Opinion
VIEWPOINT
Livio Provenzi, PsyD 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy. Rosario Montirosso, PsyD 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
“Epigenethics” in the Neonatal Intensive Care Unit Conveying Complexity in Health Care for Preterm Children Human behavioral epigenetics (HBE) is a fascinating area of research that holds promise to change our view of nature-nurture interconnection. In particular, the study of changes in DNA methylation applied to human development is revealing pathways through which early adversities are embedded in the developing biology of children, contributing to long-lasting programming of health and disease.1 Notwithstanding, HBE holds the risk of a new reductionism grounded in nurture instead of nature. Researchers and clinicians have been recently warned about the lure of epigenetics and the risk of translating animal results and interpreting human findings in a strict deterministic way.2 Critically, misleading conclusions would convey the idea of a direct impact of maternal behavior and physiology on the long-term wellbeing of infants and children, without taking into account the importance of the broader socioeconomic and health care environment. Herein, we reflect on HBE, referring to prematurity as an example to highlight potential benefits for research and clinical practice as well as ethical issues conveying a complex view of neonatal health care.
Prematurity and Neonatal Intensive Care Unit Stay as an Early Adverse Experience
Corresponding Author: Rosario Montirosso, PsyD, 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, via Don Luigi Monza 20, 23842 Bosisio Parini, Lecco, Italy (rosario.montirosso @bp.lnf.it). jamapediatrics.com
Preterm birth is a major concern for health care services. In the United States, prematurity constitutes 12% of total live births.3 Preterm infants have a moderate to severe immature neurobehavioral profile at birth, needing highintensityinterventionsanddevelopmentalcare(DC)inthe neonatal intensive care unit (NICU), with relevant economic burden for health care systems.3 Notably, despite being necessary to survival, the NICU environment exposes preterm infants to a variety of stressful conditions such as chronic pain via skin-breaking procedures, physical stressors (eg, lights and sounds), and forced maternal separation.4 As these stressors have been associated with long-lasting consequences for neurobehavioral development, preterm birth and NICU stay are a critical early adverse experience for human infants.
Early Adverse Experiences Getting Under the Skin Methylation of DNA is an epigenetic process that implies the tie of a methyl group to a cytosine-rich site, mainly within the promoter region of a gene, resulting in transcriptional activity silencing.1 This process is highly susceptible to variations in maternal care, mediating the effects of a variety of environmental stressors. In humans, genome-wide and gene-specific epigenetic alterations related to exposure to a great variety of early life stressors (eg, mundane stress, maternal depres-
sion, low socioeconomic condition) have been linked with infants’ stress reactivity later during development.1
Preterm Behavioral Epigenetics Epigenetic processes have been associated with a number of early adverse experiences in humans and, recently, with the effects of NICU-related stress on preterm infants.5 From this point of view, preterm birth and the NICU environment constitute a naturally occurring context in which stressful environment and early health care might be studied in human infants. Gene-specific alterations of DNA methylation have been reported in preterm newborns from day 0 to day 4 after birth.6 However, only 1 study to date has investigated the epigenetic vestiges of preterm birth, assessing long-term epigenetic and behavioral effects of pain exposure in premature infants.5 Preterm behavioral epigenetics (PBE) might lead to relevant findings about the biological correlates of NICU-related stressors.5,7 Moreover, it should be noted that postnatal caregiving variations also act through epigenetic modifications in animals, leading to a reversal of DNA methylation changes due to previous stress exposure.1 Hence, it can be speculated that DC in the NICU (eg, active engagement of parents in skinto-skin caregiving practices) might be effective in protecting preterm infants from long-lasting health consequences through epigenetic mechanisms. Nonetheless, PBE investigations are warranted in relation to both the adverse and protective effects of NICU stay.
“Epigenethics” in the NICU The rapid growth in HBE has been suggested to be at risk for a new form of determinism rooted in nurture, as it might convey simplistic conceptualization of maternal care effects on infant development.2 On the one side, it is certainly true that, as humans, we grow inside restricted hierarchically organized care groups in which caregiving is delivered by adults, especially during an initial period of relative unreadiness to the challenges of the outside world. Nonetheless, it should be noted that while the caregiver (usually, the mother) plays a crucial role in offspring development, adult caregiving is complex and interwoven with broader environmental care effects. Human behavioral epigenetics holds potential to reveal the effects of this broader care environment on child health, integrating intracellular (ie, DNA methylation changes) and interpersonal (eg, mother-infant relationship, socioeconomic resources, mundane stress) environments. As NICU stay is characterized by a number of protective and risk environmental factors, PBE would stand as a paradigmatic case to show that mater(Reprinted) JAMA Pediatrics July 2015 Volume 169, Number 7
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of New South Wales User on 08/04/2015
617
Opinion Viewpoint
nal care is only a piece of the puzzle and that the role of nonmaternal environmental care should be considered. As such, we preliminarily propose potential ethical caveats for PBE research, which might be useful to sustain a complex view on HBE applied to the context of critical infant health care. First, epigenetic research on animal models has revealed methylation correlates of variations in maternal care during the early sensitive period of development for better and for worse. Nonetheless, translating animal findings to humans is a misleading strategy and direct investigations in human infants are warranted, although different methodological approaches are required (eg, in humans we cannot assess for epigenetic changes directly in the central nervous system, and peripheral tissues are usually investigated).1 Second, as DC implies the active engagement of both caregivers and the clinical staff in delivering skin-to-skin support and regulation to the immature preterm infant, multiple sources of protective care are involved. Consequently, PBE would help in conveying complexity in NICU health care practice, highlighting epigenetic correlates of a complex net of stressors and care interventions. As such, PBE would guard against the assumption of a linear and deterministic view of adverse experience and caregiving effects on human early development. Third, NICU practices are highly susceptible to implicit cultural and local health philosophies and the quality of DC may vary substantially among NICUs in different countries. Preterm behavioral epi-
Conclusions Although PBE is a promising field of applied research for neonatal health care, several issues remain.5-7 Epigenetic processes may vary depending on the neurodevelopmental stage of the brain at the time of stress exposure. Thus, an interesting question is whether epigenetic changes might be developmentally time sensitive. Moreover, the epigenetic markers of NICU-related stress need to be addressed both through cross-sectional studies (ie, comparing different levels of DC and preterm infants with different clinical conditions) and longitudinally (ie, through follow-up evaluations during the first years of life). At the clinical level, identifying sensitive periods and protective care factors might support the development of timed and targeted interventions to reduce negative outcomes.7 Consequently, although avoiding any deterministic approach is imperative, there is the intriguing possibility that the quality of NICU care might be effective in reducing preterm infants’ stress exposure via epigenetic mechanisms. The application of epigenetics to prematurity can convey a complex ethics framework to inform research and clinical practice, helping to provide smarter and tailored care to preterm infants.
drafting of the work; they received no compensation.
ARTICLE INFORMATION Published Online: May 4, 2015. doi:10.1001/jamapediatrics.2015.43. Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Italian Health Ministry. Role of the Funder/Sponsor: The Italian Health Ministry had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. Additional Contributions: Sara Biloni, PsyD, Erica Casini, PsyD, Claudia Fedeli, PsyD, Barbara Premoli, PsyD, and Renato Borgatti, MD, PhD, 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Bosisio Parini, Lecco, Italy, provided insightful suggestions and comments during the
618
genetics might be useful in depicting subtle, yet influential effects of sociocultural variations in NICU care practices, underscoring the processes through which implicit choices at the level of health care systems are embedded in the developing biology of at-risk infants.
REFERENCES 1. Griffiths BB, Hunter RG. Neuroepigenetics of stress. Neuroscience. 2014;275:420-435. 2. Tang AC, Reeb-Sutherland BC, Romeo RD, McEwen BS. On the causes of early life experience effects: evaluating the role of mom. Front Neuroendocrinol. 2014;35(2):245-251. 3. Blencowe H, Cousens S, Chou D, et al; Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013;10(suppl 1):S2. 4. Vinall J, Grunau RE. Impact of repeated procedural pain-related stress in infants born very preterm. Pediatr Res. 2014;75(5):584-587.
5. Chau CM, Ranger M, Sulistyoningrum D, Devlin AM, Oberlander TF, Grunau RE. Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age. Front Behav Neurosci. 2014;8:409. 6. Kantake M, Yoshitake H, Ishikawa H, Araki Y, Shimizu T. Postnatal epigenetic modification of glucocorticoid receptor gene in preterm infants: a prospective cohort study. BMJ Open. 2014;4(7): e005318. 7. Montirosso R, Provenzi L. Implications of epigenetics and stress regulation on research and developmental care of preterm infants. J Obstet Gynecol Neonatal Nurs. 2015;44(2):174-182.
JAMA Pediatrics July 2015 Volume 169, Number 7 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of New South Wales User on 08/04/2015
jamapediatrics.com
VIEWPOINT
Livio Provenzi, PsyD 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy. Rosario Montirosso, PsyD 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
“Epigenethics” in the Neonatal Intensive Care Unit Conveying Complexity in Health Care for Preterm Children Human behavioral epigenetics (HBE) is a fascinating area of research that holds promise to change our view of nature-nurture interconnection. In particular, the study of changes in DNA methylation applied to human development is revealing pathways through which early adversities are embedded in the developing biology of children, contributing to long-lasting programming of health and disease.1 Notwithstanding, HBE holds the risk of a new reductionism grounded in nurture instead of nature. Researchers and clinicians have been recently warned about the lure of epigenetics and the risk of translating animal results and interpreting human findings in a strict deterministic way.2 Critically, misleading conclusions would convey the idea of a direct impact of maternal behavior and physiology on the long-term wellbeing of infants and children, without taking into account the importance of the broader socioeconomic and health care environment. Herein, we reflect on HBE, referring to prematurity as an example to highlight potential benefits for research and clinical practice as well as ethical issues conveying a complex view of neonatal health care.
Prematurity and Neonatal Intensive Care Unit Stay as an Early Adverse Experience
Corresponding Author: Rosario Montirosso, PsyD, 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Scientific Institute, IRCCS Eugenio Medea, via Don Luigi Monza 20, 23842 Bosisio Parini, Lecco, Italy (rosario.montirosso @bp.lnf.it). jamapediatrics.com
Preterm birth is a major concern for health care services. In the United States, prematurity constitutes 12% of total live births.3 Preterm infants have a moderate to severe immature neurobehavioral profile at birth, needing highintensityinterventionsanddevelopmentalcare(DC)inthe neonatal intensive care unit (NICU), with relevant economic burden for health care systems.3 Notably, despite being necessary to survival, the NICU environment exposes preterm infants to a variety of stressful conditions such as chronic pain via skin-breaking procedures, physical stressors (eg, lights and sounds), and forced maternal separation.4 As these stressors have been associated with long-lasting consequences for neurobehavioral development, preterm birth and NICU stay are a critical early adverse experience for human infants.
Early Adverse Experiences Getting Under the Skin Methylation of DNA is an epigenetic process that implies the tie of a methyl group to a cytosine-rich site, mainly within the promoter region of a gene, resulting in transcriptional activity silencing.1 This process is highly susceptible to variations in maternal care, mediating the effects of a variety of environmental stressors. In humans, genome-wide and gene-specific epigenetic alterations related to exposure to a great variety of early life stressors (eg, mundane stress, maternal depres-
sion, low socioeconomic condition) have been linked with infants’ stress reactivity later during development.1
Preterm Behavioral Epigenetics Epigenetic processes have been associated with a number of early adverse experiences in humans and, recently, with the effects of NICU-related stress on preterm infants.5 From this point of view, preterm birth and the NICU environment constitute a naturally occurring context in which stressful environment and early health care might be studied in human infants. Gene-specific alterations of DNA methylation have been reported in preterm newborns from day 0 to day 4 after birth.6 However, only 1 study to date has investigated the epigenetic vestiges of preterm birth, assessing long-term epigenetic and behavioral effects of pain exposure in premature infants.5 Preterm behavioral epigenetics (PBE) might lead to relevant findings about the biological correlates of NICU-related stressors.5,7 Moreover, it should be noted that postnatal caregiving variations also act through epigenetic modifications in animals, leading to a reversal of DNA methylation changes due to previous stress exposure.1 Hence, it can be speculated that DC in the NICU (eg, active engagement of parents in skinto-skin caregiving practices) might be effective in protecting preterm infants from long-lasting health consequences through epigenetic mechanisms. Nonetheless, PBE investigations are warranted in relation to both the adverse and protective effects of NICU stay.
“Epigenethics” in the NICU The rapid growth in HBE has been suggested to be at risk for a new form of determinism rooted in nurture, as it might convey simplistic conceptualization of maternal care effects on infant development.2 On the one side, it is certainly true that, as humans, we grow inside restricted hierarchically organized care groups in which caregiving is delivered by adults, especially during an initial period of relative unreadiness to the challenges of the outside world. Nonetheless, it should be noted that while the caregiver (usually, the mother) plays a crucial role in offspring development, adult caregiving is complex and interwoven with broader environmental care effects. Human behavioral epigenetics holds potential to reveal the effects of this broader care environment on child health, integrating intracellular (ie, DNA methylation changes) and interpersonal (eg, mother-infant relationship, socioeconomic resources, mundane stress) environments. As NICU stay is characterized by a number of protective and risk environmental factors, PBE would stand as a paradigmatic case to show that mater(Reprinted) JAMA Pediatrics July 2015 Volume 169, Number 7
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of New South Wales User on 08/04/2015
617
Opinion Viewpoint
nal care is only a piece of the puzzle and that the role of nonmaternal environmental care should be considered. As such, we preliminarily propose potential ethical caveats for PBE research, which might be useful to sustain a complex view on HBE applied to the context of critical infant health care. First, epigenetic research on animal models has revealed methylation correlates of variations in maternal care during the early sensitive period of development for better and for worse. Nonetheless, translating animal findings to humans is a misleading strategy and direct investigations in human infants are warranted, although different methodological approaches are required (eg, in humans we cannot assess for epigenetic changes directly in the central nervous system, and peripheral tissues are usually investigated).1 Second, as DC implies the active engagement of both caregivers and the clinical staff in delivering skin-to-skin support and regulation to the immature preterm infant, multiple sources of protective care are involved. Consequently, PBE would help in conveying complexity in NICU health care practice, highlighting epigenetic correlates of a complex net of stressors and care interventions. As such, PBE would guard against the assumption of a linear and deterministic view of adverse experience and caregiving effects on human early development. Third, NICU practices are highly susceptible to implicit cultural and local health philosophies and the quality of DC may vary substantially among NICUs in different countries. Preterm behavioral epi-
Conclusions Although PBE is a promising field of applied research for neonatal health care, several issues remain.5-7 Epigenetic processes may vary depending on the neurodevelopmental stage of the brain at the time of stress exposure. Thus, an interesting question is whether epigenetic changes might be developmentally time sensitive. Moreover, the epigenetic markers of NICU-related stress need to be addressed both through cross-sectional studies (ie, comparing different levels of DC and preterm infants with different clinical conditions) and longitudinally (ie, through follow-up evaluations during the first years of life). At the clinical level, identifying sensitive periods and protective care factors might support the development of timed and targeted interventions to reduce negative outcomes.7 Consequently, although avoiding any deterministic approach is imperative, there is the intriguing possibility that the quality of NICU care might be effective in reducing preterm infants’ stress exposure via epigenetic mechanisms. The application of epigenetics to prematurity can convey a complex ethics framework to inform research and clinical practice, helping to provide smarter and tailored care to preterm infants.
drafting of the work; they received no compensation.
ARTICLE INFORMATION Published Online: May 4, 2015. doi:10.1001/jamapediatrics.2015.43. Conflict of Interest Disclosures: None reported. Funding/Support: This work was supported by the Italian Health Ministry. Role of the Funder/Sponsor: The Italian Health Ministry had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. Additional Contributions: Sara Biloni, PsyD, Erica Casini, PsyD, Claudia Fedeli, PsyD, Barbara Premoli, PsyD, and Renato Borgatti, MD, PhD, 0-3 Center for the Study of Social Emotional Development of the At-Risk Infant, Bosisio Parini, Lecco, Italy, provided insightful suggestions and comments during the
618
genetics might be useful in depicting subtle, yet influential effects of sociocultural variations in NICU care practices, underscoring the processes through which implicit choices at the level of health care systems are embedded in the developing biology of at-risk infants.
REFERENCES 1. Griffiths BB, Hunter RG. Neuroepigenetics of stress. Neuroscience. 2014;275:420-435. 2. Tang AC, Reeb-Sutherland BC, Romeo RD, McEwen BS. On the causes of early life experience effects: evaluating the role of mom. Front Neuroendocrinol. 2014;35(2):245-251. 3. Blencowe H, Cousens S, Chou D, et al; Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013;10(suppl 1):S2. 4. Vinall J, Grunau RE. Impact of repeated procedural pain-related stress in infants born very preterm. Pediatr Res. 2014;75(5):584-587.
5. Chau CM, Ranger M, Sulistyoningrum D, Devlin AM, Oberlander TF, Grunau RE. Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age. Front Behav Neurosci. 2014;8:409. 6. Kantake M, Yoshitake H, Ishikawa H, Araki Y, Shimizu T. Postnatal epigenetic modification of glucocorticoid receptor gene in preterm infants: a prospective cohort study. BMJ Open. 2014;4(7): e005318. 7. Montirosso R, Provenzi L. Implications of epigenetics and stress regulation on research and developmental care of preterm infants. J Obstet Gynecol Neonatal Nurs. 2015;44(2):174-182.
JAMA Pediatrics July 2015 Volume 169, Number 7 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of New South Wales User on 08/04/2015
jamapediatrics.com
