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![Reference intervals for salivary cortisol [nmol/L].](profile/Elvar-Theodorsson/publication/278790569/figure/fig9/AS:341892714778634@1458524983879/Reference-intervals-for-salivary-cortisol-nmol-L.png)
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Cortisol concentrations in plasma display a circadian rhythm in adults and children older than one year. Earlier studies report divergent results regarding when cortisol circadian rhythm is established. The present study aims to investigate at what age infants develop a circadian rhythm, as well as the possible influences of behavioral regularity a...
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Aim
Infants born preterm (<37 weeks' gestation) are at risk of poor neurodevelopmental outcomes; hence, many neonatal centres routinely follow up infants using the Bayley Scales of Infant Development (BSID), although the predictive validity of the BSID for children born preterm is questionable. Our objective is to evaluate the predictive capacity o...
![Table 7 . Reference intervals for salivary cortisol [nmol/L].](profile/Elvar-Theodorsson/publication/319053955/figure/tbl4/AS:667869402640394@1536243882696/Reference-intervals-for-salivary-cortisol-nmol-L_Q320.jpg)
Objectives
To investigate at what age preterm infants develop a salivary cortisol circadian rhythm and identify whether it is dependent on gestational age and/or postnatal age. To evaluate whether salivary cortisol circadian rhythm development is related to behavioral regularity. To elucidate salivary cortisol levels in preterm infants during the f...
Background
Parents of preterm infants in the Neonatal Intensive Care Unit (NICU) environment may experience psychological distress, decreased perceived self-efficacy, and/or difficulties in establishing an adaptive parent-infant relationship. Early developmental care interventions to support the parental role and infant development are essential an...
Objective
To determine if preterm birth is associated with adaptation of the hypothalamic–pituitary–adrenal (HPA) axis and whether HPA axis programming relates to the degree of prematurity (defined as extremely preterm birth at <28 weeks or very preterm birth at 28–32 weeks gestation).
Design
This study reports findings from a prospective birth co...
Background:
Blood loss and adult blood transfusions are common during the neonatal period in preterm infants. The objective of the study was to clarify if degree of loss of fetal haemoglobin (HbF) was associated with later retinopathy of prematurity (ROP).
Methods:
Retrospective observational cohort study. In total, 452 infants born <30 gestatio...
Citations
... this may be explained by developmental factors that influence inter-and intra-individual variability in stress regulation across time during infancy. For example, prenatal stress may have altered the development of the hPa axis circadian rhythm in a way that is manifested at 6 months but not later as the rhythm continues to mature (de Weerth et al., 2003;ivars et al., 2015). caregivers also play a major role in early infant emotion regulation and usually provide a buffer against stress (engel & Gunnar, 2020). ...
Exposure to social adversity has been associated with cortisol dysregulation during pregnancy and in later childhood; less is known about how prenatal exposure to social stressors affects postnatal cortisol of infants. In a secondary analysis of data from a longitudinal study, we tested whether a pregnant woman's reports of social adversity during the third trimester were associated with their infant's resting cortisol at 1, 6, and 12 months postnatal. Our hypothesis was that prenatal exposure to social adversity would be associated with elevation of infants' cortisol. Measures included prenatal survey reports of social stressors and economic hardship, and resting cortisol levels determined from infant saliva samples acquired at each postnatal timepoint. Data were analyzed using linear mixed effects models. The final sample included 189 women and their infants (46.56% assigned female sex at birth). Prenatal economic hardship was significantly associated with infant cortisol at 6 months postnatal; reports of social stressors were not significantly associated with cortisol at any time point. Factors associated with hardship, such as psychological distress or nutritional deficiencies, may alter fetal HPA axis development, resulting in elevated infant cortisol levels. Developmental changes unique to 6 months of age may explain effects at this timepoint. More work is needed to better comprehend the complex pre- and post-natal physiologic and behavioral factors that affect infant HPA axis development and function, and the modifying role of environmental exposures.
... As infants grow older, the diurnal cortisol pattern matures in steps and gradually follows a more typical adult pattern (Gunnar & Donzella, 2002). The literature is inconclusive as to when children show a consistent diurnal cortisol rhythm, with estimates ranging from the first months (De Weerth et al., 2003;Ivars et al., 2015) to the third or even fourth year of life (Gunnar & Donzella, 2002), depending on the research method and the specific definition of a consistent diurnal cortisol rhythm. In general, absolute cortisol levels gradually decrease over the first year of life (Tollenaar et al., 2010), although intra-and inter-individual variability remain relatively large, especially up to eight months of age (De Weerth & Van Geert, 2002;Ivars et al., 2015;Tollenaar et al., 2010). ...
... The literature is inconclusive as to when children show a consistent diurnal cortisol rhythm, with estimates ranging from the first months (De Weerth et al., 2003;Ivars et al., 2015) to the third or even fourth year of life (Gunnar & Donzella, 2002), depending on the research method and the specific definition of a consistent diurnal cortisol rhythm. In general, absolute cortisol levels gradually decrease over the first year of life (Tollenaar et al., 2010), although intra-and inter-individual variability remain relatively large, especially up to eight months of age (De Weerth & Van Geert, 2002;Ivars et al., 2015;Tollenaar et al., 2010). This variability makes the study of cortisol in very young children particularly complex, and therefore researchers are recommended to measure cortisol at different moments and in different settings within the same infant and to examine individual patterns besides group-level means (Gunnar & Donzella, 2002). ...
... On average, infants in this age group (9-29 weeks) displayed a mature diurnal cortisol pattern across all settings, which is characterized by a cortisol decrease from morning to afternoon (Tryphonopoulos et al., 2014). This finding is in line with other studies into infants' cortisol levels, both in child care settings (Albers et al., 2016) and at home (Ivars et al., 2015;De Weerth et al., 2003). The absolute cortisol levels in the current study were also comparable to the absolute levels found in earlier cortisol studies with infants of the same age (Albers et al., 2016;De Weerth et al., 2003;De Weerth & Van Geert, 2002;Ivars et al., 2015;Tollenaar et al., 2010). ...
Transitioning to an out-of-home child care setting has been shown to be a challenging event for young children. One of the physiological indicators of stress, cortisol secretion, has only been studied minimally in infants yet (e.g., Albers et al., 2016). In the current replication study we therefore followed 32 healthy infants (Mage = 11.59 weeks), their mothers, and their primary professional caregivers during the transition from home to the child care center. We found that on average (1) infants’ cortisol levels were significantly lower at mid-afternoon than mid-morning both at home and child care; (2) cortisol levels at home (both time-points) were significantly higher before transition than after transition; (3) the difference between cortisol levels at child care versus home showed a (non-significant) medium effect with higher levels at child care at both time-points; (4) individual cortisol patterns illustrated large variability between infants; and (5) three exploratory correlates of cortisol secretion at child care displayed a (non-significant) small to medium effect: infants who displayed a cortisol increase over the day scored lower on infant negative emotionality, and had mothers who scored lower on sensitivity and higher on separation anxiety. Larger studies are required, including multiple caregivers and various physiological measures.
... Cortisol circadian rhythm is the fluctuating cortisol level, the highest when waking up in the morning, then decreases until the lowest level before sleeping time (Jones and Gwenin, 2021). Cortisol circadian rhythm perfectly occurs from 1 month in term infants (Ivars et al., 2015) and at 1 month corrected age in preterm infants (Ivars et al., 2017). Biologically active free cortisol enters cells by passive diffusion and can measured in all bodily fluids. ...
Purpose: Pain in neonates, especially in preterm neonates has short effects and long effects. A mother’s voice can stabilize the physiological state, support feeding, reduce pain, and promote growth and development. aimed to analyze the effect and safety of maternal voice for preterm neonatal pain, to provide scientific evidence.Design : The research design used in this study is the systematic literature review. The identification of the study uses a PRISMA flow diagram, and quality assessment uses critical appraisal tools from the Centre for Evidence-Based Medicine. The analyzed data related to the population, intervention, and outcomes (PIO components).Findings: Ten studies were included in this study, ranging from 2018 to 2023. Seven studies showed the significant efficacy of maternal voice in reducing preterm neonatal pain, and three studies no significance. Five studies show maternal voice can reduce pain significantly more than routine care, and two studies use a combination of maternal voice and other non-pharmacological management, including breast milk, taste, Non-nutritive sucking, heartbeat sounds mother voice, and mother touch therapy. Pain parameters use the Pain Scale and serum and salivary cortisol level.Implications: Maternal voice; both live or recorded, voice or heartbeat, was effective and safe in reducing pain sensation in preterm neonates.
... Cortisol concentrations were measured using commercially available kits 37 . Secreted in a pulsatile fashion, it is known to display a circadian rhythm in adults were Cortisol levels are highest in the morning and subsequently decrease to a nadir in the evening 38,39 . ...
In the last decade, clinical studies have investigated the clinical relevance of circulating cell-free-DNA (ccfDNA) as a diagnostic and prognosis tool in various diseases including cancers. However, limited knowledge on ccfDNA biology restrains its full development in the clinical practice. To improve our understanding, we evaluated the impact of the circadian rhythm on ccfDNA release in healthy subjects over a 24-h period. 10 healthy female subjects underwent blood sampling at 8am and 20 healthy male subjects underwent serial blood sampling (8:00 AM, 9:00 AM, 12:00 PM, 4:00 PM, 8:00 PM, 12:00 AM, 4 AM (+ 1 Day) and 8 AM (+ 1 Day)). We performed digital droplet-based PCR (ddPCR) assays to target 2 DNA fragments (69 & 243 bp) located in the KRAS gene to determine the ccfDNA concentration and fragmentation profile. As control, half of the samples were re-analyzed by capillary miniaturized electrophoresis (BIAbooster system). Overall, we did not detect any influence of the circadian rhythm on ccfDNA release. Instead, we observed a decrease in the ccfDNA concentration after meal ingestion, suggesting either a post-prandial effect or a technical detection bias due to a higher plasma load in lipids and triglycerides. We also noticed a potential effect of gender, weight and creatinine levels on ccfDNA concentration.
... The adrenal cortex is another candidate partial pathway since light information is conveyed from the SCN to the adrenal gland via the SCN-sympathetic nervous system (Ishida et al., 2005) and MT1 receptors are also detected in the adrenal cortex in adult animals (Torres-Farfan et al., 2003;Richter et al., 2008). Like the development of melatonin circadian rhythms, however, no clear cortisol circadian rhythms are detected in humans until approximately 1 month of age (Ivars et al., 2015(Ivars et al., , 2017, suggesting that cortisol may not contribute to the circadian mechanism for the body growth of preterm infants until that time. ...
Previous studies suggest the importance of stable circadian environments for fetuses to achieve sound physiology and intrauterine development. This idea is also supported by epidemiological and animal studies, in which pregnant females exposed to repeated shifting of light–dark cycles had increased rates of reproductive abnormalities and adverse pregnancy outcomes. In response to such findings, artificial circadian environments with light–dark (LD) cycles have been introduced to NICUs to promote better physical development of preterm infants. Such LD cycles, however, may not be fully effective for preterm infants who are less than 30 weeks gestational age (WGA) since they are too premature to be adequately responsive to light. Instead, circadian rhythmicity of incubated preterm infants less than 30 WGA may be able to be developed through stimulation of the non-visual senses such as touch and sound.
... Cortisol has a circadian rhythm, peaking in the morning and decreasing steadily throughout the day to low levels in the evening with a nadir at night. A newborn's circadian rhythm develops in the first year of life (Benjamin Neelon et al., 2015;Ivars et al., 2015;Mörelius et al., 2012). ...
This paper investigated the effect of kangaroo mother care (KMC) in the early postpartum period on cortisol levels and immune factors in breast milk. This quasi-experimental study was conducted at the obstetrics clinic of a university hospital in western Türkiye. The sample consisted of 63 mothers and their infants. All mothers had a cesarean delivery. Participants were divided into control (n = 32) and experimental groups (n = 31). The control group received routine care at the clinic. The experimental group received KMC for the first 3 days after birth in addition to the routine care at the clinic. Milk samples were collected on the third day after delivery to examine cortisol, IgA, IgM, and IgG levels. All parameters were measured using the enzyme-linked immunosorbent assay method. The experimental group had lower cortisol levels (17.740 ± 1.438) than the control group (18.503 ± 1.449) (p < .05). This result showed that the difference between the two groups was clinically significant (effect size = .53). There was no significant difference in IgA, IgM, and IgG levels between the groups (p > .05). The experimental and control groups had similar immunological factors, but the former had lower cortisol levels than the latter. Therefore, healthcare professionals should encourage mothers to provide KMC to their infants as soon as possible.
... 23 Studies have found that, in neonates, cortisol secretion begins from the first day of life but gains circadian rhythm 1 month later. 24 Prematurity is a inhibit factor for adequate cortisol secretion, and it seems that adrenal cortex may produces cortisol in order to maintain homeostasis, but it cannot respond to stressful responses. 25 Thus, studies focusing on cortisol as pain biomarker in neonates are controversial and further research is needed. ...
Introduction: Our aim was to investigate biomarkers of neonatal pain and their association with two pain scales. Methods: This prospective study included 54 full-term neonates. Levels of substance P (SubP), neurokinin A (NKA), neuropeptide Y (NPY), and cortisol were recorded and two pain scales (Premature Infant Pain Profile [PIPP] and Neonatal Infant Pain Scale [NIPS]) were used. Results: A statistically significant decrease in the levels of NPY (p = 0.02) and NKA (p = 0.03) was detected. A significant increase in NIPS scale (p < 0.001) and PIPP scale (p < 0.001) postpainful intervention was also detected. There was a positive correlation between cortisol and SubP (p = 0.01), NKA and NPY (p < 0.001) and between NIPS and PIPP (p < 0.001). A negative correlation was found for NPY with SubP (p = 0.004), cortisol (p = 0.02), NIPS (p = 0.001) and PIPP (p = 0.002). Conclusions: Novel biomarkers and pain scales may help in designing an objective tool for the quantification of neonatal pain in the everyday practice.
... It is secreted in the circadian rhythm, with its peak in the morning and nadir in the evening [1]. This pattern of cortisol release is established in infancy, as early as around one-month-old, and is present throughout life [2]. Salivary cortisol (SC) is a feasible marker for the evaluation of HPA axis activity, especially its response to stress, due to the non-invasive method of sample collection. ...
... The limit of detection was 0.53 ng/ml. The obtained results of SC were compared with the reverence intervals proposed by Ivars et al. [2]. Normal values were defined as concentrations between 25 th and 75 th percentile, which corresponded to results between 1.02 and 2.97 ng/ml. ...
... In the present study, we observed a negative correlation between the number of invasive blood samplings and mean morning SC only in term newborns. In contrast, Ivars et al. did not find any significant relationship between the number of self-reported traumas and SC concentrations in one-month-old infants [2]. There was no relationship between exposure to procedural pain and mean morning SC in premature neonates, irrespective of the degree of prematurity. ...
Introduction:
Introduction: Because neonates in the intensive care units (ICU) experience recurrent stress due to painful medical procedures, they are at risk of dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. Aim of the study: To evaluate the influence of repeated pain exposure on morning salivary cortisol (SC) in newborns admitted to the ICU.
Material and methods:
The neonates were divided into 3 groups: term (370/7-416/7 weeks), moderate to late preterm (320/7-366/7 weeks), and very preterm (< 320/7 weeks). The hospital stay was prospectively monitored for the number of the most common medical procedures. At least 2 saliva samples for morning SC were collected after completion of 35 weeks of postmenstrual age (PMA) in preterm infants and before discharge in term neonates. The results of SC were compared with the reference intervals for healthy term newborns.
Results:
The study group consisted of 57 patients: 21 term, 17 moderate to late preterm, and 19 very preterm neonates. Very preterm neonates obtained the highest values of mean morning SC in comparison to moderate to late preterm and term infants (3.83 [1.67-8.81] ng/ml vs. 2.44 [1.94-4.38] ng/ml vs. 2.15 [1.5-5.25] ng/ml, p = 0.45). The relationship between mean morning SC and the number of invasive blood samplings was found only in term newborns (Rs = -0.44, p < 0.05). 46% of all SC measurements in very preterm, 47% in moderate to late preterm, and 46% in term infants were within the reference intervals for healthy newborns.
Conclusions:
High exposure to painful procedures seems to dampen the morning SC in term, but not in preterm infants.
... At birth, neonates lose direct communication with their mother's SCN and must develop their own independent oscillating master circadian clock, undergoing a substantial change in function and reorganization of their circadian system. Infants are born with an immature circadian system that does not produce overt rhythms as evident by their absence of significant circadian rhythmicity in melatonin and cortisol rhythms and a stable sleep-wake cycle [39,93,103]. The neonatal SCN is not fully developed and contains only 13% of the adult number of AVP-expressing neurons and few VIP-expressing neurons-adult levels are attained by the first 2-3 years of life [82,104]. ...
... The circadian rhythm of cortisol in infants has been observed from as early as 2 weeks up to 9 months of age and is linked with the emergence of the sleep-wake cycle [103,[130][131][132]. The wide range in the cortisol rhythm appearance may be due to varying exposures of exogenous cortisol through breast milk. ...
In humans, an adaptable internal biological system generates circadian rhythms that maintain synchronicity of behavior and physiology with the changing demands of the 24-h environment. Development of the circadian system begins in utero and continues throughout the first few years of life. Maturation of the clock can be measured through sleep/wake patterns and hormone secretion. Circadian rhythms, by definition, can persist in the absence of environmental input; however, their ability to adjust to external time cues is vital for adaptation and entrainment to the environment. The significance of these external factors that influence the emergence of a stable circadian clock in the first years of life remain poorly understood. Infants raised in our post-modern world face adverse external circadian signals, such as artificial light and mistimed hormonal cues via breast milk, which may increase interference with the physiological mechanisms that promote circadian synchronization. This review describes the very early developmental stages of the clock and common circadian misalignment scenarios that make the developing circadian system more susceptible to conflicting time cues and temporal disorder between the maternal, fetal, infant, and peripheral clocks.
... Neonates begin to exhibit the circadian salivary cortisol rhythms analogous to that of adults (i.e., higher cortisol levels in the morning than at night) until 2-3 months of PNA (Price et al., 1983;Spangler, 1991;Mantagos et al., 1998;Joseph et al., 2015). However, an adult-type salivary cortisol circadian of term infants appears to be established actually at 1 month and remains stable throughout the first year of life (Ivars et al., 2015). All in all, these studies prove that the fetal cortisol circadian rhythms are preserved in the first few weeks of life, until the adult-type circadian rhythms are established. ...
Caffeine is the globally consumed psychoactive substance and the drug of choice for the treatment of apnea of prematurity (AOP), but its therapeutic effects are highly variable among preterm infants. Many of the molecular underpinnings of the marked individual response have remained elusive yet. Interestingly, the significant association between Clock gene polymorphisms and the response to caffeine therapy offers an opportunity to advance our understanding of potential mechanistic pathways. In this review, we delineate the functions and mechanisms of human circadian rhythms. An up-to-date advance of the formation and ontogeny of human circadian rhythms during the perinatal period are concisely discussed. Specially, we summarize and discuss the characteristics of circadian rhythms in preterm infants. Second, we discuss the role of caffeine consumption on the circadian rhythms in animal models and human, especially in neonates and preterm infants. Finally, we postulate how circadian-based therapeutic initiatives could open new possibilities to promote precision caffeine therapy for the AOP management in preterm infants.
