Gestational buprenorphine-naloxone exposure and fetal neurobehavior.

BACKGROUND: Buprenorphine-naloxone treatment may confer substantial benefits for the treatment of opioid use disorder (OUD) during pregnancy including lower risk for overdose/death, less diversion potential and reduced use of other substances. Treatment may also result in less severe Neonatal Abstinence Syndrome (NAS), but little is known about the effects of this medication on fetal neurodevelopment. METHODS: The purpose of the current study is to evaluate neurobehaviors among fetuses exposed to buprenorphine-naloxone at four time points over the second and third trimesters of gestation in pregnant women with OUD on buprenorphine-naloxone therapy. Sixty minutes of continuous fetal monitoring via fetal actocardiograph with a single wide array abdominal transducer took place at times of peak and trough buprenorphine-naloxone levels in 24 pregnant women. Data collection, which included measures of fetal heart rate and motor activity, was conducted between 24 and 36 weeks gestation, with the majority (84.6%) monitored at two or more gestational ages. Medication dose and other substance use was monitored throughout the study and infant NAS severity was assessed. RESULTS: Fetal heart rate (FHR), FHR variability, accelerations in FHR, and motor activity were suppressed when buprenorphine-naloxone levels were at pharmacologic peak as compared to trough concentrations at 36 weeks, but not earlier in gestation. Maternal medication dose was unrelated to infant NAS severity. CONCLUSIONS: Conclusions: There were evident subclinical fetal neurophysiological responses at times of peak maternal buprenorphine/naloxone levels in later gestation, similar to those previously described for buprenorphine only. Further studies evaluating the effects of these changes in fetal neurobehaviors on the longer-term infant development are needed.

Clinically defining the opioid-exposed birthing person and infant as a dyad to support bedside care, surveillance, and research.

Introduction: An increased incidence of maternal opioid use disorder (OUD) and neonatal abstinence syndrome (NAS) has prompted recommendations supporting a dyadic approach to care for birthing persons and their infants. However, there are no consensus guidelines outlining how the dyad is clinically defined. Methods: To examine how the opioid-exposed birthing person-infant dyad has been defined for purposes of data collection and research, a literature review applying the RAND/UCLA Appropriateness Method was conducted. Results: The search yielded 320 abstracts, with 110 articles identified as having a dyadic focus. While no articles included a specific definition for the dyad, 33 (30%) contained a descriptive reference to the birthing person-infant dyad. Thematic analysis revealed eight recurring elements characteristic of the dyad: (1) engagement, (2) communication, (3) bonding, (4) attachment, (5) mutual responsiveness, (6) reciprocity, (7) synchrony, and (8) attunement. Integrating these elements revealed the interactional relationship between the opioid-exposed birthing person and infant as the foundational principle that defines the dyad. Discussion: This definition shifts the focus of the opioid-exposed dyad from two individual patient populations to an interactional relationship that has broad applicability for clinical use, public health data collection, and research considerations.

Buprenorphine-Naloxone Maintenance and Lactation.

BACKGROUND: Breastfeeding among lactating people with opioid use disorder taking buprenorphine monotherapy is generally accepted, as low concentrations of buprenorphine and metabolites in human milk have been well-established. The use of buprenorphine-naloxone for pregnant and lactating people with opioid use disorder is expanding and there is no information available regarding the concentrations of naloxone and their metabolites in human milk to recommend the use of this combination medication during lactation. RESEARCH AIMS: To determine the concentrations of buprenorphine and naloxone and their primary metabolites in human milk, maternal plasma, and infant plasma, among lactating buprenorphine-naloxone maintained people and their infants. METHODS: Four lactating buprenorphine-naloxone maintained people provided plasma and human milk samples on Days 2, 3, 4, 14, and 30 postpartum. Infant plasma was obtained on Day 14. RESULTS: Concentrations of buprenorphine, norbuprenorphine and their glucuronide metabolites were present in maternal plasma and human milk at low concentrations, consistent with previous research in lactating buprenorphine monotherapy participants. Naloxone was not detected, or was detected at concentrations below the limit of quantification, in maternal plasma and in all except one human milk sample at Day 30. Naloxone was not detected or detected at concentrations below the limit of quantification in all infant plasma samples. CONCLUSION: Results support the use of buprenorphine-naloxone by lactating people who meet appropriate criteria for breastfeeding.

A Dyadic Framework of Care for Opioid-exposed Birthing Persons and Their Infants and Children.

OBJECTIVE: To develop a dyadic-centered framework focused on clinical care, surveillance, and research for birthing persons with opioid use disorder (OUD) and their infants and children. STUDY DESIGN: Between February and March 2023, an analysis was conducted within the US Department of Health and Human Services (HHS) of activities directed at opioid-exposed birthing persons and their infants and children (the dyad) to identify: 1) number of activities, stratified by type and 2) characteristics across health and supportive activities that serve the dyad vs birthing persons or infants and children individually. Descriptive and thematic analyses were used to assess quantity and characteristics of fiscal year 2023-2024 activities aggregated across eleven HHS agencies. RESULTS: Of 181 activities examined, 75 met inclusion criteria specific to serving birthing persons with OUD and opioid-exposed infants and children. Sixty-two percent of activities were dyad focused. Five categories of dyadic activities were identified: research (45%), education and training (28%), health and supportive services (21%), surveillance (4%), and quality improvement (2%). Eight specific characteristics were key to dyadic activities: a life course and generational approach, emphasis on relationship, dyadic outcomes, service wraparound, payment structures supporting dyadic care, data linkage, and social determinants of health. CONCLUSIONS: This analysis of HHS activities directed at birthing persons with OUD and opioid-exposed infants and children showed that most programs had a dyadic focus. Synthesizing elements identified from activities serving the dyad facilitated the development of a dyadic framework integrating clinical care, public health surveillance, and research.

Ondansetron to reduce neonatal opioid withdrawal severity a randomized clinical trial.

OBJECTIVE: To determine if treatment with a 5-HT3 antagonist (ondansetron) reduces need for opioid therapy in infants at risk for neonatal opioid withdrawal syndrome (NOWS). STUDY DESIGN: A multicenter, randomized, placebo controlled, double blind clinical trial of ninety (90) infants. The intervention arms were intravenous ondansetron or placebo during labor followed by a daily dose of ondansetron or placebo in infants for five days. RESULTS: Twenty-two (49%) ondansetron-treated and 26 (63%) placebo-treated infants required pharmacologic treatment (p > 0.05). The Finnegan score was lower in the ondansetron-treated group (4.6 vs. 5.6, p = 0.02). A non-significant trend was noted for the duration of hospitalization. There was no difference in need for phenobarbital or clonidine therapy, or total dose of morphine in the first 15 days of NOWS treatment. CONCLUSIONS: Ondansetron treatment reduced the severity of NOWS symptoms; and there was an indication that it could reduce the length of stay. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01965704.

Gabapentin Use During Pregnancy and Lactation With and Without Concurrent Opioid Exposure: Considerations and Future Directions.

Gabapentin is a γ-aminobutyric acid analog formally indicated for the treatment of epilepsy and neuropathic pain that is gaining increased popularity. Gabapentin has been historically considered a safe medication, including during pregnancy and lactation, with low reported concerns for misuse and use disorders. However, new empirical efforts are revealing concerns regarding the safety of widespread gabapentin use, particularly in pregnancy and for individuals with a propensity toward substance misuse. The Food and Drug Administration's full prescribing information report on gabapentin provides concerning preclinical data and then states that gabapentin is potentially "developmentally toxic" and has an unknown risk of birth impacts. Concerns have also been raised surrounding in utero exposure to gabapentin due to the onset and presentation of atypical and/or difficult to control withdrawal signs and symptoms in neonates, including those dually exposed to opioids, as well as neonatal exposure to gabapentin via breastmilk. Moreover, nonprescribed gabapentin use has become an increasing problem, with opioid use disorder being the greatest risk factor for such misuse. This article summarizes the current literature regarding gabapentin use during pregnancy and related prenatal and neonatal exposure outcomes with special consideration for interactions between gabapentin and opioid use. Taken together, the current literature suggests that gabapentin use should be considered with caution during pregnancy and during the post-partum period. Well-controlled, prospective research studies are needed to determine the extent of the risks and benefits of prescribed and nonprescribed gabapentin exposure to pregnant people and their neonates.

Standardizing the Clinical Definition of Opioid Withdrawal in the Neonate.

OBJECTIVE: To standardize the clinical definition of opioid withdrawal in neonates to address challenges in clinical care, quality improvement, research, and public policy for this patient population. STUDY DESIGN: Between October and December 2020, we conducted 2 modified-Delphi panels using ExpertLens, a virtual platform for performing iterative expert engagement panels. Twenty clinical experts specializing in care for the substance-exposed mother-neonate dyad explored the necessity of key evidence-based clinical elements in defining opioid withdrawal in the neonate leading to a diagnosis of neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS). Expert consensus was assessed using descriptive statistics, the RAND/UCLA Appropriateness Method, and thematic analysis of participants' comments. RESULTS: Expert panels concluded the following were required for diagnosis: in utero exposure (known by history, not necessarily by toxicology testing) to opioids with or without the presence of other psychotropic substances, and the presence of at least two of the most common clinical signs characteristic of withdrawal (excessive crying, fragmented sleep, tremors, increased muscle tone, gastrointestinal dysfunction). CONCLUSIONS: Results indicate that both a known history of in utero opioid exposure and a distinct set of withdrawal signs are necessary to standardize a definition of neonatal withdrawal. Implementation of a standardized definition requires both patient engagement and a mother-neonate dyadic approach mindful of program and policy implications.

Reconceptualizing non-pharmacologic approaches to Neonatal Abstinence Syndrome (NAS) and Neonatal Opioid Withdrawal Syndrome (NOWS): A theoretical and evidence-based approach. Part II: The clinical application of nonpharmacologic care for NAS/NOWS.

There has been increasing emphasis on the importance of the development of self-regulatory capacities of the individual as the cornerstone of development. The caregivers' abilities to manage their own attention, emotions, physiology and behaviors influence the development of the child's self-regulatory and interactive capacities, and thereby their overall development. Newborns prenatally exposed to psychoactive substances and/or to other prenatal stressors such as maternal poor nutrition, increased maternal stress, trauma, difficult and/or impoverished environments, in tandem with genetic predispositions, can result in alterations to their neurodevelopment that predispose them to self-regulatory problems that can be expressed at any stage of life. The care of infants with Neonatal Abstinence Syndrome (NAS)/Neonatal Opioid Withdrawal Syndrome (NOWS) and their mother/caregiver is a window of opportunity to assess the regulatory and co-regulatory capacities of both, and to provide holistic interventions with the goal of empowering the mother/caregiver in their own self-knowledge/self-regulation capacities and their crucial role in promoting the healthy development of their children. Non-pharmacologic care for the infant with NAS/NOWS is the first line of treatment and of paramount importance. Yet, current approaches are based on a limited scope of infant functioning, and the scoring systems in current use do not result in individualized and specific non-pharmacologic care of the infant, which can result in excessive or insufficient medication and a lack of caregiver appreciation for the infant's strengths, difficulties and early development. The interventions described here are based on the infant's signs of dysregulation in four neurobehavioral subsystems that can be dysregulated by NAS/NOWS, the infant's adaptive or maladaptive responses to return to a regulated functioning, and the co-regulatory behaviors of the infant and the mother/caregiver. In Part I of this two-part series on re-conceptualizing non-pharmacologic care for NAS/NOWS we laid the foundation for a new treatment approach, one grounded in developmental theory and evidence-based observations of infant and interpersonal neurobiology. Here, in Part II, we outline actionable, individually tailored evaluations and approaches to non-pharmacologic NAS/NOWS treatment based on strategies to support the regulatory capacities and development of 4 key domains: 1) autonomic; 2) motor/tone; 3) sleep/awake state control; and 4) sensory modulation subsystems.

Reconceptualizing non-pharmacologic approaches to Neonatal Abstinence Syndrome (NAS) and Neonatal Opioid Withdrawal Syndrome (NOWS): A theoretical and evidence-based approach.

Discussions about non-pharmacologic interventions for Neonatal Abstinence Syndrome and Neonatal Opioid Withdrawal Syndrome (NAS/NOWS) have been minor compared with wider attention to pharmacologic treatments. Although historically under-recognized, non-pharmacologic interventions are of paramount importance for all substance-exposed infants and remain as a first line therapy for the care of infants affected by NAS. Here we examine the role of non-pharmacologic interventions for NAS/NOWS by incorporating theoretical perspectives from different disciplines that inform the importance of individualized assessment of the mother-caregiver/infant dyad and interventions that involve both individuals. NAS/NOWS is a complex, highly individualized constellation of signs/symptoms that vary widely in onset, duration, severity, expression, responses to treatment and influence on long-term outcomes. NAS/NOWS often occurs in infants with multiple prenatal/postnatal factors that can compromise neurobiological self-regulatory functioning. We propose to rethink some of the long-held assumptions, beliefs, and paradigms about non-pharmacologic care of the infant with NAS/NOWS, which is provided as non-specific or as "bundled" in current approaches. This paper is Part I of a two-part series on re-conceptualizing non-pharmacologic care for NAS/NOWS as individualized treatment of the dyad. Here, we set the foundation for a new treatment approach grounded in developmental theory and evidence-based observations of infant neurobiology and neurodevelopment. In Part II, we provide actionable, individually tailored evaluations and approaches to non-pharmacologic NAS/NOWS treatment based on measurable domains of infant neurobehavioral functioning.

Definitions of neonatal abstinence syndrome in clinical studies of mothers and infants: an expert literature review.

Neonatal abstinence syndrome (NAS) results from discontinuation of in utero exposures to opioids/substances. The rising incidence of NAS has prompted an increased need for accurate research and public health data. To examine how NAS has been defined in clinical studies of opioid-exposed mothers and infants, a review process was developed based on the RAND/UCLA Appropriateness Method, yielding 888 abstracts. Per inclusion criteria, 57 abstracts underwent full-text review. To define NAS, studies cited using modified versions of the Finnegan NAS scoring tool (n = 21; 37%), ICD-9/10 coding (n = 17; 30%), original Finnegan tool (n = 16; 28%), Eat Sleep Console (n = 3; 5%), and Lipsitz (n = 3; 5%) tools, (3 cited 2+ tools). Most studies utilized subjective NAS scoring/assessment algorithms and neonatal coding as key elements defining NAS. While most cited opioid exposure as integral to their inclusion criteria, 26% did not. These approaches highlight the need for a more refined and standardized definition of NAS.

A Core Outcome Set for Neonatal Opioid Withdrawal Syndrome.

BACKGROUND: As rates of neonatal opioid withdrawal are increasing, the need for research to evaluate new treatments is growing. Large heterogeneity exists in health outcomes reported in current literature. Our objective is to develop an evidence-informed and consensus-based core outcome set in neonatal opioid withdrawal syndrome (NOWS-COS) for use in studies and clinical practice. METHODS: An international multidisciplinary steering committee was established. A systematic review and a 3-round Delphi was performed with open-ended and score-based assessments of the importance of each outcome to inform clinical management of neonatal opioid withdrawal. Interviews were conducted with parents and/or caregivers on outcome importance. Finally, a consensus meeting with diverse stakeholders was held to review all data from all sources and establish a core set of outcomes with definitions. RESULTS: The NOWS-COS was informed by 47 published studies, 41 Delphi participants, and 6 parent interviews. There were 63 outcomes evaluated. Final core outcomes include (1) pharmacologic treatment, (2) total dose of opioid treatment, (3) duration of treatment, (4) adjuvant therapy, (5) feeding difficulties, (6) consolability, (7) time to adequate symptom control, (8) parent-infant bonding, (9) duration of time the neonate spent in the hospital, (10) breastfeeding, (11) weight gain at hospital discharge, (12) readmission to hospital for withdrawal, and (13) neurodevelopment. CONCLUSIONS: We developed an evidence-informed and consensus-based core outcome set. Implementation of this core outcome set will reduce heterogeneity between studies and facilitate evidence-based decision-making. Future research will disseminate all the findings and pilot test the validity of the NOWS-COS in additional countries and populations to increase generalizability and impact.

Outcome reporting in neonates experiencing withdrawal following opioid exposure in pregnancy: a systematic review.

BACKGROUND: Neonatal withdrawal secondary to in utero opioid exposure is a growing global concern stressing the psychosocial well-being of affected families and scarce hospital resources. In the ongoing search for the most effective treatment, randomized controlled trials are indispensable. Consistent outcome selection and measurement across randomized controlled trials enables synthesis of results, fostering the translation of research into practice. Currently, there is no core outcome set to standardize outcome selection, definition and reporting. This study identifies the outcomes currently reported in the literature for neonates experiencing withdrawal following opioid exposure during pregnancy. METHODS: A comprehensive literature search of MEDLINE, EMBASE and Cochrane Central was conducted to identify all primary research studies (randomized controlled trials, clinical trials, case-controlled studies, uncontrolled trials, observational cohort studies, clinical practice guidelines and case reports) reporting outcomes for interventions used to manage neonatal abstinence syndrome between July 2007 and July 2017. All "primary" and "secondary" neonatal outcomes were extracted by two independent reviewers and were assigned to one of OMERACT's core areas of "pathophysiological manifestation", "life impact", "resource use", "adverse events", or "death". RESULTS: Forty-seven primary research articles reporting 107 "primary" and 127 "secondary" outcomes were included. The most frequently reported outcomes were "duration of pharmacotherapy" (68% of studies, N = 32), "duration of hospital stay" (66% of studies, N = 31) and "withdrawal symptoms" (51% of studies, N = 24). The discrepancy between the number of times an outcome was reported and the number of articles was secondary to the use of composite outcomes. Frequently reported outcomes had heterogeneous definitions or were not defined by the study and were measured at different times. Outcomes reported in the literature to date were mainly assigned to the core areas "pathophysiologic manifestations" or "resource use". No articles reported included parent or former patient involvement in outcome selections. CONCLUSIONS: Inconsistent selection and definition of primary and secondary outcomes exists in the present literature of pharmacologic and nonpharmacologic interventions for managing opioid withdrawal in neonates. No studies involved parents in the process of outcome selection. These findings hinder evidence synthesis to generate clinically meaningful practice guidelines. The development of a specific core outcome set is imperative.

Treatment for substance use disorders in pregnant women: Motivators and barriers.

BACKGROUND: Pregnancy is a unique opportunity to provide broad and necessary medical care for women- including treatment for Substance Use Disorders (SUD). The standard of care for SUD in pregnant women is treatment at a comprehensive care facility. There is little existing qualitative research exploring what brings pregnant women with SUD to treatment and what barriers to treatment exist for this population. This study explored women's self-reported reasons for pursuing treatment or hesitating to do so. METHODS: This qualitative study used interviews to explore common factors that motivate pregnant women with SUD to seek comprehensive care during pregnancy and common hesitations/ barriers to treatment. The study population included 20 women in treatment at a comprehensive care facility for pregnant and parenting women at Johns Hopkins. Participants volunteered to do interviews which were recorded and transcribed for analysis. RESULTS: Interviews revealed several major themes in motivators to seek treatment: readiness to stop using, concern for the baby's health, concern about custody of the baby or other children, wanting to escape violent environments or homelessness, and seeking structure. Barriers to treatment included fear of loss of custody, not wanting to be away from children/partner, concern about stigma or privacy, and lack of childcare and transportation. CONCLUSIONS: This study revealed common motivators to seek treatment and barriers to treatment for pregnant women with SUD. These themes may help direct future studies and guide efforts to increase access to crucial care in this vulnerable population.

Maternal buprenorphine treatment during pregnancy and maternal physiology.

BACKGROUND: Buprenorphine, used for opioid use disorder (OUD) treatment during pregnancy, provides unknown effects on maternal physiological activity. The primary aim of this report is to document acute effects of buprenorphine administration on indicators of maternal autonomic functioning. Effects of maternal buprenorphine dose and other substance exposures on maternal measures were examined, as were neonatal abstinence syndrome (NAS) outcomes. METHODS: Forty-nine pregnant, buprenorphine-maintained women yielded maternal physiologic information (heart rate and variability, electrodermal activity, and respiratory rate) at 24, 28, 32 and 36 weeks gestation. Monitoring at trough and peak maternal medication levels was implemented to ascertain acute physiologic effects of buprenorphine administration. RESULTS: Buprenorphine administration accelerated maternal heart rate and reduced variability at two gestational ages (24 and 36 weeks) and suppressed sympathetic (electrodermal) activation at 24, 28 and 32 weeks at times of peak maternal medication levels. Maternal autonomic parameters were unrelated to polysubstance exposure with the exception of cigarette smoking. Heavier smoking dampened maternal heart rate variability across gestation and potentiated reactivity to buprenorphine at 24 and 36 weeks. Heavier smoking was also associated with reduced electrodermal activity at 36 weeks. Buprenorphine dose was unrelated to observed effects. Larger degree of maternal heart rate reactivity to buprenorphine administration was related to more severe NAS expression. CONCLUSIONS: These findings detail the maternal autonomic response to buprenorphine administration but also illustrate the significant effect of concurrent cigarette use on maternal autonomic regulation. This suggests the importance of smoking-reduction strategies in the comprehensive, medication-assisted treatment of women with OUD.

Neonatal Abstinence Syndrome.

This review examines the continuum of care of opioid-exposed infants, including the assessment of the neonate, diagnosis of neonatal abstinence syndrome, management of the syndrome including nonpharmacologic and pharmacologic care, approach to breastfeeding, pediatric follow-up care, and integration of care of the mother-infant dyad.

Prenatal buprenorphine exposure and neonatal neurobehavioral functioning.

AIMS: Assessments of effects of prenatal opioid exposure on the neonate have consisted principally of evaluations of neonatal abstinence syndrome (NAS) to determine the need for pharmacotherapy. The purpose of this study was to comprehensively evaluate the effects of gestational maternal buprenorphine maintenance on newborn neurobehavioral functioning. STUDY DESIGN: Maternal substance use history and psychosocial demographics that can contribute to the neurobehavioral functioning of the infant were explored. Infants were assessed using the NICU Network Neurobehavioral Scale (NNNS) to measure their neurologic and behavioral functioning and signs of stress/abstinence on days 3, 14 and 30 of life. SUBJECTS: Participants were 41 pregnant buprenorphine-maintained women and their infants. RESULTS: Maternal buprenorphine dose at delivery was negatively correlated with infant quality of movement and self-regulation, and positively correlated with the central nervous system parameters of stress/abstinence at day 3 of life. As maternal buprenorphine dose increased, the mean morphine dose that the infant required for NAS treatment significantly increased. No differences were found when comparing the NNNS domain scores between infants who required pharmacotherapy for NAS versus those who did not at day 3 of life. CONCLUSIONS: Buprenorphine exposure during pregnancy can alter neonatal neurobehavioral and physiological responses to stimuli. A systematic evaluation of the newborn's functional domains above NAS assessment alone is crucial to address the challenges created by neurobehavioral dysregulation associated with substance exposure, improve caregiver/infant interaction and developmental trajectory. Comprehensive pre/postnatal treatment of buprenorphine-maintained mothers can lead to healthier outcomes for the dyad.