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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Maternal buprenorphine treatment | Experimental | Buprenorphine maintenance during pregnancy |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Buprenorphine | Drug | Daily sublingual buprenorphine treatment of pregnant, opioid dependent women from up to 34 weeks gestation through one month of infant age. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Fetal Heart Rate | Fetal heart rate in beats per minute at time of trough and peak maternal buprenorphine levels | 24, 28, 32 and 36 weeks of gestation |
| 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 | 24, 28, 32 and 36 weeks of gestation |
| Accelerations of Fetal Heart Rate | Number of accelerations of fetal heart rate exhibited during the 60 minute recordings | 24, 28, 32 36 weeks of gestation |
| Fetal Movement | Fetal movement (number x duration of fetal movements) during the 60 minute recordings at times of trough and peak maternal buprenorphine levels | 24, 28, 32, 36 weeks of gestation |
| 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. | 24, 28, 32, 36 weeks of gestation |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Lauren M Jansson, MD | Johns Hopkins University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Center for Addiction and Pregnancy | Baltimore | Maryland | 21224 | United States | ||
| Johns Hopkins Bayview Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20868741 | Background | Jansson LM, Dipietro JA, Velez M, Elko A, Williams E, Milio L, O'Grady K, Jones HE. Fetal neurobehavioral effects of exposure to methadone or buprenorphine. Neurotoxicol Teratol. 2011 Mar-Apr;33(2):240-3. doi: 10.1016/j.ntt.2010.09.003. Epub 2010 Sep 22. | |
| 29223912 | Derived | Velez ML, McConnell K, Spencer N, Montoya L, Tuten M, Jansson LM. Prenatal buprenorphine exposure and neonatal neurobehavioral functioning. Early Hum Dev. 2018 Feb;117:7-14. doi: 10.1016/j.earlhumdev.2017.11.009. Epub 2017 Dec 7. |
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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 were recruited from a comprehensive care treatment facility for pregnant and postpartum women with substance use disorders between Feb 2012 and March 2016
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| ID | Title | Description |
|---|---|---|
| FG000 | Maternal Buprenorphine Treatment | Daily sublingual buprenorphine treatment of pregnant, opioid dependent women Subjects undergo maternal-fetal monitoring at any combination of the following gestational time periods: 24, 28,32, 36 weeks of gestation |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Fetal Heart Rate | Fetal heart rate in beats per minute at time of trough and peak maternal buprenorphine levels | Participants active in the protocol at 24, 28, 32 and 36 weeks, respectively | Posted | Mean | Standard Deviation | beats per minute | 24, 28, 32 and 36 weeks of gestation |
|
3 years, 3 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Maternal Buprenorphine Treatment | Buprenorphine maintenance during pregnancy Buprenorphine: Daily sublingual buprenorphine treatment of pregnant, opioid dependent women from up to 34 weeks gestation through one month of infant age. Two severe adverse events were reported in the same infant patient. One infant had congenital heart disease and polydactyly |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Severe adverse event | Congenital, familial and genetic disorders | Non-systematic Assessment | One infant born to a buprenorphine maintained mother in the protocol had polydactyly The infant had a family history of polydactyly |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cholestasis of pregnancy | Hepatobiliary disorders | Non-systematic Assessment | Three participants developed cholestasis of pregnancy. All three had concurrent Hepatitis C infection and were therefore at increased risk for this condition. |
Small sample size
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Lauren M Jansson | Johns Hopkins University School of Medicine | 410-550-5438 | ljansson@jhmi.edu |
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| ID | Term |
|---|---|
| D009357 | Neonatal Abstinence Syndrome |
| ID | Term |
|---|---|
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D019966 | Substance-Related Disorders |
| D064419 | Chemically-Induced Disorders |
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| ID | Term |
|---|---|
| D002047 | Buprenorphine |
| ID | Term |
|---|---|
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
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|
| Baltimore |
| Maryland |
| 21224 |
| United States |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Education | Mean | Standard Deviation | years |
|
| Age at first substance use | Mean | Standard Deviation | years |
|
| Age at regular substance use | Mean | Standard Deviation | years |
|
| Duration of regular substance use upon treatment entry | Mean | Standard Deviation | years |
|
| Gestational age upon treatment entry | Mean | Standard Deviation | weeks |
|
| Length of time in treatment prior to delivery | Mean | Standard Deviation | days |
|
| Buprenorphine dose at 24 weeks if gestation | Mean | Standard Deviation | mg |
|
| Buprenorphine dose at 28 weeks if gestation | Mean | Standard Deviation | mg |
|
| Buprenorphine dose at 32 weeks if gestation | Mean | Standard Deviation | mg |
|
| Buprenorphine dose at 36 weeks if gestation | Mean | Standard Deviation | mg |
|
| Urine toxicology screenings during treatment | Mean | Standard Deviation | number of screenings |
|
| Positive research urine toxicology screening at delivery | Mean | Standard Deviation | percent positive urine tox. screenings |
|
| FHR 32 Weeks Trough |
Fetal heart rate in beats per minute at 32 weeks of gestation at time of trough maternal buprenorphine level |
| OG003 | FHR 36 Weeks Trough | Fetal heart rate in beats per minute at 36 weeks of gestation at time of trough maternal buprenorphine level |
| OG004 | FHR 24 Weeks Peak | Fetal heart rate in beats per minute at 24 weeks of gestation at time of peak maternal buprenorphine level |
| OG005 | FHR 28 Weeks Peak | Fetal heart rate in beats per minute at 28 weeks of gestation at time of peak maternal buprenorphine level |
| OG006 | FHR 32 Peak | Fetal heart rate in beats per minute at 32 weeks of gestation at time of peak maternal buprenorphine level |
| OG007 | FHR 36 Peak | Fetal heart rate in beats per minute at 36 weeks of gestation at time of peak maternal buprenorphine level |
|
|
|
| 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 | Per protocol | Posted | Mean | Standard Deviation | msec | 24, 28, 32 and 36 weeks of gestation |
|
|
|
|
| Primary | Accelerations of Fetal Heart Rate | Number of accelerations of fetal heart rate exhibited during the 60 minute recordings | Posted | Mean | 95% Confidence Interval | accelerations | 24, 28, 32 36 weeks of gestation |
|
|
|
|
| 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 | Posted | Mean | Standard Deviation | seconds | 24, 28, 32, 36 weeks of gestation |
|
|
|
|
| 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. | Posted | Mean | Standard Deviation | percentage of time FM assoc w FHR change | 24, 28, 32, 36 weeks of gestation |
|
|
|
|
| 0 |
| 49 |
| 1 |
| 49 |
| 15 |
| 49 |
|
| congenital heart disease | Cardiac disorders | Non-systematic Assessment | One infant born to a buprenorphine maintained mother was born with a congenital heart disease. The infant had a family history of congenital heart disease. |
|
|
| Bacterial vaginosis | Infections and infestations | Non-systematic Assessment | One subject developed bacterial vaginosis |
|
| choroid plexus cysts | Nervous system disorders | Non-systematic Assessment | One fetal subject had choroid plexus cysts on fetal sonogram |
|
| cardiomegaly | Cardiac disorders | Non-systematic Assessment | 2 fetal subjects had mild cardiomegaly on fetal sonogram |
|
| pneumonia | Infections and infestations | Non-systematic Assessment | One infant was born with congenital pneumonia |
|
| fetal growth restriction | General disorders | Non-systematic Assessment | One fetus was diagnosed with fetal growth restriction (but was average for gestational age at delivery) |
|
| chorioamnionitis | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment | Two maternal subjects had chorioamnionitis at delivery |
|
| Fetal stress at delivery | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment | Two fetuses exhibited fetal stress at the time of delivery |
|
| psychiatric concern | General disorders | Non-systematic Assessment | One maternal subject developed a psychiatric concern warranting hospitalization |
|
| fetal arrythmia | Cardiac disorders | Non-systematic Assessment | One fetus had a cardiac arrhythmia |
|
| maternal dehydration | General disorders | Non-systematic Assessment | One maternal subject developed decreased fetal HRV and fetal tachycardia, was dx with dehydration |
|
| nonreactive fetal tracing, fetal hear rate deceleration | Pregnancy, puerperium and perinatal conditions | Non-systematic Assessment |
|
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| D001523 | Mental Disorders |
| D006572 |
| Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |