MOM NEST Study: Maternal Opioid Medication: Naltrexone Efficacy Study

Study Overview
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Brief Summary
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This is a multi-center prospective comparative cohort study examining the safety, efficacy, pharmacokinetics, and pharmacogenomics of naltrexone for pregnant women with opioid use disorder. Pregnancy, delivery, and maternal and infant outcomes to 12 months post-delivery will be examined and compared with a cohort treated with buprenorphine/naloxone.

Detailed Description
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Fifty pregnant women stabilized pre-pregnancy on oral or extended-release naltrexone (XR-NTX) and 50 comparison women on buprenorphine/naloxone (BPH) from Boston Medical Center and the University of North Carolina will be enrolled in this multi-center prospective comparative cohort study. The specific aims of this project are: 1) Safety and Efficacy: To compare maternal outcomes (safety, relapse, retention in care), fetal outcomes (growth, fetal distress), and infant outcomes (neonatal abstinence syndrome, growth, neurodevelopment) during pregnancy until 12 months post- delivery; An exploratory part of this aim is to collect safety and efficacy data on women receiving NTX for alcohol use disorder (AUD). We will collect maternal, fetal and infant outcomes related to prenatal alcohol exposure. 2) Pharmacokinetics: To determine the pharmacokinetics of NTX in pregnant and postpartum women; 3) Genetics and Epigenetics: To examine the association between genetic variants and epigenetic modification in the mu-opioid receptor (OPRM1) gene, as well as global DNA methylation changes after treatment with NTX and BPH within the mother, placenta, and infant; and 4) Breast milk: To measure breast milk concentrations of NTX and corresponding infant relative dose to determine safety for lactating women.

Official Title
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Safety, Efficacy, Pharmacokinetics, and Pharmacogenomics of Extended-Release Naltrexone in Pregnant Women

Conditions
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Opioid-use Disorder, Neonatal Abstinence Syndrome, Pregnancy, High Risk, Alcohol Use Disorder

Intervention / Treatment
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* Other: Pharmacokinetic analysis
* Other: Safety and Efficacy
* Genetic: Genetic and epigenetic analysis
* Other: Breast milk analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women between 6 - 30 6/7 weeks gestation, receiving prenatal care at Boston Medical Center (BMC) or the University of North Carolina (UNC) Plan to deliver infant at BMC or UNC Diagnosis of opioid use disorder (OUD) or alcohol use disorder (AUD) in the current pregnancy on prescribed oral or extended-release naltrexone; or buprenorphine/naloxone for the treatment of OUD English speaking Singleton pregnancy Exclusion Criteria: OUD on prescribed methadone, or no maintenance medication OUD on Subutex formulation of buprenorphine Severe psychiatric illness or cognitively impairing ability to provide informed consent Current maternal incarceration Women who present for care >31 0/7 weeks Multiple gestation pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Naltrexone<br>Pregnant women with opioid use disorder on prescribed oral or extended-release naltrexone and their infants. Biospecimens collected from this group will undergo pharmacokinetic analysis, genetic and epigenetic analysis, and breast milk analysis. This group will also receive safety and efficacy interventions. | Other: Pharmacokinetic analysis<br>* Pharmacokinetic analysis of maternal blood, maternal urine, cord blood, infant blood and urine for dyads in the naltrexone group at various time points in the pregnancy, at delivery, and 4 weeks postpartum.<br>Other: Safety and Efficacy<br>* Examination of the safety and efficacy of naltrexone and comparison of outcomes with the buprenorphine/naloxone cohort. Outcomes examined will include: 1) maternal outcomes (relapse, retention in care, preterm labor); 2) fetal outcomes (growth, fetal anomalies, fetal distress, cortisol levels); and 3) infant outcomes (NAS, growth, neurodevelopment via NNNS exam at 4 weeks and Bayley exam at 12 months of age).<br>Genetic: Genetic and epigenetic analysis<br>* Maternal blood and saliva DNA samples will be genotyped for single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) to look for associations with effectiveness of NTX and BPH. In addition, DNA methylation levels in the OPRM1 promoter within maternal and infant saliva and placenta at delivery and 4 weeks postpartum will be examined. Lastly, we will compare genome-wide DNA methylation levels at delivery and 4 weeks postpartum in mother-infant dyads.<br>Other: Breast milk analysis<br>* Mothers in the naltrexone group will have their breast milk analyzed at 4 weeks post-delivery for naltrexone levels, with corresponding maternal and infant plasma levels.<br>|
| Buprenorphine/Naloxone<br>Pregnant women with opioid use disorder on prescribed buprenorphine/naloxone and their infants. Biospecimens collected from this group will undergo genetic and epigenetic analysis and the group will also receive safety and efficacy interventions. | Other: Safety and Efficacy<br>* Examination of the safety and efficacy of naltrexone and comparison of outcomes with the buprenorphine/naloxone cohort. Outcomes examined will include: 1) maternal outcomes (relapse, retention in care, preterm labor); 2) fetal outcomes (growth, fetal anomalies, fetal distress, cortisol levels); and 3) infant outcomes (NAS, growth, neurodevelopment via NNNS exam at 4 weeks and Bayley exam at 12 months of age).<br>Genetic: Genetic and epigenetic analysis<br>* Maternal blood and saliva DNA samples will be genotyped for single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) to look for associations with effectiveness of NTX and BPH. In addition, DNA methylation levels in the OPRM1 promoter within maternal and infant saliva and placenta at delivery and 4 weeks postpartum will be examined. Lastly, we will compare genome-wide DNA methylation levels at delivery and 4 weeks postpartum in mother-infant dyads.<br>|
| Naltrexone - alcohol use disorder<br>Pregnant women with alcohol use disorder on prescribed naltrexone (oral or extended-release) and their infants. Biospecimens collected from this group will undergo pharmacokinetic analysis, genetic and epigenetic analysis, and breast milk analysis. This exploratory group will also receive safety and efficacy interventions. | Other: Pharmacokinetic analysis<br>* Pharmacokinetic analysis of maternal blood, maternal urine, cord blood, infant blood and urine for dyads in the naltrexone group at various time points in the pregnancy, at delivery, and 4 weeks postpartum.<br>Genetic: Genetic and epigenetic analysis<br>* Maternal blood and saliva DNA samples will be genotyped for single nucleotide polymorphisms in the mu opioid receptor gene (OPRM1) to look for associations with effectiveness of NTX and BPH. In addition, DNA methylation levels in the OPRM1 promoter within maternal and infant saliva and placenta at delivery and 4 weeks postpartum will be examined. Lastly, we will compare genome-wide DNA methylation levels at delivery and 4 weeks postpartum in mother-infant dyads.<br>Other: Breast milk analysis<br>* Mothers in the naltrexone group will have their breast milk analyzed at 4 weeks post-delivery for naltrexone levels, with corresponding maternal and infant plasma levels.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal drug use relapse | Maternal relapse of illicit and/or unprescribed drug use from maternal/provider report and or from urine toxicology testing at any point during the pregnancy and up to 12 months after delivery | up to 12 months post-delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Naltrexone side effects or adverse events | Number and type of side effects or adverse events such as injection site reactions, gastrointestinal upset, syncope, headaches, or dizziness reported by participant or provider | up to 12 months post-delivery | 
| Fetal heart rate monitoring from NST | Mean fetal heart rate (FHR), FHR variability, and episodic accelerations of FHR (count) from each routine care non-stress test (NST) in the third trimesters. | 27- 41 weeks gestation | 
| Biophysical profile score calculated from NST | The biophysical profile uses electronic fetal heart rate monitoring to examine the fetus. There are five components measured during the biophysical examination (fetal breathing movements, gross body movement, fetal tone, amninotic fluid volume and whether the NST is reactive or nonreactive. A score of 2 points is given for each component The points are then added for a possible maximum score of 10. The test is continued until all criteria are met or 30 minutes have elapsed. HIgher scores are more favorable. | 27 - 41 weeks gestation | 
| Maternal hair cortisol levels | Hair cortisol levels will be obtained from maternal hair samples obtained at birth and 4 weeks after delivery, and compared between the naltrexone and buprenorphine groups. Higher hair cortisol levels in the mother may indicate exposure to higher levels of stress over the preceding 3 months period. | Birth and 4 weeks post-delivery | 
| Infant hair cortisol levels | Hair cortisol levels will be obtained from infant hair samples obtained at birth and 4 weeks after delivery, and compared between the naltrexone and buprenorphine groups. Higher hair cortisol levels in the infant may indicate exposure to higher levels of stress over the preceding 3 months period. | Birth and 4 weeks post-delivery | 
| Fetal growth based on ultrasound measurements | Fetal growth will be assessed at the time of routine growth scans at 18-20, and then q4 weeks until delivery. Fetal size will be compared to Intergrowth standards to produce z-scores and SGA (<10%ile) for averaged 2nd and 3rd trimester measurements. | 18 - 41 weeks gestation | 
| Congenital fetal anomalies by ultrasound | Fetal, placental, or amniotic fluid anomalies identified during routine ultrasounds in the second and third trimesters will be documented. | 18 - 41 weeks gestation | 
| Congenital anomalies by physical examination | Infants will be routinely assessed at birth during the physical examination for any external anomalies. | Birth | 
| Diagnosis of Neonatal Abstinence Syndrome (NAS) | NAS diagnosis will be based on opioid withdrawal signs and symptoms in the infant after delivery as assessed by NAS withdrawal scores (either the Finnegan score or the via the ESC (Eat, Sleep, Console) assessment tool. The Finnegan scale assesses 21 of the most common signs of neonatal drug withdrawal syndrome and is scored on the basis of pathological significance and severity of the adverse symptoms, which sometimes requires pharmacological treatment. Measurements are performed every 4 hours, typically with 2-3 consecutive scores that are equal to or greater than 8, or 1-2 scores of 12 or greater, pharmacologic treatment for withdrawal is started. For the ESC assessment, clinicians assess whether or not the infant has poor feeding, is unable to sleep for at least 1 hour after feeding, and is consolable (rating of 1-3) due to symptoms of opioid withdrawal. Poor feeding, sleeping, or consolability triggers a huddle and possible start of pharmacologic treatment. | From birth to 30 days | 
| Infant need for pharmacologic treatment | The need for pharmacologic treatment will be recorded as Y/N as will the need for adjunctive agents. | From birth to 30 days | 
| Infant need for adjunctive agent | The need for adjunctive agents will be recorded as Y/N | From birth to 30 days | 
| Infant opioid replacement pharmacologic treatment | The total mgs of morphine/methadone needed for pharmacologic treatment and the total number of total opioid treatment days will be obtained from the birth hospitalization medical records. | From birth to 30 days | 
| Infant birth hospitalization length of stay | Number of continuous days infant hospitalized after birth. | From birth to 30 days | 
| Infant weight | Growth parameters of infant weight in grams will be obtained by the clinician at birth, 4 weeks, and 12 months at each study visit. Percentiles will be calculated. | Birth, 4 weeks, and 12 months | 
| Infant length | Growth parameters of infant length measured by the clinician in cm will be obtained at birth, 4 weeks, and 12 months at each study visit. Percentiles will be calculated. | Birth, 4 weeks, and 12 months | 
| Infant head circumference | Growth parameters of infant head circumference in cm will be obtained by the clinician at birth, 4 weeks, and 12 months at each study visit. Percentiles will be calculated. | Birth, 4 weeks, and 12 months | 
| Infant neurobehavior-function assessed by the NNNS | The NICU Network Neurobehavioral Scale (NNNS) is a comprehensive assessment of both neurologic integrity and behavioral functioning, including signs of stress. It assesses the full range of infant neurobehavioral performance (orientation to auditory and visual stimuli); infant stress (color changes, tremors, startles), neurologic functioning (reflexes, tone); some features of gestational age; self-soothing capacities; states and their organization. The 13 summary scores (i.e., orientation, habituation, hypertonicity, hypotonicity, excitability, arousal, lethargy, non-optimal reflexes, asymmetric reflexes, stress, self-regulation, quality of movement, handling) are typically used to summarize a clinical examination . | 4 weeks of age | 
| Infant neurodevelopment assessed by Bayley III | The Bayley III is a standard series of measurements used to assess the development of infants and toddlers, ages 1-42 months. It has 5 scales, 3 administered with child interaction - cognitive, motor, language, and 2 with parent questionnaires- social-emotional, adaptive behavior. A developmental quotient (DQ) is derived from the results. | 12 months of age | 
| Pharmacokinetic analysis of maternal naltrexone levels | Naltrexone levels from maternal blood and plasma will be obtained at regular intervals for pharmacokinetic analysis. | 2nd trimester, 3rd trimester, delivery, 2-4 days after delivery, 4 weeks post-delivery | 
| Pharmacokinetic analysis of infant naltrexone levels | Naltrexone levels from infant blood and plasma will be obtained at regular intervals for pharmacokinetic analysis. | Delivery, 2-4 days after delivery, 4 weeks post-delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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naltrexone, buprenorphine/naloxone, maternal relapse, retention in care, pharmacokinetics, pharmacogenetics