Neonatal Abstinence Syndrome
Conditions
Keywords
Stochastic Resonance, Fetus/Newborn Infant, Drug Withdrawal, Substance Abuse
Brief summary
The purpose of this study is to examine the efficacy of a specially-constructed crib mattress that delivers gentle vibrations (stochastic vibrotactile stimulation) as a complementary, non-pharmacological intervention for treating drug withdrawal in newborns exposed to opioids in utero.
Detailed description
This study will test the therapeutic efficacy of stochastic vibrotactile stimulation (SVS) for reducing withdrawal symptoms, pharmacological treatment and hospitalization, and for improving neurobehavioral developmental outcomes in opioid-exposed newborns. Candidates at-risk for NAS due opioid exposure in utero will be identified to investigators by medical caregiver and/or prescreened using HIPAA Waiver for recruitment (maternal-prenatal; infant-postnatal). Infants will be randomized into either SVS (complementary to standard of care) or Treatment as Usual (TAU), restricted by equipment (mattress) availability. Infants will be enrolled and assigned to a condition within 48 hours post birth and participate throughout hospitalization. Infants assigned SVS will receive daily intervention of continuous intervals of SVS throughout hospitalization using a specially constructed crib mattress that delivers gentle vibrations at preset intervals. Specific Aim 1. Determine the efficacy of SVS as a non-pharmacological therapy complementary to standard of care for reducing severity and duration of opioid withdrawal in newborns compared to TAU alone. Quantify clinical variables: NAS severity, treatment days, days in hospital, velocity of weight gain, cumulative morphine dose. Specific Aim 2. Compare neurobehavioral outcomes in fetal drug-exposed infants between infants who received SVS and those who received TAU. Longitudinal outcomes assessment at 6-months and 1 year to test whether early intervention with SVS compared to standard care improves physical, social, emotional and cognitive development.
Interventions
Infant crib mattress will be replaced with a specially constructed mattress (non-commercially available) to provide gentle, stochastic vibration during mattress stimulations.
Sponsors
University of Pittsburgh
National Institute on Drug Abuse (NIDA)
University of Massachusetts, Worcester
Elisabeth B Salisbury
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Hours to 18 Months
Healthy volunteers
No
Inclusion criteria
Eligible subjects are infants currently in the NICU or Newborn Nursery at University of Massachusetts Memorial Hospital or at Magee Women's Hospital of UPMC and: * Full-term infants (≥37 wks gestational age) * Newborns at risk for NAS due to opioid-exposure in utero * At-risk infants will be infants who present with confirmed meconium and/or urine toxicology report and/or documented medical record for opioids (e.g., methadone, buprenorphine/subutex, oxycodone, heroin); may also have prenatal exposure to benzodiazepines, barbiturates, amphetamines, cannabinoids, alcohol, nicotine and/or caffeine.
Exclusion criteria
Eligible infants meeting the inclusion criteria above will be excluded from participation in the study if he/she: * Born less than \<37weeks. * Has a clinically significant congenital abnormality * Has a clinically significant fetal anomaly * Has hydrocephalus or intraventricular hemorrhage \>grade 2 * Has a seizure disorder not related to drug withdrawal * Has a clinically significant cardiac shunt * Has anemia (hemoglobin\<8g/dL) * Requires mechanical respiratory support * Has MRSA or infection at time of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurobehavioral Outcomes Assessment | 6 month and 12 months of life | Scores for Cognitive Domain Bayley Scales of Infant and Toddler Development Third Edition. The standardized scores have a mean of 100 and standard deviation (SD) of 15. Scores below 1 SD (= or less than 84) is considered below normal. Scores above 1 SD (\>115) represent higher than normal functioning. |
| Number of Participants Administered Morphine Treatment | Participants will be monitored for the duration of their newborn nursery stay, which is an expected mean of 7 days | Number of infants treated with morphine (first line pharmacotherapy at both sites). Number of infants who received pharmacotherapy (met clinical criteria to treat), index of NAS severity (per Finnegan scores). |
| Cumulative Pharmacological Treatment- Morphine Dose | Participants will be monitored for the duration of their hospitalization, which is an expected mean of 21 days | Normalized cumulative morphine dose for infants who completed treatment at respective hospital site (mg/kg). |
| Hospitalization Length of Stay | Day of life infants discharged home, which is an expected mean of 21 days. | Day of life discharged home for untreated and treated infants who completed hospitalization at study site. Duration of infant hospitalization-Days |
| Hospitalization Length of Stay for Untreated Infants | Day of life untreated infants discharged home, which is an expected mean of 21 days. | Day of life discharged home for untreated infants (infants whose Finnegan scores did not meet criteria to treat) who completed hospitalization at study site. Duration of infant hospitalization-Days |
| Hospitalization Length of Stay for Treated Infants | Day of life treated infants discharged home, which is an expected mean of 21 days. | Day of life discharged home for treated infants (infants whose Finnegan scores met criteria to treat) who completed hospitalization at study site. Duration of infant hospitalization-Days |
| Length of Pharmacological Treatment-Duration | Participants will be monitored for the duration of their hospitalization, which is an expected mean of 21 days | For infants who received pharmacotherapy, total days of morphine treatment. |
| Trajectory of Symptom Severity Among Treated Infants | Day of life infant started morphine treatment | Days to start morphine treatment based on Finnegan severity scores among infants who met clinical criteria to treat |
| Velocity of Weight Gain | Participants will be monitored for the duration of their hospitalization, which is an expected mean of 21 days | Weight loss precedes weight gain in newborns. Days to weight nadir, defined as the lowest weight following birthweight. Velocity of weight gain was measured as days to return to birthweight, i.e., the day on which weight reached or surpassed birthweight following initial weight loss from birth. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Respiratory Rate | Assess respiratory rate for about 12 consecutive hours at week 1 of infant hospitalization | Respiratory rate at 1 week of age assessed for about 12 consecutive hours in a subset of subjects |
Countries
United States
Participant flow
Recruitment details
Infants recruited at UMass between March 9, 2017 and February 25, 2020; Infants recruited at Pitt between and August 18, 2017 and March 10, 2020. Enrollment was terminated early due to Covid-19 in-person study restrictions and unanticipated reduction and relocation of project personnel (208 recruited/220 anticipated enrollment).
Participants by arm
| Arm | Count |
|---|---|
| Stochastic Vibrotactile Stimulation (SVS) Infants randomized to this arm will receive daily intervals of continuous SVS (ON) and no SVS (OFF) throughout hospitalization, starting within 48-hrs post birth. SVS will be complementary to standard of clinical care (e.g., clinically-determined pharmacological management; routine parental/volunteer holding; breast and/or bottle feed).
Stochastic Vibrotactile Stimulation (SVS): Infant crib mattress will be replaced with a specially constructed mattress (non-commercially available) to provide gentle, stochastic vibration during mattress stimulations. | 105 |
| Treatment as Usual (TAU) Infants randomized to this arm will be enrolled within 48-hours post birth and receive treatment as usual (TAU)- standard of clinical care (e.g., clinically-determined pharmacological management, routine/volunteer holding; breast and/or bottle feed). Infants will not receive any SVS. | 103 |
| Total | 208 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Subsequently met exclusion/withdrawal criteria | 3 | 5 |
| Overall Study | Transferred to another hospital | 8 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 4 |
Baseline characteristics
| Characteristic | Stochastic Vibrotactile Stimulation (SVS) | Treatment as Usual (TAU) | Total |
|---|---|---|---|
| Age, Continuous | 39.1 weeks STANDARD_DEVIATION 1.2 | 38.9 weeks STANDARD_DEVIATION 1.2 | 39.0 weeks STANDARD_DEVIATION 1.2 |
| Birthweight | 3081 grams STANDARD_DEVIATION 528 | 3054 grams STANDARD_DEVIATION 445 | 3068 grams STANDARD_DEVIATION 488 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 11 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants | 85 Participants | 175 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 19 Participants | 17 Participants | 36 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) White | 75 Participants | 78 Participants | 153 Participants |
| Sex: Female, Male Female | 58 Participants | 57 Participants | 115 Participants |
| Sex: Female, Male Male | 47 Participants | 46 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 105 | 1 / 103 |
| other Total, other adverse events | 0 / 105 | 0 / 103 |
| serious Total, serious adverse events | 1 / 105 | 1 / 103 |
Outcome results
Primary
Cumulative Pharmacological Treatment- Morphine Dose
Normalized cumulative morphine dose for infants who completed treatment at respective hospital site (mg/kg).
Time frame: Participants will be monitored for the duration of their hospitalization, which is an expected mean of 21 days
Population: Analyzed cohort who received morphine treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Cumulative Pharmacological Treatment- Morphine Dose | 7.3 mg/kg | Standard Deviation 6.6 |
| Treatment as Usual (TAU) | Cumulative Pharmacological Treatment- Morphine Dose | 8.2 mg/kg | Standard Deviation 7.5 |
p-value: 0.62t-test, 2 sided
Primary
Hospitalization Length of Stay
Day of life discharged home for untreated and treated infants who completed hospitalization at study site. Duration of infant hospitalization-Days
Time frame: Day of life infants discharged home, which is an expected mean of 21 days.
Population: Untreated and treated infants who completed hospitalization at study site.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Hospitalization Length of Stay | 11.5 day of life discharged home | Standard Deviation 11 |
| Treatment as Usual (TAU) | Hospitalization Length of Stay | 13.5 day of life discharged home | Standard Deviation 14.6 |
p-value: 0.29t-test, 2 sided
Primary
Hospitalization Length of Stay for Treated Infants
Day of life discharged home for treated infants (infants whose Finnegan scores met criteria to treat) who completed hospitalization at study site. Duration of infant hospitalization-Days
Time frame: Day of life treated infants discharged home, which is an expected mean of 21 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Hospitalization Length of Stay for Treated Infants | 24.1 day of life discharged home | Standard Deviation 12.7 |
| Treatment as Usual (TAU) | Hospitalization Length of Stay for Treated Infants | 27.7 day of life discharged home | Standard Deviation 17 |
p-value: 0.36t-test, 2 sided
Primary
Hospitalization Length of Stay for Untreated Infants
Day of life discharged home for untreated infants (infants whose Finnegan scores did not meet criteria to treat) who completed hospitalization at study site. Duration of infant hospitalization-Days
Time frame: Day of life untreated infants discharged home, which is an expected mean of 21 days.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Hospitalization Length of Stay for Untreated Infants | 5.9 day of life discharged home | Standard Deviation 1.6 |
| Treatment as Usual (TAU) | Hospitalization Length of Stay for Untreated Infants | 5.7 day of life discharged home | Standard Deviation 1.3 |
p-value: 0.55t-test, 2 sided
Primary
Length of Pharmacological Treatment-Duration
For infants who received pharmacotherapy, total days of morphine treatment.
Time frame: Participants will be monitored for the duration of their hospitalization, which is an expected mean of 21 days
Population: Analyzed cohort who received morphine treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Length of Pharmacological Treatment-Duration | 19.9 days | Standard Deviation 12.7 |
| Treatment as Usual (TAU) | Length of Pharmacological Treatment-Duration | 21.6 days | Standard Deviation 9.4 |
p-value: 0.56t-test, 2 sided
Primary
Neurobehavioral Outcomes Assessment
Scores for Cognitive Domain Bayley Scales of Infant and Toddler Development Third Edition. The standardized scores have a mean of 100 and standard deviation (SD) of 15. Scores below 1 SD (= or less than 84) is considered below normal. Scores above 1 SD (\>115) represent higher than normal functioning.
Time frame: 6 month and 12 months of life
Population: Study infants who participated in follow-up assessments post hospitalization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Neurobehavioral Outcomes Assessment | Cognitive Score at 6 months | 99.1 score on a scale | Standard Deviation 17.6 |
| Stochastic Vibrotactile Stimulation (SVS) | Neurobehavioral Outcomes Assessment | Cognitive Score at 12 months | 101.5 score on a scale | Standard Deviation 13.1 |
| Treatment as Usual (TAU) | Neurobehavioral Outcomes Assessment | Cognitive Score at 6 months | 98.1 score on a scale | Standard Deviation 15.6 |
| Treatment as Usual (TAU) | Neurobehavioral Outcomes Assessment | Cognitive Score at 12 months | 98.8 score on a scale | Standard Deviation 13.2 |
Primary
Number of Participants Administered Morphine Treatment
Number of infants treated with morphine (first line pharmacotherapy at both sites). Number of infants who received pharmacotherapy (met clinical criteria to treat), index of NAS severity (per Finnegan scores).
Time frame: Participants will be monitored for the duration of their newborn nursery stay, which is an expected mean of 7 days
Population: Analyzed infants: completed hospitalization at respective study site
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Number of Participants Administered Morphine Treatment | 29 Participants |
| Treatment as Usual (TAU) | Number of Participants Administered Morphine Treatment | 31 Participants |
p-value: 0.6Chi-squared
Primary
Trajectory of Symptom Severity Among Treated Infants
Days to start morphine treatment based on Finnegan severity scores among infants who met clinical criteria to treat
Time frame: Day of life infant started morphine treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Trajectory of Symptom Severity Among Treated Infants | 2.5 day of life started treatment | Standard Deviation 1.2 |
| Treatment as Usual (TAU) | Trajectory of Symptom Severity Among Treated Infants | 2.9 day of life started treatment | Standard Deviation 1.8 |
p-value: 0.25t-test, 2 sided
Primary
Velocity of Weight Gain
Weight loss precedes weight gain in newborns. Days to weight nadir, defined as the lowest weight following birthweight. Velocity of weight gain was measured as days to return to birthweight, i.e., the day on which weight reached or surpassed birthweight following initial weight loss from birth.
Time frame: Participants will be monitored for the duration of their hospitalization, which is an expected mean of 21 days
Population: Nadir was obtained in treated and untreated infants who completed hospitalization at study site. Weight gain was obtained only in pharmacologically treated infants; untreated infants were discharged prior to weight gain.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Stochastic Vibrotactile Stimulation (SVS) | Velocity of Weight Gain | Nadir | 4.98 days | Standard Deviation 1.49 |
| Stochastic Vibrotactile Stimulation (SVS) | Velocity of Weight Gain | Return to Birthweight | 12.38 days | Standard Deviation 3.87 |
| Treatment as Usual (TAU) | Velocity of Weight Gain | Return to Birthweight | 13.48 days | Standard Deviation 4.01 |
| Treatment as Usual (TAU) | Velocity of Weight Gain | Nadir | 5.05 days | Standard Deviation 1.55 |
Other Pre-specified
Respiratory Rate
Respiratory rate at 1 week of age assessed for about 12 consecutive hours in a subset of subjects
Time frame: Assess respiratory rate for about 12 consecutive hours at week 1 of infant hospitalization