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Preterm newborns can be exposed early to significant perinatal stress, and this stress can increase the risk of altered socioemotional development. Sustained social withdrawal in infants is an early indicator of emotional distress which is expressed by low reactivity to the environment, and if persistent, is frequently associated with altered psychological development. Infants born prematurely have a higher probability of developing sustained social withdrawal (adjusted odds ratio 1.84, 95% CI 1.04-3.26) than infants born full term, and there is a correlation between weight at birth and sustained social withdrawal at 12 months of age.
The aims of this study are to compare the effect of the interactive guidance intervention to that of routine pediatric care on sustained social withdrawal in infants born moderately or late preterm and to explore the relationship between sustained social withdrawal in these infants and factors such as neonatal intensive care unit hospitalization variables, parental depression, and posttraumatic stress symptoms.
This study is designed as a multicenter randomized controlled trial. Moderate and late preterm newborns and their parents were recruited and randomized (1:1 allocation ratio) to control and experimental groups. During neonatal intensive care unit hospitalization, daily duration of skin-to-skin contact, breastfeeding, and parental visits were recorded. Also, a daily score for neonatal pain and painful invasive procedures were recorded. After discharge from neonatal intensive care, for the duration of the study, both groups will attend follow-up consultations with neonatologists at 2, 6, and 12 months of age (corrected for gestational age) and will receive routine pediatric care. Every consultation will be recorded and assessed with the Alarm Distress Baby Scale to detect sustained social withdrawal (indicated by a score of 5 or higher). The neonatologists will perform an interactive guidance intervention if an infant in the intervention group exhibits sustained social withdrawal. In each follow-up consultation, parents will fill out the Edinburgh Postnatal Depression Scale, the modified Perinatal Posttraumatic Stress Disorder Questionnaire, and the Impact of Event Scale–revised.
Recruitment for this trial started in September 2017. As of May 2020, we have completed enrollment (N=110 infants born moderately or late preterm). We aim to publish the results by mid-2021.
This is the first randomized controlled trial with a sample of infants born moderately or late preterm infants who will attend pediatric follow-up consultations during their first year (corrected for gestational age at birth) with neonatologists trained in the Alarm Distress Baby Scale and who will receive this interactive guidance intervention. If successful, this early intervention will show significant potential to be implemented in both public and private health care, given its low cost of training staff and that the intervention takes place during routine pediatric follow-up.
ClinicalTrials.gov NCT03212547; https://clinicaltrials.gov/ct2/show/NCT03212547.
DERR1-10.2196/17943
In infants in the normal range of development, skills to engage with caregivers such as initiating and maintaining eye contact, vocalizing, using facial expressions, and using body movements, emerge during the first two months after birth [
Infants can display social withdrawal behaviors as a reaction to minor transient perturbations when interacting with caregivers or when agitated or tired; however, infants are usually able to reengage as soon as they regain the full attention of the caregivers [
Sustained social withdrawal has typically been associated with severe pathological conditions in infancy such as posttraumatic stress disorder [
The Alarm Distress Baby Scale is a well-validated screening tool designed to assess sustained social withdrawal in infants between 2 and 24 months of age in primary care settings such as routine medical checkups or testing [
Infants born preterm often spend their first days, weeks, or even months in a neonatal intensive care unit where they undergo numerous painful and invasive procedures [
Several studies have shown that the prevalence of psychopathologies appeared to be significantly higher in infants born preterm than in infants born full term. So far, most studies have focused on infants born very prematurely and have shown high prevalence of autistic spectrum disorders [
In their first year (corrected for gestational age), infants born preterm have a higher probability of developing sustained social withdrawal (adjusted odds ratio 1.84, 95% CI 1.04-3.26) when compared to that of infants born full term [
In Chile, preterm birth rates have been increasing over the last decade. In 2016, 8.3% of live births were preterm (gestational age less than 37 weeks) [
Since intervention becomes more challenging as problems in infancy grow more complex or more severe [
The Alarm Distress Baby Scale [
The main objective of this study is to compare the effect of an interactive guidance intervention on sustained social withdrawal scores in infants born moderately or late preterm compared to those of infants born moderately or late preterm in routine pediatric care.
The study is designed as a randomized controlled trial (NCT03212547), in order to remove bias in treatment allocation and the effect of possible confounding variables [
Only preterm infants born from single or twin pregnancy (monochorionic or dichorionic), born between 32 weeks 0 days and 36 weeks 6 days gestation (as determined by neonatologist), hospitalized within the first 48 hours after birth, and remaining at least 48 hours in the neonatal intensive care unit were eligible to participate in this study. Parents of the infants were required to be Spanish speaking and have stable living arrangements to ensure the effectiveness of the interactive guidance intervention (carried out by Spanish-speaking neonatologists). Parents of infants born preterm were recruited from two neonatal intensive care units—Clinica Alemana de Santiago and Hospital San Jose—by a principal investigator or co-investigator of the study or by the neonatal study coordinator. Clinica Alemana de Santiago is a private health center located in a district of Santiago, Chile with a poverty rate of 0.1% whereas Hospital San Jose is a public health center located in a district of Santiago, Chile with a poverty rate of 8.2% [
Infants were not eligible for participation in this study if their mother had history of or confirmed exposure to cocaine, marijuana, or other illicit mind-altering substances during pregnancy; if the infant had a neurological disease that impairs development that was confirmed at birth; if the infant had major congenital malformations, suspected or confirmed genetic disorders; and if perinatal asphyxia occurred at birth (defined as an Apgar score less than 3 at 1 minute or an Apgar score less than 5 at 5 minutes, or cord pH less than 7.0 at birth).
For this study, in 2017, Bonifacino et al [
One fundamental element of the training was that the professionals learned not only to detect the sustained social withdrawal behaviors (and to score these behaviors using the Alarm Distress Baby Scale), but also to meaningfully show the parents how—in terms of communication or contact—their infants seek interaction, with the objective of reducing sustained social withdrawal behaviors.
Participants of the study will be recruited during their admission to the neonatal intensive care units by members of the researcher team and enrolled and randomized by a study coordinator to either the intervention or the control group. The infant will be randomized in a 1:1 allocation using SPSS Statistics (version 25.0; IBM Corp), stratified by hospital center (Clinica Alemana de Santiago or Hospital San Jose) in blocks of four. Also, infants will be stratified into two groups, single or twin pregnancy, in order to isolate the intervention effect from that of other covariables (such as mother of twins learning). The Hospital San Jose sample will also be stratified into two groups, whether the infant is included or is not included in the Kangaroo Care program, since only Hospital San Jose currently offers this program that aims to promote mother infant bonding, and which could potentially act as a confounding variable.
As shown in
Interactive Guidance Intervention plan for infants born moderately or late preterm with primary and secondary outcome variables recorded during NICU admission and during medical checkups at 2, 6, and 12 months of corrected age. ADBB: Alarm Distress Baby scale; EPDS: Edinburgh Postnatal Depression scale; IES-R: Impact of Event scale–revised; IGI: Interactive Guidance Intervention; NICU: neonatal intensive care; PPQ-M: modified Perinatal Posttraumatic Stress Disorder Questionnaire; SSW: sustained social withdrawal.
The families of the infants born moderately or late preterm, randomly assigned to intervention or control group, will remain blind to which group they belong. Families will receive feedback on their infant’s Alarm Distress Baby Scale score by telephone after the final assessment at the 12-month medical checkup and will be offered further assessment and intervention, if needed.
Neonatologists who care for participants during the trial will be aware of whether the infant is in the intervention or control group. The Alarm Distress Baby Scale–trained neonatologists will only perform follow-up for the intervention group, and neonatologists who provide routine pediatric care will only perform follow-up for the control group.
The principal investigator (JBL) will also be an external evaluator. Though, an Alarm Distress Baby Scale–trained psychologist, JBL will not participate in the follow-up of any of the infants and will be blind to the Alarm Distress Baby Scale scores of the Alarm Distress Baby Scale–trained neonatologists. Scores will be entered into the database by an independent agent who is blind to the group category.
The Alarm Distress Baby Scale–trained neonatologists will be blind to the Alarm Distress Baby Scale scores of the external evaluators and to those of the other Alarm Distress Baby Scale–trained neonatologists. Once they record an Alarm Distress Baby Scale score, this data will be collected by a study coordinator, who is blind to the group category.
Data collection assessors will collect all study data (all variables) and upload the data into the database. They were not trained in the Alarm Distress Baby Scale, are blind to the group category, and do not have contact with the infants or their families.
We used the G*Power 3 software (Psychonomic Society Inc) to determine the minimum sample size required for obtaining a significant medium effect size (an effect size of 0.25), given α=.05 and a statistical power of 0.80 (β=.20), using the results presented in Bonifacino et al [
Alarm Distress Baby Scale [
Edinburgh Postnatal Depression Scale [
Impact of Event Scale–revised [
Modified Perinatal Posttraumatic Stress Disorder Questionnaire [
Premature Infant Pain Profile [
As shown in
Summary of the steps of the interactive guidance intervention during medical checkup.
The main objective of this intervention is to reduce sustained social withdrawal behaviors in moderately and late preterm infants by (1) detecting sustained social withdrawal behaviors during medical checkup, (2) becoming attuned with the interaction rhythm of the infant, (3) meaningfully showing parents how their infant seeks to interact by pointing out specific interactive behaviors (every interaction skill displayed by the infant), and ( 4) inviting parents to engage in the interaction.
Infants born preterm have a higher probability of developing sustained social withdrawal, and withdrawn infants show poor performance during interaction [
In the intervention group, this interactive guidance intervention will be performed if the trained neonatologist detects sustained social withdrawal during the 2, 6, and 12-month medical checkups. The interactive guidance intervention will be performed during the 20 to 30-minute medical checkup and will not require any extra time. The interactive guidance intervention will be supplemented with a written guide for parents called Early Interaction Guidelines. The objective of this written guideline is to enhance the effect of interactive guidance intervention.
In the control group, infants will receive routine pediatric care. At the 2, 6, and 12-month medical checkups (also lasting 20 to 30 minutes), parents will be given a Development Stimulation Guide which has been adapted from Ministry of Health of Chile Guidelines for the Stimulation of Development [
If any infant in the study (in either the intervention or the control group) shows sustained social withdrawal (a score or 5 or higher on the Alarm Distress Baby Scale) at the 12-month medical checkup, they will be offered additional interventions by the researcher team.
The primary outcome is sustained social withdrawal assessed using the Alarm Distress Baby Scale. The Alarm Distress Baby Scale categorizes the level of sustained social withdrawal according to the sum of the score—scores from 0 to 4 indicate no sustained social withdrawal, scores from 5 to 9 indicate moderate sustained social withdrawal, and scores equal to or higher than 10 indicate severe sustained social withdrawal. Infants born moderately or late preterm will be assessed with the Alarm Distress Baby Scale during medical checkups at 2, 6, and 12 months of age.
The secondary outcomes measured during neonatal intensive care unit admission are neonatal pain and daily duration of parental visits, skin-to-skin contact, and breastfeeding; and the secondary outcomes measured after medical discharge are postpartum depression symptoms and posttraumatic stress symptoms which will be assessed at the 2, 6, and 12-month medical checkups. A socioeconomic survey, a substance-use survey, and a perinatal background questionnaire will be used to obtain additional information from the parents of the infants.
Two-tailed paired
The study was approved by the
The clinical trial is ongoing. It was funded in December 2016, approved by institutional review board on April 25, 2017. Data collection started on September 19, 2017. As of May of 2020, enrollment has been completed (N=110 infants born moderately or late preterm). We aim to publish the results by mid-2021. The data sets from this study will be available by request from the corresponding author, once results have been published.
This project is a logical continuation of the work in Bonifacino et al [
This is the first randomized controlled trial that will be performed with infants born moderately or late preterm at follow-up pediatric checkups. The implementation of an interactive guidance intervention will allow Alarm Distress Baby Scale–trained professionals who use this interactive guidance intervention as a model to intervene for infants at risk.
One of the limitations of this study is the possibility that the parents of infants included in the intervention group will share information with parents of infants included in the control group. For this reason, twins are randomized together (both either in the control or in the intervention group). Additionally, all parents included in the study will be asked to refrain from sharing the written guides used in the study with others until the study is finished.
Another limitation is the pain protocol established at each institution. Clinica Alemana de Santiago has had a standardized pain protocol since 2012 that includes administering the Premature Infant Pain Profile every 3 hours while, in Hospital San Jose, the standardized pain protocol does not include the Premature Infant Pain Profile. Before the start of study recruitment, training was performed by nurses of Clinica Alemana de Santiago in order to teach the midwives in Hospital San Jose how to administer the Premature Infant Pain Profile. At Hospital San Jose, this is only done for the infants included in the study.
The interactive guidance intervention does not involve any risk to the participating infants and parents. The neonatologists will follow routine medical care protocols at medical checkups and will only perform the interactive guidance intervention (verbally) if they detect sustained social withdrawal. Currently, the neonatologists on the investigation team are the only follow-up neonatologists trained in the Alarm Distress Baby Scale in Chile, so these infants will receive an evaluation and an intervention that is otherwise not currently available in either the public or in the private health system. Finally, if any infant scores 5 or higher on the Alarm Distress Baby Scale at the 12-month medical checkup (final assessment), they will be offered further assessment and intervention.
This investigation is funded by the Grant Fund 2016 of Clinica Alemana de Santiago granted by their Academic and Scientific Department. The Investigation and Clinical Trials Unit of Clinica Alemana de Santiago, which is a division of the Academic and Scientific Department, supervises all clinical trials realized in Clinica Alemana de Santiago assuring compliance with the Good Clinical Practices and the requirements of the Health Public Institute of Chile in accordance with their current Guide of Inspection of Clinical and Pharmacological Studies. The funding body has not participated in the study design, data collection, data analysis, interpretation of data, or in writing the manuscript.
The authors gratefully acknowledge the heads of the Investigation and Clinical Trials Unit of Clinica Alemana de Santiago, Pablo Lavados and Maria Alicia Mordojovich, for supervising this PhD investigation. Also, Jorge Roque, Deputy Director of the Medical Area of Clinica Alemana de Santiago, the former head of the neonatal intensive care unit of Clinica Alemana de Santiago, Marcial Osorio and the head of the neonatal intensive care unit of Hospital San Jose, Agustina Gonzalez, and Paola Henriquez, the study coordinator, for supporting the investigation. We want to acknowledge the Spain Association for Infant Mental Health Since Gestation and the Doctoral Programme in Clinical and Health Psychology of University of Valencia for their supervision and support. Thank you to the nurse and midwife staff at Clinica Alemana de Santiago and Hospital San Jose neonatal intensive care units. We also like to thank our collaborative partners doing the data collection: Katherine Rossel, Emilia Rey, Juan Carlos Muñoz, Patricia Vernal, Ximena Solivelles, Andrea Hoces, Francisca Cortes, Maria Paz Aguilera, and Daniela Galleguillos. Without their efforts, the study would not have been possible.
JBL conceived and designed the study, drafted the manuscript, and coordinated the Clinica Alemana de Santiago and Hospital San Jose research teams. MPR participated in the study design, provided critical review, and coordinated the Clinica Alemana de Santiago research team. AG, PPS, and SS participated in the study design and provided critical review. MMN coordinated Hospital San Jose research team and provided critical review. HC, JGM, LM, and LL provided critical review. AM and RSG participated in the manuscript and provided critical review. AMS planned the statistical analysis and provided critical review. All authors read and approved the final manuscript.
This study is funded by the Academic and Scientific Department of Clinica Alemana de Santiago, and the study protocol has undergone peer review by the funding body. Clinica Alemana de Santiago is part of a nonprofit Chilean-German charity corporation and adheres to the Good Clinical Practices and the requirements of the Instituto de Salud Pública de Chile (Public Health Institute of Chile) in accordance with their current Guide of Inspection of Clinical and Pharmacological Studies.