Neonatal Abstinence Syndrome
Conditions
Keywords
Buprenorphine, Methadone, Fetal neurobehavior, Infant neurobehavior
Brief summary
This research will track the longitudinal neurobehavioral development of the buprenorphine-exposed fetus across gestation through 1 month of age in an effort to determine the safety of this medication for use during gestation, the relationship between maternal physiologic changes due to buprenorphine administration and newborn functioning, and to determine potential fetal neurobehavioral markers that may predict Neonatal Abstinence Syndrome expression and infant neurobehavioral outcome. Comparisons to results from a similar project in methadone-exposed pregnancies will be made. This proposal seeks to advance the way the investigators inform the treatment of the opioid dependent woman during pregnancy and her infant after birth.
Detailed description
There is an increase in the prevalence of illicit opiate use among women of childbearing age in many countries today. Methadone is the treatment of choice for opioid dependency during pregnancy in the US because it markedly diminishes withdrawal symptoms and craving and blocks opioid effects, however, in utero exposure results in significant depression of fetal neurobehaviors such as fetal heart rate and heart rate variability and fetal motor activity, and significant neonatal abstinence syndrome (NAS) in the majority of exposed infants. Since its approval in 2002, the prescription of buprenorphine for opioid dependence has increased dramatically but, as with methadone, this mediation is not approved for use during pregnancy. Currently, women treated with buprenorphine prior to pregnancy are transitioned to methadone treatment due to a lack of information regarding the effects of buprenorphine on the developing fetus and infant. Pilot work by this research team suggests that buprenorphine- as compared to methadone-exposed fetuses display more optimal neurobehavioral functioning in the second and third trimesters of pregnancy. Although these results are encouraging, there is a critical need to explore fully the effects of this medication on the fetus and infant to adequately advise care providers and patients regarding its use. This is particularly true given the imminent publication of a pivotal study comparing buprenorphine to methadone treatment during pregnancy which has suggested the optimality of buprenorphine for the treatment of opioid dependence during pregnancy, and is likely to result in increasing numbers of women being treated with off-label buprenorphine during pregnancy. This proposal seeks to explore the effect of buprenorphine on maternal physiology and fetal neurobehavioral functioning longitudinally as a measure of the development of the fetal nervous system. Additionally, the neurobehavioral profile and NAS of the buprenorphine-exposed infant up to one month will be delineated in an effort to provide information necessary to provide optimal pharmacologic and non-pharmacologic treatment of NAS. Furthermore, this group has previously explored similar parameters in methadone-exposed fetuses and infants, and results of this study can be compared to those historical data. These parameters will advance our understanding of the way the investigators view and implement the future pharmacologic treatment of the opiate dependent woman during pregnancy and her infant after birth, and inform clinicians, health insurance companies and regulatory agencies in the provision of optimal care to the opioid dependent pregnant woman and her offspring before and after birth.
Interventions
DRUGBuprenorphine
Daily sublingual buprenorphine treatment of pregnant, opioid dependent women from up to 34 weeks gestation through one month of infant age.
Sponsors
Johns Hopkins University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 40 Years
Healthy volunteers
No
Inclusion criteria
* Current opioid dependence as defined by Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-R criteria * 18-40 years of age with uncomplicated singleton pregnancies * Accurate gestational age dating verified by ultrasound * Gestation of less than 34 weeks * Stabilization on buprenorphine for one week prior to study procedures
Exclusion criteria
* Complications of pregnancy, including gestational diabetes, polyhydramnios, hypertension, placenta previa or significant risk of preterm delivery (i.e. incompetent cervix) * Evidence of fetal malformation detected by prenatal ultrasound * Significant general maternal health problems that can affect fetal functioning, including Type I or gestational diabetes, alterations in thyroid functioning, HIV infection or hypertension. * Significant maternal psychopathology that would preclude informed consent (i.e. schizophrenia) * Alcohol dependency per DSM IV R criteria (see ascertainment methods below) * Women stable on methadone maintenance (defined as more than 3 days of methadone dosing) * Women entering drug treatment reporting using street methadone (for more than 3 days)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fetal Heart Rate | 24, 28, 32 and 36 weeks of gestation | Fetal heart rate in beats per minute at time of trough and peak maternal buprenorphine levels |
| Fetal Heart Rate Variability | 24, 28, 32 and 36 weeks of gestation | Fetal heart rate variability at 24, 28, 32 and 36 weeks of gestation at times of trough and peak maternal buprenorphine levels |
| Accelerations of Fetal Heart Rate | 24, 28, 32 36 weeks of gestation | Number of accelerations of fetal heart rate exhibited during the 60 minute recordings |
| Fetal Movement | 24, 28, 32, 36 weeks of gestation | Fetal movement (number x duration of fetal movements) during the 60 minute recordings at times of trough and peak maternal buprenorphine levels |
| Fetal Movement - Fetal Heart Rate Coupling | 24, 28, 32, 36 weeks of gestation | The integration between fetal movements and heart rate (FM-FHR coupling) was quantified as the proportion of time individual movements were associated with a change in FHR, using previously developed criteria. FM-FHR coupling reflects coactivation of the sympathetic and parasympathetic components of the autonomic nervous system. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from a comprehensive care treatment facility for pregnant and postpartum women with substance use disorders between Feb 2012 and March 2016
Pre-assignment details
Participants must have an opioid use disorder, a singleton, generally uncomplicated pregnancy, be between 18 and 40 years of age, have accurate gestational age dating of less than 34 weeks, willing to receive obstetric care at the center and deliver their infant at the hospital affiliated with the treatment facility.
Participants by arm
| Arm | Count |
|---|---|
| Fetal Daily sublingual buprenorphine treatment of pregnant, opioid dependent women Subjects completing any maternal-fetal monitoring at any combination of the following gestational ages: 24, 28, 32 36 weeks | 49 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 17 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 59 |
Baseline characteristics
| Characteristic | Fetal |
|---|---|
| Age at first substance use | 19.8 years STANDARD_DEVIATION 4.8 |
| Age at regular substance use | 21.0 years STANDARD_DEVIATION 4.6 |
| Age, Continuous | 27.6 years STANDARD_DEVIATION 4.4 |
| Buprenorphine dose at 24 weeks if gestation | 12.0 mg STANDARD_DEVIATION 7.1 |
| Buprenorphine dose at 28 weeks if gestation | 12.3 mg STANDARD_DEVIATION 6 |
| Buprenorphine dose at 32 weeks if gestation | 12.7 mg STANDARD_DEVIATION 6.3 |
| Buprenorphine dose at 36 weeks if gestation | 12.8 mg STANDARD_DEVIATION 6.5 |
| Duration of regular substance use upon treatment entry | 6.5 years STANDARD_DEVIATION 4.4 |
| Education | 11.5 years STANDARD_DEVIATION 1.9 |
| Gestational age upon treatment entry | 21.3 weeks STANDARD_DEVIATION 7 |
| Length of time in treatment prior to delivery | 121.1 days STANDARD_DEVIATION 56.7 |
| Positive research urine toxicology screening at delivery | 19.7 percent positive urine tox. screenings STANDARD_DEVIATION 25.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 49 Participants |
| Sex: Female, Male Male | 0 Participants |
| Urine toxicology screenings during treatment | 16.4 number of screenings STANDARD_DEVIATION 8 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 49 |
| other Total, other adverse events | 15 / 49 |
| serious Total, serious adverse events | 1 / 49 |
Outcome results
Primary
Accelerations of Fetal Heart Rate
Number of accelerations of fetal heart rate exhibited during the 60 minute recordings
Time frame: 24, 28, 32 36 weeks of gestation
| Arm | Measure | Value (MEAN) |
|---|---|---|
| FHR 24 Weeks Trough | Accelerations of Fetal Heart Rate | 0.52 accelerations |
| FHR 28 Weeks Trough | Accelerations of Fetal Heart Rate | 1.59 accelerations |
| FHR 32 Weeks Trough | Accelerations of Fetal Heart Rate | 3.57 accelerations |
| FHR 36 Weeks Trough | Accelerations of Fetal Heart Rate | 5.28 accelerations |
| FHR 24 Weeks Peak | Accelerations of Fetal Heart Rate | 0.43 accelerations |
| FHR 28 Weeks Peak | Accelerations of Fetal Heart Rate | 2.12 accelerations |
| FHR 32 Peak | Accelerations of Fetal Heart Rate | 2.29 accelerations |
| FHR 36 Peak | Accelerations of Fetal Heart Rate | 2.25 accelerations |
p-value: 0.0001Hierarchical Linear Modeling
Primary
Fetal Heart Rate
Fetal heart rate in beats per minute at time of trough and peak maternal buprenorphine levels
Time frame: 24, 28, 32 and 36 weeks of gestation
Population: Participants active in the protocol at 24, 28, 32 and 36 weeks, respectively
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHR 24 Weeks Trough | Fetal Heart Rate | 145.7 beats per minute | Standard Deviation 5.8 |
| FHR 28 Weeks Trough | Fetal Heart Rate | 143.3 beats per minute | Standard Deviation 5.4 |
| FHR 32 Weeks Trough | Fetal Heart Rate | 138.6 beats per minute | Standard Deviation 6 |
| FHR 36 Weeks Trough | Fetal Heart Rate | 136.3 beats per minute | Standard Deviation 7.1 |
| FHR 24 Weeks Peak | Fetal Heart Rate | 143.9 beats per minute | Standard Deviation 6.4 |
| FHR 28 Weeks Peak | Fetal Heart Rate | 141.0 beats per minute | Standard Deviation 4.8 |
| FHR 32 Peak | Fetal Heart Rate | 135.4 beats per minute | Standard Deviation 6.3 |
| FHR 36 Peak | Fetal Heart Rate | 131.3 beats per minute | Standard Deviation 6.1 |
p-value: 0.001Hierarchical Linear Modeling
Primary
Fetal Heart Rate Variability
Fetal heart rate variability at 24, 28, 32 and 36 weeks of gestation at times of trough and peak maternal buprenorphine levels
Time frame: 24, 28, 32 and 36 weeks of gestation
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHR 24 Weeks Trough | Fetal Heart Rate Variability | 5.4 msec | Standard Deviation 1.3 |
| FHR 28 Weeks Trough | Fetal Heart Rate Variability | 6.7 msec | Standard Deviation 1.9 |
| FHR 32 Weeks Trough | Fetal Heart Rate Variability | 7.5 msec | Standard Deviation 3 |
| FHR 36 Weeks Trough | Fetal Heart Rate Variability | 7.9 msec | Standard Deviation 2.1 |
| FHR 24 Weeks Peak | Fetal Heart Rate Variability | 4.9 msec | Standard Deviation 1.5 |
| FHR 28 Weeks Peak | Fetal Heart Rate Variability | 7.3 msec | Standard Deviation 1.8 |
| FHR 32 Peak | Fetal Heart Rate Variability | 7.0 msec | Standard Deviation 2.7 |
| FHR 36 Peak | Fetal Heart Rate Variability | 6.3 msec | Standard Deviation 2.1 |
p-value: <0.002Hierarchical Linear Modeling
Primary
Fetal Movement
Fetal movement (number x duration of fetal movements) during the 60 minute recordings at times of trough and peak maternal buprenorphine levels
Time frame: 24, 28, 32, 36 weeks of gestation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHR 24 Weeks Trough | Fetal Movement | 1496.2 seconds | Standard Deviation 752 |
| FHR 28 Weeks Trough | Fetal Movement | 1390.0 seconds | Standard Deviation 795.4 |
| FHR 32 Weeks Trough | Fetal Movement | 1458.7 seconds | Standard Deviation 674.6 |
| FHR 36 Weeks Trough | Fetal Movement | 1446.7 seconds | Standard Deviation 979.5 |
| FHR 24 Weeks Peak | Fetal Movement | 1613.0 seconds | Standard Deviation 575.6 |
| FHR 28 Weeks Peak | Fetal Movement | 1385.7 seconds | Standard Deviation 674.5 |
| FHR 32 Peak | Fetal Movement | 1381.2 seconds | Standard Deviation 830.7 |
| FHR 36 Peak | Fetal Movement | 1038.2 seconds | Standard Deviation 756.2 |
p-value: 0.008Hierarchical Linear Modeling
Primary
Fetal Movement - Fetal Heart Rate Coupling
The integration between fetal movements and heart rate (FM-FHR coupling) was quantified as the proportion of time individual movements were associated with a change in FHR, using previously developed criteria. FM-FHR coupling reflects coactivation of the sympathetic and parasympathetic components of the autonomic nervous system.
Time frame: 24, 28, 32, 36 weeks of gestation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FHR 24 Weeks Trough | Fetal Movement - Fetal Heart Rate Coupling | 0.13 percentage of time FM assoc w FHR change | Standard Deviation 0.06 |
| FHR 28 Weeks Trough | Fetal Movement - Fetal Heart Rate Coupling | 0.21 percentage of time FM assoc w FHR change | Standard Deviation 0.07 |
| FHR 32 Weeks Trough | Fetal Movement - Fetal Heart Rate Coupling | 0.23 percentage of time FM assoc w FHR change | Standard Deviation 0.1 |
| FHR 36 Weeks Trough | Fetal Movement - Fetal Heart Rate Coupling | 0.25 percentage of time FM assoc w FHR change | Standard Deviation 0.11 |
| FHR 24 Weeks Peak | Fetal Movement - Fetal Heart Rate Coupling | 0.09 percentage of time FM assoc w FHR change | Standard Deviation 0.06 |
| FHR 28 Weeks Peak | Fetal Movement - Fetal Heart Rate Coupling | 0.20 percentage of time FM assoc w FHR change | Standard Deviation 0.09 |
| FHR 32 Peak | Fetal Movement - Fetal Heart Rate Coupling | 0.21 percentage of time FM assoc w FHR change | Standard Deviation 0.1 |
| FHR 36 Peak | Fetal Movement - Fetal Heart Rate Coupling | 0.20 percentage of time FM assoc w FHR change | Standard Deviation 0.1 |
p-value: 0.002Hierarchical Linear Modeling