A Study of Breastfeeding in Buprenorphine Maintained Women
Condition: Opioid Dependency
Study type: Observational

Summary: 
      Goals: The overarching goals for this proposed research are to provide pilot data for a study
      to inform the FDA regarding the safety of breastfeeding infants of mothers on buprenorphine
      maintenance and to develop guidelines for the practitioner treating buprenorphine maintained
      women who wish to breastfeed.

      Background: There is an increase in the prevalence of illicit opiate use among women of
      childbearing age. Recently, a large multisite study has suggested buprenorphine as an
      alternative to methadone for use in this population. As a consequence, buprenorphine is
      likely to be delivered to larger populations of pregnant and post-partum women. The
      population of prenatally opioid-exposed neonates is a particularly vulnerable population.
      Advances in neuroscience, molecular biology and epigenetics indicate that greater attention
      should be given to strategies that prevent, reduce, or mitigate the consequences of
      significant adversity on the developing brain. Breast milk and breastfeeding offer
      significant health and other benefits that are particularly salient for this group. Today,
      there is a near complete lack of information regarding the safety of buprenorphine
      maintenance and lactation, making it unlikely that providers will endorse or mothers will
      adopt this practice.

      Methods: Five pregnant buprenorphine maintained breastfeeding women and their neonates will
      be enrolled. Subjects will selected by buprenorphine maintenance in the postpartum period and
      enrollment in a parent protocol and by decision to breast feed their infants. Subject will
      provide breast milk at times of peak maternal buprenorphine levels on days 2, 3, 4, 14 and 30
      after delivery to determine buprenorphine and norbuprenorphine concentrations. Subjects will
      also provide plasma at times of peak buprenorphine levels for determination of buprenorphine
      and norbuprenorphine concentrations on the same days. Concentrations of buprenorphine and
      norbuprenorphine in the plasma of infants will be determined on approximately day 14 of life.
      The relationship between maternal dose, maternal and infant plasma concentrations, and breast
      milk concentrations of buprenorphine and norbuprenorphine will be determined, and ingestible
      infant dose calculated.
    

Detailed description: 
      This study recruits participants from a funded trial evaluating fetal neurobehavior and
      maternal physiology among a population of opioid dependent and buprenorphine maintained
      pregnant women. Those women electing to breastfeed will be approached for participation in
      this study at 36 weeks of gestation.

      Study Procedures Study participants will have urine toxicology testing for the following drug
      classes/cut off values: cocaine/300 ng/mL; methamphetamines/1000ng/mL; methadone/300ng/mL;
      MDMA/500 ng/mL; MOP/300 ng/mL; oxycodone/100 ng/mL; PCP/25 ng/mL; benzodiazepines/300ng/mL;
      buprenorphine/10 ng/mL; marijuana/50ng/mL weekly as part of study procedures in addition to
      weekly random urine toxicology screening provided at CAP for the study period of 36 weeks
      until delivery. To ensure that participants are not using illicit substances or abusing licit
      substances and are candidates for the institution and continuation of breastfeeding, subjects
      will continue to provide urine toxicology testing as above for the period of time from
      delivery to day 30 postpartum. Subjects noted to be doing so will be discharged from the
      protocol and referred to their substance abuse treatment counselor for appropriate
      consequences.

      Data collection protocol: Upon delivery, the nursing staff at the hospital of delivery will
      contact study staff for initiation of study procedures. Women will have plasma and breast
      milk samples obtained by study personnel on days 2, 3, 4, 14 and 30 at times of peak (2 ½
      hours after sublingual dosing) maternal buprenorphine levels. Infant weight will be collected
      on these days. Days of data collection will be determined by the, 2nd, 3rd, 4th 24 hour
      periods after birth of the infant. The 14th, and 30th day data collections will occur on the
      weekday nearest the 24 hour period on those days. Infant NICU Network Neurobehavioral Scale
      scores on days 3, 14 and 30 and infant NAS scores as below are collected as part of the
      parent protocol and data abstracted for this protocol.

      Maternal plasma: Using 3mL vacutainer green-top collection tubes, 3 cc of blood will be
      collected via venupuncture by one of two study RNs, one responsible for inpatient specimen
      collection (i.e. while the mother and infant are hospitalized after delivery) and one
      responsible for outpatient specimen collection (after hospital discharge). Blood samples will
      be collected on ice and within two hours, cold centrifuged to harvest the plasma. Plasma will
      be stored in polypropylene tubes and stored at -20°C. Plasma will be collected at times of
      peak maternal buprenorphine levels on days 2, 3, 4, 14 (approximately) and 30 (approximately)
      after infant delivery.

      Breast milk: Breast milk samples will be collected after the infant has completed feeding
      from the same breast via electric pump and consist of approximately 5 cc of breast milk at
      time of peak maternal buprenorphine levels on days 2,3,4, 14 and 30 after infant delivery.
      Breast milk will be stored at -20°C within two hours of collection.

      Analysis of breast milk and plasma samples: Plasma and breast milk samples will be analyzed
      by the Chemistry and Drug Metabolism Section of the Intramural Research Program of the
      National Institute on Drug Abuse, National Institutes of Health in Baltimore, Maryland under
      the direction of Dr. Marilyn A. Huestis.

      Infant plasma: 1cc of infant blood will be taken by heel stick on the weekday nearest day 14
      of life. The 14 day blood sample will be coincident with a routine infant blood test (PKU
      testing) when possible. Blood samples will be collected on ice and within two hours, cold
      centrifuged to remove plasma. Plasma will be stored in polypropylene tubes and stored at
      -20°C until analysis.

      Other infant data: Infant weight will be obtained at each data collection point (i.e. days
      2,3,4, 14 and 30).

      Other maternal data: Maternal compliance to drug treatment will be abstracted from daily
      treatment records. Poor compliance to treatment will be determined on an individual basis via
      discussion with the subject's counselor, but in general compliance will be determined by
      attendance to daily therapy at CAP with no unexcused or unexplained absence from treatment in
      the 30 days subsequent to delivery.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Ten buprenorphine maintained women who deliver and infant and desire to breastfeed
      
Biospecimen description: 
      Maternal urine, plasma and breast milk INnfant plasma
    
Keywords: Breast milk; Breastfeeding; Lactation; Buprenorphine; Opioid