during hospitalization per total days of hospitalization in NICU.

Table 3 shows that most children born preterm presented a mean score <60 on all symptoms of behavior problems. There was a statistically significant difference in the prevalence of the behavior problems between the two ages assessed; furthermore, the behavior problems decreased from 18-36 months to the later 4–5 years of age. Children born preterm had significantly lower scores of total and externalizing behavior problems, specifically attentional, aggressive, and oppositional defiant symptoms at 4–5 years of age compared to the previous phase. Otherwise, no significant changes were found between the two phases regarding the internalizing behavior problems and any other specific symptom.

Table 3.

Behavior problems (CBCL1½-5 y scores) in children born preterm at 18–36 months and later 4–5 years of age (n = 70).

Behavior problems (CBCL ½-5 y scores)	18–36 months mean (SD)	4–5 years mean (SD)	df	F	p-value	η_p²
Total behavior problems	56 (±11)	54 (±10)	1	4.50	0.04	0.06
Externalizing behaviors	57 (±11)	54 (±10)	1	9.22	0.003	0.12
Attentional problems	59 (±9)	56.5 (±7)	1	6.08	0.02	0.08
Aggressive behavior	59 (±9)	56 (±7)	1	6.41	0.01	0.08
Internalizing behaviors	53.5 (±11)	54 (±10)	1	0.32	0.57	0.005
Emotionally reactive	56 (±7)	56.5 (±7.5)	1	0.36	0.55	0.005
Anxious/depressed	56 (±7)	56 (±7)	1	0.000	1.00	<0.0001
Somatic complaints	56 (±7.5)	56 (±7.5)	1	0.04	0.84	0.001
Withdrawn	56 (±7.5)	56 (±7)	1	0.24	0.62	0.004

SD = Standard deviation; p-value in repeated-measure ANOVA; η_p² = partial eta squared; df = degrees of freedom; F = F-test; CBCL1½-5y = Child Behavior Checklist (range of scores = 50 -100).

Discussion

The main findings of the present study showed that the neonatal acute stress experience during NICU hospitalization predicted the total behavior problems and the externalizing behavior problems in children born preterm at preschool age. Previous studies also found that neonatal stress impacted behaviors throughout childhood. The neonatal pain-related stress was a predictor of total behavior problems at 7 years old (Chau et al., 2014) and attention problems at 18–36 months of age (Gaspardo et al., 2018) in children born preterm. Neonatal pain-related stress was associated with negative alterations in early and later developmental outcomes (Valeri et al., 2015). Additionally, pain and stress exposure in the NICU can alter brain development in preterm newborns (Batalle et al., 2017).

In the present study, low gestational age and more internalizing behavior problems at toddlerhood predicted latterly internalizing behavior problemas at 4–5 years of age. The association between lower gestational age and more internalizing behavior problems could be related to deficits across multiple levels of the hypothalamic-pituitary-adrenal (HPA) axis in preterm infants (Finken et al., 2017). During early development, the HPA axis in very preterm infants is characterized by an inability to secrete sufficient glucocorticoids (e.g., cortisol) to meet the physiological demands of stress or disease (Finken et al., 2016). Consequently, preterm newborns present difficulties in coping with stress that is related to invasive and painful procedures in the NICU environment. Additionally, throughout development, the HPA axis in preterm infants becomes hyperactive, presenting an increase in the rate of cortisol secretion (Finken et al., 2011; van der Voorn et al., 2016), which could partially explain internalizing behaviors in these children (Finken et al., 2017). The pattern of reactivity and biobehavioral regulation in preterm infants in response to painful procedures performed in the NICU were shown to influence the expression of temperament in early childhood (Klein et al., 2009). High reactivity in preterm infants during painful blood collection procedures in the NICU was a predictor of higher negative affectivity and impulsivity scores at 18–32 months of age. Negative affectivity, in turn, is a temperament factor associated with internalizing behavior problems (Cassiano et al., 2016; Crawford et al., 2011; Gartstein et al., 2012).

Despite a decrease in total and externalizing behavior problems from toddlerhood to preschool age, the behavior problems at an early age predicted the occurrence of the same type of problems at later age, showing stability in behavior profile. This finding confirms previous studies that evaluated the stability of behavior problems in children born preterm, indicating that the occurrence of total behavior problems in preterm infants remained at ∼50% between 3-5 years of age (Gray et al., 2004; Hornman et al., 2016).

In the current study, the decrease in externalizing behavior problems in children born preterm at preschool age was consistent with a previous study of children born preterm and who were followed longitudinally from childhood to adulthood (Breeman et al., 2016). The decrease in externalizing behavior problems around 4 years of age could be associated with a socialization process and the maturation of perspective-taking and frustration-tolerance abilities that occur throughout development (Campbell, 2002).

Furthermore, the decrease in externalizing behavior problems could be also explained by a developmental self-regulation process that occurs during childhood, usually well-established around 5 years of age (Feldman, 2009; Sameroff, 2009). The development of self-regulation occurs through the following phases: physiological regulation, emotional regulation, attentional regulation, and self-regulation (Olson et al., 2009). The regulation of attention occurs during the second year of life when the attentional system undergoes reorganization. Children develop the ability to focus attention on different sources, maintain attention in a task in the face of distraction, and maintain a task in memory (Sameroff, 2009). Self-regulation that develops during the preschool years refers to the capacity for behavioral adaptation, executive function, and self-restraint in the face of social demands (i.e., the child becomes increasingly able to learn to adapt flexibly to situations in life with different patterns of conduct) (Feldman, 2009; Sameroff, 2009). Therefore, self-regulation in the child is related to their behavior functioning (Bates et al., 2009; Bridgett et al., 2015; Sameroff, 2009).

Self-regulation process at childhood is associated with an improvement in the temperament regulation, specifically in the effortful control factor (Bates et al., 2009; Bridgett et al., 2015). Additionally, temperament is related to behavior problems (Cassiano et al., 2016; Gartstein et al., 2012). The development of temperament initially presents reactive systems that become progressively more regulated as fear-inhibition, and attention-control regulation systems mature (Putnam et al., 2001). Higher extraversion and negative emotional reactivity in infancy and early childhood can be regulated by increased self-regulatory abilities as children become older (Bates et al., 2010). At preschool age, regulatory systems of temperament (i.e., effortful control) undergo rapid development, and children present better voluntary and intentional regulation of attention and behavior (Rothbart et al., 2003).

In the current study, internalizing behavior problems showed a stability profile from 18-36 months to 4–5 years of age. A previous study found that internalizing behavior problems were stable at 2 and 3 years of age and decreased at 4 and 5 years of age in children born preterm (Schappin et al., 2018). However, in this previous study, the authors considered that the initially high level of internalizing problems in some children might have caused a ceiling effect in which such problems were unlikely to increase further.

Our study shows the combination of predictors of neonatal conditions and behavioral problems at childhood, highlighting the relevance of the implementation of developmental care in the NICU and follow-up after discharge programs. These programs could prevent the development of behavior problems in preterm children. The children in the present study were hospitalized in a NICU, were enrolled in a developmental care program, and received non-pharmacological management of pain (e.g., skin-to-skin contact, palmar restraint, sucrose, and psychological support from parents). Also, they participated in a follow-up program. These programs could protect the children by reducing the negative impact of preterm birth on later development, considering the predominance of normal behavior profile in the sample.

The present study has some limitations. First, children born prematurely with severe clinical conditions, such as grade III or IV intracranial hemorrhage, were excluded from the sample. Therefore, the generalization of the findings to high-risk preterm infants sample should be applied with caution. Second, behavior problems were evaluated exclusively by maternal- report questionnaire. The use of multiple informants could reduce potential bias during the data collection of this variable. Future studies could use multiple informants to evaluate child behaviors, and explore new questions related to examine the stress premature infants’ parents as a predictor, include high-risk preterm infant samples, and assess behavior problems associated with temperament longitudinally.

Footnotes

Acknowledgements

The authors thank all of the parents and their children who participated in the study.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was partially supported by grant no. 2013/12509-5 and 2015/50502-8 from the São Paulo Research Foundation (FAPESP), Coordination for the Improvement of Higher Education Personnel (CAPES) - Finance Code 001, and the National Council for Scientific and Technological Development.

ORCID iD

Rafaela GM Cassiano

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