Fetal and Infant Effects of Maternal Buprenorphine Treatment

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.

Study Overview

• Status: Completed
• Conditions: Neonatal Abstinence Syndrome
• Intervention / Treatment: Drug: Buprenorphine

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.

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Bayview Medical Center
    • Baltimore, Maryland, United States, 21224
      • Center for Addiction and Pregnancy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Maternal buprenorphine treatment; Buprenorphine maintenance during pregnancy	Drug: Buprenorphine; Daily sublingual buprenorphine treatment of pregnant, opioid dependent women from up to 34 weeks gestation through one month of infant age.; Other Names: Subutex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Johns Hopkins University

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: March 19, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (Estimate): March 22, 2012

Study Record Updates

• Last Update Posted (Actual): September 26, 2017
• Last Update Submitted That Met QC Criteria: August 28, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Methadone; Buprenorphine; Fetal neurobehavior; Infant neurobehavior
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Infant, Newborn, Diseases; Neonatal Abstinence Syndrome; Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Narcotic Antagonists; Buprenorphine
• Other Study ID Numbers: 00051600

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No