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Assessment of cortisol as a neonatal pain biomarker in the application of non-pharmacological analgesia therapies: systematic review and meta-analysis

BMC Pediatrics volume 25, Article number: 243 (2025) Cite this article

Abstract

Background

In the history of Neonatology, decades ago pain has been little studied because it was believed that newborns didn’t have the capacity to experience pain. Nowadays, there is enough evidence for the existence of neonatal pain but its adequate treatment is an aspect that is continuously evolving. The objective of this study was to evaluate the effectiveness of non-pharmacological analgesia therapies used to alleviate pain in newborns by analysing neonatal cortisol levels as biological markers of pain.

Methods

A systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the Cochrane Collaboration Handbook. Searches were performed in databases such as PubMed, Web of Science, Scopus, CINAHL, Cochrane Library and Science Direct until the end of May 2024. The search identified 1075 articles, of which 10 studies met the inclusion criteria and had the necessary data to develop the meta-analysis. Furthermore, in each meta-analysis, subgroups were performed: non-pharmacological analgesia vs. placebo, and pre-post intervention by gestational age.

Results

The meta-analysis found that breastfeeding exhibited a moderate effect size (SMD = -0.63; 95% CI = -1.07 to -0.19), sucrose showed a small effect (SMD = -0.15; 95% CI = -0.55 to 0.26), and skin to skin contact exhibited a large effect (SMD = -1.34; 95% CI = -2.21 to -0.46). Patients under 28 weeks have less post-intervention pain and showed a large effect (SMD = 1.44; 95% CI = 0.47 to 2.40), between 28 and 32 weeks they have more post-intervention pain and presented a small effect (SMD = -0.43; 95% CI = -0.86 to -0.0), and over 32 weeks they have an increased post-intervention pain and exhibited a large effect (SMD = -1.08; 95% CI = -1.65 to -0.51).

Conclusions

Non-pharmacological therapies showed efficacy in pain reduction based on neonatal cortisol levels. Skin to skin contact is the most effective method to reduce pain from invasive procedures, such as heel pricks in preterm infants under 28 weeks. Breastfeeding also demonstrated to be an effective and safe alternative to use for pain relief and to reduce cortisol levels. However, the cortisol results indicate that sucrose was not effective in reducing neonatal pain.

Trial registration

PROSPERO: CRD42023463831.

Peer Review reports

Background

The International Association for the Study of Pain (IASP) defines acute pain as “an unpleasant somatic or visceral sensation caused by actual or potential tissue injury” [1, 2]. In the past, it was thought that infants lacked the ability to sense pain due to the incomplete myelination of their nervous system [3]. However, there is now sufficient evidence indicating that neonates do indeed experience pain, given that the neurophysiological and anatomical elements necessary for pain transmission develop prior to 24 weeks of gestational age. Conversely, the inhibitory mechanisms that respond to nociception and alleviate pain require several months to fully mature [3, 4]. Following their initial moments of life, infants are subjected to a series of invasive procedures, with heel pricks for screening endocrinometabolic conditions being the most common. Often these premature infants, classified as “preterm” need to be admitted to Neonatal Intensive Care Units (NICUs), where they may undergo up to 10–15 painful interventions daily [5, 6]. The World Health Organization (WHO), estimates that approximately 15 million preterm births occur annually [7]. On a national scale in 2023, data from the National Institute of Statistics (INE) of Spain, indicated that there were 19.879 preterm births [8]. This condition stands as one of the primary contributors to perinatal mortality and morbidity [9].

Research indicates that untreated moderate-intense pain can impact the neurodevelopment of newborns, leading to changes in motor skills, cognitive functions, and behavior, including increased heart rate and decreased oxygen saturation [10]. Consequently, it is imperative to alter clinical approaches and minimize stimuli to ensure the well-being of these infants. This shift in approach has encouraged the adoption of innovative care models like the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) [11, 12]. One of the objectives of this approach is to evaluate the capacity of newborns to manage stress prior to, during, and after invasive procedures [13]. Furthermore, this approach sets forth a range of tactics, encompassing non-pharmacological interventions, to mitigate neonatal discomfort in minor invasive procedures. These interventions comprise breastfeeding, skin to skin contact, and oral administration of sucrose, among others [14, 15]. These measures have been introduced to avoid the potential adverse effects that medications may trigger in neonates, owing to disparities in pharmacokinetics and pharmacodynamics compared to adult patients. This leads to a slower elimination of drugs, resulting in a more pronounced and prolonged effect. Because of this, it’s important to analyse whether non-pharmacological measures are really effective or not, in order to enhance their use [16, 17].

The incapacity of newborns to communicate their perception of pain has led to the development of tools for evaluating and assessing pain. These instruments rely on observing physiological and behavioural shifts that neonates undergo when experiencing pain [18]. Three of the most commonly employed validated scales are the Premature Infant Pain Profile (PIPP), used to assess acute and procedural pain in preterm newborns from 28 weeks of gestation, to full term infants of 40 weeks [19]. Similarly, the Neonatal Infant Pain Scale (NIPS), is extensively used to evaluating acute pain in preterm and full term infants [20]. And finally, the Neonatal Infant Acute Pain Assessment Scale (NIAPAS), used for assessing acute pain in preterm and full-term infants in the NICU [21].

Analyzing the interpretation of this scales is a great challenge since the signs and symptoms of pain can be confused with feelings of hunger or discomfort. They are even difficult to use in cases of newborns with neurological damage or under sedation infusions, due to the limited physical response [22].

That’s why the use of biomarkers such as cortisol levels can be key for the detection and measurement of infant stress, improving pain relief attention and management [23]. Cortisol is a steroid hormone or glucocorticoid produced by the adrenal gland that is released in response to stress. Because it is liposoluble, it enters in saliva through the intracellular pathway, and its salivary concentration is not dependent on saliva flow, and closely approximates its free concentration in plasma [24, 25]. Until 5–6 months of age, circadian rhythms are not established, so the endogenous cortisol levels shown by newborns are independent and unrelated with the day/night cycle [26]. Neonatal cortisol levels in preterm newborns can range from 0.6 nmol/L to 52.1 nmol/L, with an average of 5.5 nmol/L [27]. Therefore, values higher than those considered normal would indicate the presence of pain [28].

As per the American Academy of Pediatrics (AAP), alleviating pain in newborns is an area that requires further attention [29]. Despite existing studies evaluating the effectiveness of employing non-pharmacological methods for pain relief, a consensus regarding their application has not yet been established, and there are few articles in the literature that evaluate neonatal pain using cortisol levels. The field of neonatal pain management is constantly evolving, for this reason, the aim of this study was to evaluate the effectiveness of non-pharmacological analgesia methods used to alleviate pain in newborns undergoing invasive procedures by analysing neonatal cortisol levels as biological markers of pain.

Methods

The present systematic review and meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [30], adhering to the suggestions outlined in the Cochrane Collaboration Handbook [31]. The International Prospective Register of Systematic Reviews (PROSPERO) registration number is CRD42023463831.

Data sources

A systematic review of the literature in PubMed, Cochrane Library, Web of Science, Scopus, CINHAL, and Science Direct databases was conducted up from the beginning to the end of May 2024. Following an assessment of non-pharmacological treatment modalities, the search criteria encompassed the subsequent terms: (“analgesia” OR “breastfeeding” OR “skin to skin contact” OR “sucrose”) AND (“cortisol” OR “neonatal pain”) AND (“nursing care” OR “heel prick”). Additionally, references cited in the chosen articles were scrutinized for potential inclusion in this review. Two authors independently determined whether studies fulfilled the inclusion criteria through examination of titles, abstracts, keywords and the full text. A third author was asked if there was a disagreement on any criteria in any article.

Study selection

The studies were chosen based on the following inclusion criteria, studies which include: (1) infants with a minimum gestational age of 28 weeks, regardless of sex or ethnic group; (2) infants with a weight exceeding 1 kg; (3) infants with an Apgar test score higher than 5 in the initial 5 min; (4) an evaluation of neonatal pain using cortisol levels; (5) a comparison of three non-pharmacological analgesia methods and their effect pre and post intervention; (6) a comparison of cortisol levels according to weeks of gestational age; and (7) a design as randomized controlled trial (RCT) or quasi-experimental design. Studies were excluded on the basis of the following, when: (1) involving infants with congenital anomalies; (2) included pain assessment without using cortisol levels; or (3) were ineligible by design as narrative reviews, observational studies, letters to the editor, or case reports.

Data extraction and quality assessment

The selected studies provided the following data: author information and year or publication, country where the intervention took place, sample details (size, gestational age, birth weight, Apgar test scores, and pain assessment); and intervention characteristics (type and dose). The interventions were categorized as follows based on their characteristics: breastfeeding, skin to skin contact and oral sucrose, because these are the three most commonly used techniques in neonatal units, because of their simplicity, safety and ease of administration. The risk of bias (ROB) in randomized controlled trials was evaluated using the Cochrane RoB2 tool. This instrument includes the evaluation of five areas: randomization process, deviations from intended interventions, missing data on outcomes, measurement of outcomes, and selection of reported outcomes [32].

The overall ROB for individual trials was classified as “low risk” if the study received a low risk in all key domains; “some concern” if any area was assessed as having some concern; and “high risk” if at least one area was rated as high risk, or multiple areas were rated as some concern. Additionally, the ROB in non-randomized studies was evaluated using the ROBINS-I tool, which includes seven areas: confounding, selection of participants, classification of interventions, deviations from intended interventions, missing data on outcomes, measurement of outcomes, and selection of reported outcomes [33]. The assessment of potential bias was categorized as “low risk” if the study received low rating across all domains, “moderate risk” if it received moderate ratings across all domains, “serious risk” if it was deemed significant in at least one domain, and “critical risk” if it was considered critical in at least one domain. This process was independently performed by two authors, they reviewed each publication to confirm its adherence to the specified inclusion criteria. A third author was asked if there was a disagreement on any criteria in any article. Decisions regarding which data had to be incorporated in the systematic review and meta-analysis were reached through collective deliberation.

Data synthesis and analysis

Only 10 studies met the inclusion criteria and had the necessary data to develop the meta-analysis. Furthermore, in each meta-analysis, subgroups were performed: non-pharmacological analgesia vs. placebo, and pre-post intervention by gestational age. The meta-analysis and statistical analyses were performed using Review Manager Software (RevMan, Version 5.3). Standardized mean differences (SMDs) and a 95% CI were used for the data analysis. The heterogeneity among trials was measured using the I2 statistic. I2 values of 25%, 50%, and 75% represent small, moderate, and large degrees of heterogeneity. According to Cohen guidelines, SMDs of 0.2 represent small effect, values around 0.5 medium effect, and values higher than 0.8 large effect size [34]. The significance criterion was established at P < 0.05. The asymmetry was evaluated using funnel plots for indicating the possible risk of publication of small studies [35].

Results

Study selection

The search identified 1075 articles, which was reduced to 346 after the duplicates were removed. After the full review process, the studies were included in the systematic review and meta-analysis [36,37,38,39,40,41,42,43,44,45]. Figure 1 shows the flow diagram of the study selection process.

Fig. 1
figure 1

Flow diagram of the study selection process

Full size image

Study characteristics

This systematic review and meta-analysis focused on the non-pharmacological treatment of neonatal pain and its efficacy measured by cortisol levels included 10 studies: 1 on breastfeeding [36], 2 on oral sucrose [37, 38], and 4 on skin to skin contact [39,40,41,42]. On the other hand, 3 articles studied the differences in cortisol levels according to the gestational age of the patients [43,44,45]. The total number of participants was 521, with gestational ages ranging from 28 to 39 weeks. The studies were carried out on three continents (4 in America, 4 in Europe, and 2 in Asia). Some studies compared the effect of non-pharmacological therapies such as breastfeeding, skin to skin contact, and oral sucrose with standard nursing care. The characteristics of all included studies are presented in Table 1.

Table 1 Characteristics of included studies on neonatal pain and non-pharmacological analgesia
Full size table

Risk of Bias

As per the RoB2 assessment in RCTs, only the 14,3% of the studies exhibited a high risk, while 28,6% displayed a moderate risk, and finally the 57,1% indicated a low risk. The details of the included trials are shown in Supplementary Fig. 1 and Supplementary Table 1. In RCTs, the ROBINS-I scale showed that 60% of the articles had a low risk, 20% displayed a moderate risk, 10% serious risk, and another 10% critical risk. Supplementary Fig. 2 presents the details of ROBINS-I scale.

Effects of non-pharmacological therapies on cortisol levels

The meta-analysis found that non-pharmacological therapies presented a large effect (SMD = -0.89; 95% CI = -1.49 to -0.28; n = 388; z = 2.88; P = 0.004) on neonatal pain with high heterogeneity (I2 = 86%) when compared with control group or standard nursing care (Fig. 2).

Fig. 2
figure 2

Effects of non-pharmacological therapies on cortisol levels in neonatal patients. The forest plot illustrates the overall effects on pain between experimental and control groups. Squares represent the standardized (Std.) mean difference (SMD) for each trial. Diamonds represent the pooled SMD across trials

Full size image

The subgroup breastfeeding exhibited a moderate effect size (SMD = -0.63; 95% CI = -1.07 to -0.19; n = 84; z = 2.81), significant differences (P = 0.005). Sucrose vs. control group showed a small effect size (SMD = -0.15; 95% CI = -0.55 to 0.26; n = 95; z = 0.70); and non-significant differences (P = 0.48), between experimental and control group, and there is no heterogeneity (I2 = 0%). Skin to skin contact exhibited a large effect size (SMD = -1.34; 95% CI = -2.21 to -0.46; n = 209; z = 2.99), significant differences (P = 0.003), and high heterogeneity (I2 = 86%). The funnel plot presented a potential publication bias (Supplementary Fig. 3).

Differences in cortisol levels according to weeks of gestational age

The meta-analysis found that differences in weeks of gestational age presented a small effect (SMD = 0.07; 95% CI = -1.00 to 1.14; n = 250; z = 0.13; P = 0.90) on cortisol levels with high heterogeneity (I2 = 93%), when compared pre and post-intervention groups (Fig. 3).

Fig. 3
figure 3

Differences in cortisol levels according to weeks of gestational age. The forest plot illustrates the overall effects on pre and post-intervention pain. Squares represent the standardized (Std.) mean difference (SMD) for each trial. Diamonds represent the pooled SMD across trials

Full size image

Patients under 28 weeks have less post-intervention pain and showed a large effect (SMD = 1.44; 95% CI = 0.47 to 2.40; n = 108; z = 2.92), significant differences (P = 0.004), and high heterogeneity (I2 = 78%).

Patients between 28 and 32 weeks have more post-intervention pain and presented a small effect (SMD = -0.43; 95% CI = -0.86 to -0.0; n = 86; z = 1.98), non-significant differences (P = 0.05). Finally, patients over 32 weeks have an increased post-intervention pain and exhibited a large effect (SMD = -1.08; 95% CI = -1.65 to -0.51; n = 56; z = 3.74), significant differences (P = 0.0002), and there is no heterogeneity (I2 = 0%). The funnel plot presented a potential publication bias (Supplementary Fig. 4).

Discussion

This systematic review and meta-analysis evaluate the effectiveness of non-pharmacological analgesia methods, used to alleviate pain in newborns undergoing invasive procedures by analysing neonatal cortisol levels as biological markers of pain. Our results suggest that the application of breastfeeding as a non-pharmacological intervention significantly reduces neonatal pain measured by cortisol levels, after heel lance. Similarly, the use of skin to skin contact has a positive and significant effect on lowering neonatal cortisol levels. However, the cortisol data show that administration of sucrose prior to heel prick was not effective in reducing pain. Specifically, our findings indicate that skin to skin contact has even more effect than breastfeeding on lowering cortisol levels, and thus, on neonatal pain. According to gestational age, newborns under 28 weeks have lower cortisol levels and less post-intervention pain, so non-pharmacological therapies are effective in this group of patients. But, on the other side, patients between 28 and 32 weeks have higher cortisol levels after procedures compared to pre-intervention levels. Likewise, newborns over 32 weeks experience more pain following interventions, indicating that the non-pharmacological methods studied are not effective in reducing pain in this group.

The effect of cortisol has been studied as the most commonly selected biomarker to measure both acute and chronic stress responses, but in the pediatric population it is an area that needs further research and development [46, 47]. Cortisol is a glucocorticoid hormone produced in the adrenal cortex, its synthesis begins around 28–30 weeks of gestation, and it is regulated by the hypothalamic-pituitary-adrenal axis (HPA). For this reason, cortisol levels in preterm infants are lower than in term infants, and data from our meta-analysis refute this statement [48,49,50]. Specifically, salivary cortisol is considered a feasible option for assessing HPA axis activity, due to the non-invasive method of sample collection, which would be ideal to implement in neonatal units [51]. The analysis explores how cortisol levels can predict the presence of stress in newborns and how these levels can decrease when non-pharmacological analgesia therapies are employed [52, 53].

Stress is a generic term that includes various symptoms such as pain, agitation or irritability [54]. Infants born preterm have impaired stress regulation, based on cortisol production values considered normal. Preterm babies spend their first weeks of life in the NICU receiving critical care [55]. Stress related to this unit has been associated with cortisol levels that are dysregulated in preterm infants in response to a stressor [56]. Research has found associations between exposure to neonatal pain and neonatal stress due to the number of invasive procedures during the NICU stay [55].

Preterm infants are more sensitive to pain and stress, which cannot be distinguished in neonates with pain assessment tools, hence the term ‘pain/stress’ is used [57]. In addition, higher cortisol levels were associated with greater exposure to pain/stress. It is important to note that infants exposed to more pain/stress from invasive procedures showed elevated cortisol levels prior to cortisol testing [55]. Multiple factors may contribute to these higher cortisol levels in preterm infants including cumulative stress related to multiple procedures [58]. It is ethically problematic to apply pain or a specific stimulus to young children for research purposes. The lack of standardised protocols for the assessment of stress reactivity has hindered the reproducibility and replicability of infant physiological stress studies [55].

In a systematic review the main selected articles established that cortisol is a reliable indicator of physiological stress. Furthermore, variations in cortisol throughout the day may be an indicator of a state of perceived high stress [54]. Cortisol reactivity in infancy has been assessed in various experimental settings including physical stressors (e.g. blood draw). The results of one meta-analysis emphasize that strong cortisol responses to painful stimuli have been observed [59].

The published studies indicate that newborns who received breastfeeding showed a quicker stabilization after heel lance [60,61,62]. This is due to the high lactose content in breast milk and essential amino acids like L-tryptophan, which promote the release of internal pain-relieving opioids including beta-endorphins. These substances are involved in reducing the transmission of pain to the nervous system [63, 64]. In addition, after ingestion of breast milk, cholecystokinin (CKK), a neuropeptide that induces a calming effect by causing drowsiness, is released [65, 66]. These mechanisms explain the ability of breastfeeding to relieve pain and to be one of the most widely used approaches with the highest level of evidence [67, 68]. The results of our meta-analysis are consistent with these investigations, showing that breastfeeding is one of the most effective therapies for reducing pain in newborns, undergoing invasive procedures such as heel prick.

Regarding the influence of the skin to skin contact, research suggests that groups in which this method has been implemented achieved lower cortisol levels during and after heel prick [69, 70]. Our outcomes align with these investigations, as skin to skin contact has been shown to have a positive and significant impact on reducing cortisol levels and neonatal pain. The way skin to skin contact generates analgesic effect is through direct mother-infant interaction combined with maternal smell, bonding and heartbeat [71, 72]. These processes stimulate the release of hormones such as oxytocin in the newborn, which decreases sympathetic nervous system function, and correlates with a calm and restful state, that ultimately improves hemodynamic stability [73].

Finally, concerning to the use of oral sucrose, there are contradictions in published evidence. There is a stream of articles recommending its use because the sweet taste of sucrose causes the release of endorphins and serotonins, producing and analgesic effect that lasts between 5 and 10 min [74, 75]. These publications conclude that sucrose is successful in reducing the manifestations of neonatal pain [76]. Conversely, other studies suggest that this non-pharmacological therapy does not seem to reduce heel stick pain compared to breastfeeding and skin to skin contact [77,78,79,80]. Data for our meta-analysis also indicate that there is no difference in cortisol levels between the control and intervention groups. In addition, questions regarding the most effective dose and concentration per day, as well as possible long-term negative impact of sucrose use, remain unresolved. Therefore, the effectiveness of using this method is not conclusive yet [81].

Non-pharmacological interventions to reduce stress in newborns may be brain-protective. During weeks to months in the NICU, very preterm infants are exposed to a high number of life-saving skin-breaking procedures and interventions, as well as routine handling that elicit behavioral, physiological and hormonal responses [57].

Nursing has the capacity to be at the forefront of care, being a driver of change for innovation in healthcare [82]. The use of new methods to measure and reduce pain aims to humanise nursing care, by encouraging the involvement of parents as primary caregivers [83, 84]. The union of the family with the care team is essential to achieve the maximum wellbeing, and communication is the basis for providing adequate care [85]. Nursing care in these units involves combining aspects derived from new technologies with the human dimension, due to the direct and continuous contact established with patient and her family [86]. Care centred only on pathological and procedural aspects would not take into account the newborn as a biopsychosocial being. The nursing team occupies a privileged place in neonatal units, as it is able to minimise the impact of this experience [87].

Study limitations

An important limitation is the small number of published articles evaluating cortisol levels and non-pharmacological analgesia therapies in neonatal patients. The high heterogeneity of the reviewed studies can be explained by the inclusion of studies in which participants had different sample sizes and gestational ages. Additionally, discrepancies in the type of intervention and dose administered may have influenced the overall consistency of the results. Only studies published in English were included in this meta-analysis. Also, we only included randomized controlled trials, and quasi-experimental studies. So our results are limited to the studies included in this review. Therefore, additional research is imperative to bolster the confidence needed to implement non-pharmacological analgesia therapies in neonatal units.

Conclusions

The non-pharmacological therapies examined showed that skin to skin contact is the most effective method to reduce pain measured by cortisol levels, from invasive procedures such as heel pricks in preterm infants under 28 weeks. Breastfeeding also demonstrated to be an effective and safe alternative to use for pain relief and to reduce cortisol levels. However, the cortisol data indicate that sucrose was not effective in reducing neonatal pain. These measures highlight the importance of integrating proactive approaches to mitigate acute pain derived from standard nursing care. The use of these therapies may lead to a reduction in the use of drugs in neonatal units, avoiding possible side effects, as they are considered a more natural alternative to the conventional pharmacological paradigm. In terms of research, this meta-analysis accentuates the identification of gaps in existing knowledge and underlines the need for further investigations to validate the safety and effectiveness of the suggested interventions.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

IASP:

International Association for the Study of Pain

NICUs:

Neonatal Intensive Care Units

WHO:

World Health Organization

INE:

National Institute of Statistics

NIDCAP:

Newborn Individualized Developmental Care and Assessment Program

PIPP:

Premature Infant Pain Profile

NIPS:

Neonatal Infant Pain Scale

NIAPAS:

Neonatal Infant Acute Pain Assessment Scale

AAP:

American Academy of Pediatrics

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT:

Randomized Controlled Trial

ROB:

Risk of Bias

ROBINS-I:

Risk of Bias in Non-Randomized Studies

SMDs:

Standardized Mean Differences

HPA:

Hypothalamic-Pituitary-Adrenal axis

CKK:

Cholecystokinin

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Authors and Affiliations

  1. Faculty of Physiotherapy and Nursing, University of Castilla-La Mancha, Toledo, 45071, Spain

    Inmaculada García-Valdivieso, Jorge Sánchez-Infante, Abel Checa Peñalver, Juan Manuel Pérez-Pozuelo & Sagrario Gómez-Cantarino

  2. Faculty of Health Sciences, Francisco de Vitoria University, Madrid, 28223, Spain

    Jorge Sánchez-Infante & Sonsoles Hernández-Iglesias

  3. DCIF University of Oviedo, Asturias, 33203, Spain

    Pablo Pando Cerra & Fernando Peña Cambón

  4. Department of Business Administration, School of Industrial and Aerospace Engineering, University of Castilla-La Mancha, Toledo, 45071, Spain

    Benito Yáñez-Araque

  5. Health and Social Research Center, University of Castilla-La Mancha, Cuenca, 16071, Spain

    Celia Álvarez-Bueno

  6. Faculty of Health Science, Autonomous University of Chile, Talca, 1670, Chile

    Celia Álvarez-Bueno

  7. Health Science Research Unit, Nursing (UICISA:E), Coimbra Nursing School (ESEnfC), Coimbra, 3004-011, Portugal

    Sagrario Gómez-Cantarino

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Contributions

Conceptualization I.G.-V and S.G.-C; methodology I.G.-V, J.S.-I and P.P.C; formal analysis I.G.-V, J.S.-I, C.A.-B and S.G.-C; investigation I.G.-V, J.S.-I, P.P.C and S.G.-C; resources B.Y.-A, S.H.-I, and F.P.C; data curation I.G.-V, J.S.-I, B.Y.-A and S.G.-C; writing—original draft preparation I.G.-V, J.S.-I and S.G.-C; writing—review and editing I.G.-V, J.S.-I, P.P.C, B.Y.-A and S.G.-C; visualization A.C.P and J.M.P-P; supervision P.P.C, S.H.-I, F.P.C and S.G.-C; project administration P.P.C, S.H.-I, F.P.C and S.G.-C. All authors reviewed the manuscript.

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Correspondence to Pablo Pando Cerra.

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García-Valdivieso, I., Sánchez-Infante, J., Pando Cerra, P. et al. Assessment of cortisol as a neonatal pain biomarker in the application of non-pharmacological analgesia therapies: systematic review and meta-analysis. BMC Pediatr 25, 243 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12887-025-05577-w

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Keywords

BMC Pediatrics

ISSN: 1471-2431

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