A Randomized Controlled Trial to Improve Mother-Infant Synchrony Among Women With Childhood Adversity

Study Overview
=================
Brief Summary
-----------------
Childhood adversity affects almost two-thirds of the US population, is a major risk factor for the leading causes of disease and increases US economic health burdens. Childhood adversity also alters biologic systems, such as the oxytocin hormone, that can affect attachment behavior. This innovative study has the potential to advance science and improve mother-infant interaction by testing an early life, home-based, multisensory behavioral intervention (called ATVV), targeting the oxytocin system, to promote synchronous early mother-infant interaction, especially critical for mothers who have experienced childhood adversity. This two-group randomized clinical trial will test the ATVV's effect on oxytocin system function and quality of mother-infant interaction. The investigators will enroll 250 first-time healthy mothers carrying a single baby who have a history of childhood adversity, and obtain baseline data in their third trimester of pregnancy. Soon after birth (before hospital discharge), mothers (and babies) who continue to be eligible are randomized into the intervention group and taught to give ATVV daily for 3 months, or randomized into the Attention Control education group and taught safe infant care. After birth, the investigators check-in frequently with mothers through weekly phone calls. There are 3 study visits at 1, 2 and 3 months after birth that include survey questions and collection of maternal blood and infant saliva. Mothers and babies are also video-recorded at 3 months after birth for 4 minutes to assess mother-infant interaction. The investigators follow-up with a phone call at 6 months after birth. While both groups will benefit from the content and attention the investigators give mothers, the investigators hypothesize that, compared to the education group, mothers and infants in the intervention group will have improved oxytocin system function and more synchronous mother-infant interaction.

Detailed Description
-----------------
Childhood adversity (e.g., abuse, neglect, or household dysfunction), is a common experience significantly contributing to the leading causes of death and increased US economic health burdens. Childhood adversity causes long-term alterations on the nervous, endocrine, and immune systems well into adulthood, including dampening of the neuropeptide oxytocin (OXT). A healthy OXT system facilitates responsive social engagement and promotes maternal-infant (M-I) synchrony (reciprocal gaze, affect speech, and touch). Optimal M-I synchrony fuels early brain development and prevents low empathy, disruptive behavior, poor social adaptation, cognitive deficits, and psychopathology in children. The investigators posit that mothers with childhood adversity will have more difficulty with M-I synchrony, due in part to a dampened OXT system, and will benefit from interventions that improve responsive, nurturing, engagement by epigenetic regulation of the OXT system. Most interventions are costly, complex, and time-consuming. The investigators aim to fill this gap by testing whether a simple early behavioral intervention (ATVV) will improve OXT system function and M-I synchrony in mothers with childhood adversity. The ATVV (Auditory, Tactile, Visual, Vestibular) is a 15-minute behavioral intervention that is a multisensory infant massage contingent on infant cues. The investigators extend the known success of ATVV with preterm infants to full-term infants. The investigators will compare M-I synchrony at 3 postnatal months in 250 first-time mothers (and their full-term infants) randomized to apply ATVV daily from birth to 3 months (n =125) or receive infant care education in an attention control group (n = 125). The investigators apply a rigorous measure of M-I synchrony that micro-codes video-recorded M-I behavior quantifying shared gaze, affect, speech, and touch. Coding requires only 3-minutes of interaction and is valid when infants can reliably interact starting by 3 months of age. The investigators will also assess ATVV's effect on maternal and infant peripheral OXT level, a known biomarker of M-I synchrony. OXT levels relate to quality of M-I synchrony, yet the investigators extend this knowledge to identify an epigenetic role of the oxytocin receptor gene (OXTR). The investigators will analyze maternal plasma for OXTR methylation, OXTR gene expression, OXTR protein, and oxytocin peptide in pregnancy, and at 1, 2, and 3 postnatal months (along with infant saliva OXT). The investigators propose a single-site, randomized, two-group, attention-controlled clinical trial (N=250 M-I dyads) to test the efficacy of the ATVV multisensory behavioral intervention to improve OXT system function and M-I synchrony. Adult, nulliparous, English or Spanish speaking women carrying a single fetus, and scoring 2 or higher on the Adverse Childhood Experiences scale will be enrolled. The investigators will obtain baseline OXT, demographics and survey data in the third trimester. Soon after birth (pre-hospital discharge), M-I dyads who continue to be eligible (e.g., full-term gestation) are randomized into the intervention group (n = 125) and taught to administer ATVV daily for 3 months or randomized into the Attention Control group (n = 125) and taught normal safe infant care. There are postnatal study visits at 1, 2 and 3 months. The investigators follow-up with a phone call at 6 postnatal months (3-months after the intervention period ends) to assess self-report parenting behavior (a proxy for quality of M-I interaction) that the investigators also measure at postnatal months 1, 2, and 3. Aim 1: Evaluate the efficacy of daily ATVV over 3 postnatal months among mothers with childhood adversity. The investigators hypothesize that compared to the Attention Control group (n=125), M-I dyads in the ATVV group (n=125) will exhibit: H1: Higher oxytocin function (i.e., decreased OXTR methylation at candidate sites, and increased OXTR messenger ribonucleic acid (mRNA), OXTR protein, and OXT in maternal plasma, and increased OXT in infant saliva) at 1, 2, and 3 postnatal months. H2: More synchronous eye-to-eye gaze [primary], positive affect [primary], speech, and touch at 3 postnatal months. Aim 2: Identify molecular mechanisms in the OXT system underlying M-I synchrony (N=250). H1: Lower M-I synchrony will be associated with dampening of the OXT system, evidenced by increased OXTR methylation at candidate sites, and decreased OXTR mRNA, OXTR protein, and OXT in maternal plasma, and decreased OXT in infant saliva at 3-postnatal months. Regression based methods (including covariates) will assess ATVV effects on M-I synchrony and OXT measures, and identify relations among M-I synchrony and oxytocin measures. Clustering methods will be used to discover molecular profiles. An early behavioral intervention that successfully promotes M-I synchrony in vulnerable women through epigenetic regulation of the OXT system can then be tested in a multi-site clinical implementation trial with other high-risk groups. Protocol: The Recruiter will introduce the study to potentially eligible pregnant women. Eligible women who are interested in joining will be consented and scheduled for a 3rd trimester baseline study visit at the university. The investigators will draw blood for OXT measures, and collect data in REDCap on demographics, maternal characteristics, and self-report surveys. Research team members will keep track of when participants have given birth and meet them in a study site hospital before discharged. The investigators will collect data on mother and infant health, birth events, and other covariates. At the hospital visit, women are randomly assigned to either the ATVV group and taught how to administer the intervention on a daily basis, or are randomly assigned to the Attention Control group and taught safe infant newborn care. All participants will receive daily texts to measure daily stress, and intervention participants also document frequency of the intervention. Using Participatory Guidance to address women's needs, the investigators will call women each week after birth for a check-in. In the intervention group, any challenges with the intervention will be discussed and problem-solved. In the Attention Control group, age-appropriate safe infant care will be discussed. After the hospital visit, monthly study visits at 1, 2, and 3 months include collecting maternal blood and infant saliva, and self-report surveys in REDCap. Women will either complete REDCap surveys online before each visit, or complete them at the study visit. To check intervention fidelity, mothers in the ATVV group demonstrate how they perform the intervention with their infant. The team member instructs mothers how to adapt the ATVV to their maturing infant and discuss any challenges with the intervention. Mothers in the Attention Control group are taught age-appropriate safe infant care. At the 3rd month study visit, the investigators collect behavioral outcome data on M-I synchrony. All M-I dyads will be video recorded freely interacting with each other for 4 minutes (coding occurs on the last 3 minutes). Video recording occurs when the infant is alert and ready to interact, > 30 minutes after the end of a breastfeeding or formula feeding, and data collection order may be adjusted if the baby is sleepy or fussy. Interactions are micro-coded frame by frame on a computerized system (Noldus, Wageningen, The Netherlands), consistent with previous research on parent-infant synchrony. Coders, blinded to group assignment, are trained to 90% inter-rater reliability. Our last interaction with participants is a phone call at 6-postnatal months to explore duration of the intervention's effect using the Parenting Stress Index.

Official Title
-----------------
A Randomized Controlled Trial to Improve Mother-Infant Synchrony Among Women With Childhood Adversity

Conditions
-----------------
Parent-Child Relations, Maternal Behavior, Infant Behavior

Intervention / Treatment
-----------------
* Behavioral: ATVV
* Behavioral: Attention control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pregnant Healthy (gestational diabetes is acceptable) Greater than or equal to 18 years old Nulliparous (previous miscarriage(s) and/or abortion(s) acceptable) Speak and read English or Spanish Score greater than or equal to 2 on the Adverse Childhood Experience (ACE) survey Expect to deliver a healthy infant Expect to deliver a full-term infant (greater than or equal to 37 weeks and 0/7 days) Expect to deliver a singleton infant Exclusion Criteria: Multiparous Have no access to a cell phone during the first 3 postnatal months Carrying multiple fetuses Taking anti-depressant(s) during pregnancy Taking illicit drugs Do not speak and read English or Spanish; Under 18 years of age Score less than 2 on the Adverse Childhood Experience (ACE) survey Deliver an infant diagnosed with conditions that could affect normal development or the oxytocin system Pre-term gestation (less than 37 weeks and 0/7 days) Intrauterine growth retardation (IGR) Small for gestational age (SGA) Chromosomal anomaly including Down syndrome (trisomy 21) Trisomy 13 trisomy 18 Klinefelter syndrome Turner syndrome Triple X syndrome Congenital anomaly including Heart defect Musculoskeletal defect Neural tube defect Cystic Fibrosis Haemophilia Microcephaly

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This randomized clinical trial uses group comparison of an intervention group and an education control group.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Behavioral ATVV intervention<br>A multi-sensory behavioral intervention that includes auditory, tactile, visual and vestibular (ATVV) stimulation contingent upon infant cues. | Behavioral: ATVV<br>* A 15-minute behavioral intervention that mothers administer once daily to their infant for 3 months providing Auditory, Tactile, Visual, and Vestibular (ATVV) stimulation. Multisensory stimuli are presented in gradual progression. Mother-infant engagement is attempted throughout ATVV so that mothers learn to identify, interpret and adapt to their infants cues. ATVV can be given without eye to eye gaze making it appropriate for newborns. ATVV is offered contingent on infant cues to promote self-regulation and withdrawn if any persistent disengagement cues. Mothers are taught how to adapt ATVV as their infant grows. Fidelity to the intervention is checked with weekly phone calls and monthly study visits. Mothers also receive a daily text from REDCap to document an intervention frequency log.<br>* Other names: multisensory infant massage plus;|
| Active Comparator: Attention control<br>An attention control group that receives education on safe infant care and the same amount of attention as the intervention group. | Behavioral: Attention control<br>* Mothers in the Attention Control group receive a similar amount of daily texts, weekly phone call and in-person study visit attention as mothers in the ATVV group, but with distinctly different content. Over the first 3 postnatal months, mothers learn safe infant-care that includes content on diapers, infant clothing, blankets, infant care including bathing, sleep positions, sleep habits, holding the baby, safety of infant equipment, breastfeeding, formula, and age appropriate toys.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mother-Infant Synchrony, Gaze and Affect | 3-minute video-recordings of mothers freely interacting with their infant and micro-coded later for mother-infant behaviors that reflect mother-infant synchrony. Behaviors are categorized into mutually exclusive codes. The most robust behavior categories for mothers and infants (individually and in synchrony) are gaze and affect. | 84 +/- 7days from birth (approximately 3 months after birth) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mother-Infant Synchrony, Vocalization and Touch | 3-minute video-recordings of mothers freely interacting with their infant and micro-coded later for mother-infant behaviors that reflect mother-infant synchrony. Behaviors are categorized into mutually exclusive codes. The second most robust behavior categories for mothers and infants (individually and in synchrony) are vocalization and touch. | 84 +/- 7days from birth (approximately 3 months after birth) | 
| Oxytocin receptor gene DNA methylation reflecting epigenetic marks | Using maternal plasma, % OXTR DNA methylation will be measured at candidate cytosine-phosphate-guanosine (CpG) sites -1001, -959, -934, -924, -901, and -860 that were selected based on their implication in previous studies relating to psychosocial behaviors. There is also cost-effectiveness in using the selected assay to co-target additional CpG regions implicated in the literature relating to psychosocial behaviors. Methylation is measured using bisulfite conversion (EZ DNA Lightning Kit), followed by high-throughput next-generation sequencing of polymerase chain reaction (PCR) amplicons (Illumina MiSeq) at the University of Arizona Genetics Core. | Baseline at 31weeks +/- 2 weeks gestation and every 28 days +/- 7 days from birth to 3 months | 
| Oxytocin receptor gene expression | Using maternal plasma, OXTR mRNA level will be measured using quantitative Real-Time PCR (qRT-PCR) that demonstrates total OXTR gene expression. This reflects the DNA transcribed (copied) into RNA before translation produces protein. Analysis is performed by the College of Nursing Biological Core Laboratory. | Baseline at 31weeks +/- 2 weeks gestation and every 28 days +/- 7 days from birth to 3 months | 
| Oxytocin receptor protein | Using maternal plasma, total protein expression of OXTR will be measured to reflect the amount of OXT receptors available to bind with OXT peptides. Analysis is performed by the College of Nursing Biological Core Laboratory using Anti-OXTR antibody and Western Blot (considered to be the gold standard). | Baseline at 31weeks +/- 2 weeks gestation and every 28 days +/- 7 days from birth to 3 months | 
| Oxytocin peptide | Using maternal plasma and infant saliva, the ELISA assay will be used to report OXT peptide level. Samples are analyzed at the University of Arizona Laboratory for the Evolutionary Endocrinology of Primates (LEEP) in duplicate by enzyme immunoassay (EIA) using the Oxytocin ELISA kit (Enzo; ADI-901-153A-0001). | Baseline at 31weeks +/- 2 weeks gestation and every 28 days +/- 7 days from birth to 3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Oxytocin, DNA methylation, Massage, Mothers, Infant, Adverse childhood experiences, Mother-infant interaction, Maternal behavior, Infant behavior, Receptor, oxytocin, Randomized controlled trial