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The PATHS toolkit, a product of CTN-0080, offers evidence-based educational resources about the use of medication to treat opioid use disorder (OUD) during and after pregnancy. Resources include an introductory video, a range of printable downloads (flyers, discussion guide, factsheets, posters, and a workbook), and social media downloads to make dissemination of the tools easy and effective.

The toolkit is available in English and Spanish, and also includes a version culturally tailored for American Indian/Alaska Native communities.

This is the primary outcomes article for CTN-0080. Importance: Treating opioid use disorder (OUD) in pregnancy with sublingual buprenorphine is an evidence-based practice, but it has disadvantages that could be addressed with an extended-release formulation.

Objective: To evaluate the effectiveness and safety of extended-release buprenorphine vs sublingual buprenorphine for OUD in pregnancy through 12 months post partum.

Design, setting, and participants: This 2-group, open-label, noninferiority, randomized clinical trial was conducted between July 2, 2020, and October 30, 2024, among adults with OUD and a singleton pregnancy of 6 to 30 weeks’ gestational age at 13 outpatient cross-disciplinary peripartum OUD treatment sites.

Interventions: Randomization to sublingual or extended-release buprenorphine (weekly formulation during pregnancy, monthly formulation optional post partum if not breastfeeding).

Main outcomes and measures: The primary and key secondary outcomes were illicit opioid abstinence during pregnancy and the postpartum period, respectively, defined as the proportion of weekly collected urine samples negative for illicit opioids. If noninferiority was demonstrated at a margin of 0.15, testing for superiority was planned. Key secondary infant outcomes from medical records were opioid treatment for neonatal opioid withdrawal syndrome (NOWS; yes or no) and number of opioid treatment days for NOWS.

Results: Among 140 randomized participants, the mean (SD) age was 31.2 (4.6) years. There were 10 Black participants (7.1%), 10 Hispanic participants (7.1%), 116 (82.9%) White participants, and 14 participants (10.0%) who belonged to additional groups. All but 2 were already prescribed sublingual buprenorphine. Study completion was 98% through pregnancy (137 participants) and 81% through 12 months post partum (114 participants). Illicit opioid abstinence was higher during pregnancy for participants receiving extended-release vs sublingual buprenorphine (82.5% vs 72.6%; mean difference, 9.84 [95% CI, 1.72 to 17.95] percentage points; P = .009). Postpartum abstinence rates declined and were similar in both groups (60.2% vs 59.5%; mean difference, 0.65 [98% CI, -12.72 to 14.02] percentage points; P = .45). Those receiving extended-release buprenorphine experienced fewer serious adverse events during pregnancy (8.7% vs 26.8%; P = .007) and post partum (6.0% vs 18.6%; P = .04). Nonserious adverse events rates did not differ between groups, but more were deemed medication-related for extended-release participants during pregnancy (26.1% vs 7.0%; P = .003). Infants exposed to extended-release vs sublingual buprenorphine did not differ in need for opioid treatment (30.2% vs 26.5%; relative risk, 1.14 [98% CI, 0.54 to 1.99]; P = .64) or mean (SE) treatment days (10.9 [2.2] vs 14.8 [3.0] days; relative risk, 0.73 [98% CI, 0.36 to 1.51]; P = .28). At birth, extended-release-exposed neonates had larger mean (SE) head circumferences than those exposed to sublingual buprenorphine (34.0 [0.2] vs 33.4 [0.2] cm; mean difference, 0.63 [95% CI, -0.00 to 1.26] cm; P = .049).

Conclusions and relevance: The findings of this randomized clinical trial support weekly extended-release buprenorphine for OUD treatment during pregnancy.

Related protocols: CTN-0080

Objective: Identify sociodemographic and substance use characteristics associated with pregnancy intention and explore the relationship between pregnancy intent and postpartum contraception interest among pregnant individuals with opioid use disorder (OUD).

Methods: Secondary analysis of baseline data collected in the Medication Treatment for OUD in Expectant Mothers trial (CTN-0080), which evaluated injectable versus sublingual buprenorphine. Current pregnancy intention was classified as “intended,” “mistimed,” “unwanted,” or “ambivalent.” Postpartum contraceptive interest was categorized into highly effective, effective, less effective, or none. Participant characteristics and contraceptive interest was compared across intention categories using Fisher’s Exact and Kruskal-Wallis tests.

Results: Of 155 participants who completed baseline screening, 137 (88%) did not report any contraceptive use prior to their current pregnancy. Twenty-eight percent reported intended pregnancies, 27% mistimed, 15% never wanted, and 30% were ambivalent towards their current pregnancy. Individuals reporting intended pregnancies disclosed less substance use in the past ninety days and twelve months compared to other categories. Forty-seven percent of participants desired highly effective contraception after delivery, 28% desired effective contraception, 4% desired less effective contraception, and 21% did not desire any contraception. Participants reporting an unwanted pregnancy were significantly more interested in sterilization, while participants reporting a mistimed pregnancy were significantly more interested in a postpartum long-acting reversible contraception.

Conclusions: Our findings that individuals with intended pregnancies report less recent substance use suggests that reproductive health decision-making may be difficult to prioritize during periods of active addiction. In addition, the lack of association between pregnancy intention and postpartum contraceptive interest underscores a need for novel ways to support perinatal individuals with OUD in family planning conversations that honor their reproductive autonomy, values, and desires.

Related protocols: CTN-0080

Background: Opioid use disorder (OUD) during pregnancy is a leading contributor to peripartum morbidity and mortality, with overdose deaths rising significantly in recent years. Despite the identification of various factors associated with overdose events, including social, demographic, psychiatric, and neonatal outcomes, the relative contributions of these factors to peripartum overdose history (or lack thereof) remain unclear. Thus, this study aims to characterize factors associated with lifetime opioid-involved overdose events among currently pregnant individuals receiving buprenorphine (BUP) treatment for OUD.

Methods: Treatment-seeking pregnant individuals with an estimated gestational age of 6 to 30 weeks were enrolled in a large multisite randomized controlled trial evaluating 2 BUP formulations for OUD. Participant baseline demographic, substance use, and mental health data were collected using validated measures, and random forest modeling identified key factors associated with lifetime opioid overdose events.

Results: The 140 pregnant participants (Mage = 31.2 years, SD = 4.7; 87.1% White) reported an average of 8.7 years (SD = 5.8) of opioid use, with 92.1% endorsing lifetime prescription opioid use and 82.9% reporting heroin use. The average lifetime number of nonfatal opioid overdose events was 4.8 (SD = 12.1); an overdose was reported by 55% of the sample (n = 77). Random forest analysis (area under the receiver operating characteristic curve = 0.797) incorporating sociodemographic, substance use, and mental health characteristics found that the most important factors associated with lifetime overdose events were, in order, lifetime heroin use, trauma exposure, reliance on partners or parents for financial support, depressive symptoms, and lifetime cocaine use.

Conclusions: These findings underscore the critical need to address substance use, co-occurring mental health, and socioeconomic challenges that are associated with previous opioid overdose. Identifying and targeting key modifiable overdose risk factors can inform the development of tailored interventions to improve outcomes for this population.

Related protocols: CTN-0080

Introduction: Cigarette smoking rates among pregnant women with opioid use disorder (OUD), are significantly higher than those found in the general population.

Methods: We conducted a secondary analysis of baseline data from a multisite, randomized clinical trial comparing two different buprenorphine formulations on outcomes during pregnancy. Cigarette use and smoking cessation goals were evaluated with the Fagerström Test for Nicotine Dependence and the Thoughts About Abstinence (TAA) questionnaire respectively. Factors associated with differences in cigarette use and smoking cessation goals were compared.

Results: Among 156 participants, 85 (54.5 %) reported that they currently smoked cigarettes. Most participants had a desire to quit smoking (TAA score = 6), but they had low expectations of success (TAA score = 4) and a relatively high perceived difficulty (TAA score = 6.5) of quitting during pregnancy. Among participants who smoked, less than half (45.5 %) had a smoking cessation goal. Participants who had a smoking cessation goal were significantly more likely to have a stronger desire to quit and higher expectations of success in quitting than participants who did not have a goal.

Conclusions: Many pregnant women with OUD would like to quit or reduce smoking during pregnancy. A combination of pharmacologic and non-pharmacologic interventions to reduce or eliminate cigarette use should be incorporated into obstetric and substance use treatment clinical settings. Smoking cessation interventions should be aligned with patients’ goals and preferences.

Related protocols: CTN-0080

Introduction: Given the continued rise in opioid exposed pregnancies and overdose during the postnatal period, it is critical to identify risk characteristics among this population to enable clinicians to better tailor interventions. This exploratory study sought to develop a deeper understanding of overdose risk characteristics among pregnant people with opioid use disorder and which characteristics may contribute to differing risk profiles.

Methods: Design and participants. This exploratory secondary analysis utilized baseline data from a large-scale national multi-site randomized controlled trial that compared two buprenorphine formulations among treatment seeking pregnant individuals with opioid use disorder.

Assessments: For risk group identification, the Personal Opioid-Overdose Risk Survey was used. Trauma history experience was assessed using the Trauma History Screen and substance use history was captured using the DSM-5 Checklist and Treatment Services Review V6.

Analyses: Latent class analysis identified unique subgroups of participants based on overdose risk factors. Latent class group membership was associated with trauma history and substance use characteristics using logistic and stepwise logistic regression.

Results: Three distinct classes of overdose risk emerged: the tolerance and polysubstance/alcohol use (HIGH-ALC) class (n = 14, 10 %), synthetic opioid and polysubstance use (LOW-ALC/FENT) class (n = 65, 46.4 %), and the low risk (LOW-RISK) class (n = 61, 43.6 %). The HIGH-ALC class reported the most (non-opioid) substance use in the last 12 months with 6 times higher odds of marijuana use (95 % CI, 1.01-35.67) and 17.48 times higher odds of cocaine use (95 % CI, 3.45-88.48) compared to the LOW-RISK class. The LOW-ALC/FENT class (n = 65, 46.4 %) had the highest reports of childhood physical abuse, greater odds of experiencing intimate partner violence regarding recovery (OR = 4.82, 95 % CI = 1.90-12.26), and greater odds of a threat to safe living (OR = 3.35, 95 % CI = 0.72-15.66). The LOW-RISK class (n = 61, 43.6 %) had the lowest reports of polysubstance use in the last 12 months and the least reports of both childhood sexual trauma and adulthood sexual trauma.

Conclusions: Through better understanding distinct patient overdose risk profiles, healthcare providers can deliver more targeted prevention interventions to address individual needs and improve maternal outcomes.

Related protocols: CTN-0080

Trauma screening is recommended for pregnant persons with opioid use disorder (OUD), but there is limited literature on screening results from buprenorphine treatment. This study’s objectives were to 1) describe the types, and severity, of traumatic events reported and 2) evaluate the associations between trauma and health-related quality of life (HRQoL).

Baseline data from an ongoing trial were analyzed (CTN-0080). Participants were 155 pregnant persons with OUD receiving, or enrolling in, buprenorphine treatment at one of 13 sites. The experience, and relative severity, of 14 high magnitude stressors were assessed with the trauma history screen. The Patient-Reported Outcomes Measurement Information System-29+2 was used to assess 8 HRQoL domains.

Traumatic stressors were reported by 91% of the sample (n = 155), with 54.8% reporting a lifetime persisting posttraumatic distress (PPD) event and 29.7% reporting a childhood PPD event. The most prevalent lifetime PPD event was sudden death of a close family/friend (25.8%); physical abuse was the most prevalent childhood PPD event (10.3%). Participants with lifetime PPD, relative to no PPD, reported significantly greater pain interference (P = 0.02). Participants with childhood PPD, relative to no PPD, had significantly worse HRQoL overall (P = 0.01), and worse pain intensity (P = 0.002), anxiety (P = 0.003), depression (P = 0.007), fatigue (P = 0.002), and pain interference (P < 0.001).

Conclusions: A majority of pregnant persons enrolled/enrolling in buprenorphine treatment reported persisting posttraumatic distress with sudden death of close family/friend being the most prevalent originating event; clinicians should consider the impact that the opioid-overdose epidemic may be having in increasing trauma exposure in patients with OUD.

Related protocols: CTN-0080

Weekly and monthly CAM2038 (Brixadi®) extended-release subcutaneous buprenorphine (XR bup) has been available in Europe and Australia for several years and was approved by the Food and Drug Administration in May 2023. Little is known about the clinical experience of patients and providers using this new medication during prenatal care. Two cases of pregnant persons with opioid use disorder receiving weekly XR bup in an ongoing randomized multi-site outpatient clinical trial (CTN-0080) are presented along with a brief review of the pharmacology and literature on XR bup formulations. The cases in pregnancy illustrate how treatment with the weekly formulation is initiated including how to make dose adjustments, which may be necessary given the longer half-life; it takes 1 month to achieve steady state. Injection site pain with medication administration was time limited and managed readily. Other injection site reactions experienced included subcutaneous erythema and induration that was delayed in onset and typically mild, resolving with minimal intervention. Delivery management and breastfeeding recommendations while on weekly XR bup were not different compared to sublingual buprenorphine (SL bup).

Conclusions: Weekly XR bup is a new treatment for opioid use disorder that may be used in the obstetric population. Obstetric and addiction medicine clinicians should be aware of this new formulation as its use is expected to increase.

Related protocols: CTN-0080

Pregnant individuals with substance use disorders face complex issues that may serve as barriers to treatment entry and retention. Several professional organizations have established recommendations on comprehensive, collaborative approaches to treatment to meet the needs of this population, but information on real-world application is lacking. Sites participating in the NIDA CTN-0080 “Medication treatment for Opioid use disorder in expectant Mothers (MOMs)”–a randomized clinical trial of extended release compared to sublingual buprenorphine among pregnant and postpartum individuals (PPI)–were selected, in part, because they have a collaborative approach to treating PPI with opioid use disorder (OUD). However, organizational differences among sites and how they implement expert recommendations for collaborative care could impact study outcomes.

Prior to study launch at each of the 13 MOMs sites, investigators used the Pregnancy and Addiction Services Assessment (PAASA) to collect information about organizational factors. Input from a team of addiction, perinatal, and economic evaluation experts guided the development of the PAASA. Investigators programmed the PAASA into a web-based data system and summarized the resultant site data using descriptive statistics.

Study sites represented four US census regions. Most sites were specialty obstetrics & gynecology (OB/GYN) programs providing OUD services (n = 9, 69.2 %), were affiliated with an academic institution (n = 11, 84.6 %), and prescribed buprenorphine in an ambulatory/outpatient setting (n = 11, 84.6 %); all sites offered access to naloxone. Sites reported that their population was primarily White, utilized public insurance, and faced numerous psychosocial barriers to treatment. Although all sites offered many services recommended by expert consensus groups, they varied in how they coordinated these services.

Conclusions: By providing the organizational characteristics of sites participating in the MOMs study, this report assists in filling the current gap in knowledge regarding similar programs providing services to PPI with OUD. Collaborative care programs such as those participating in MOMs are uniquely positioned to participate in research to determine the most effective models of care and to determine how research can be integrated into those clinical care settings.

Related protocols: CTN-0080

Opioid use disorder (OUD) in pregnant women has increased significantly in recent years. Maintaining these women on sublingual (SL) buprenorphine (BUP) is an evidence-based practice but BUP-SL is associated with several disadvantages that an extended-release (XR) BUP formulation could eliminate.

The National Drug Abuse Treatment Clinical Trials Network (CTN) is conducting an intent-to-treat, two-arm, open-label, pragmatic randomized controlled trial, Medication treatment for Opioid-dependent expectant Mothers (MOMs; CTN-0080), to compare mother and infant outcomes of pregnant women with OUD treated with BUP-XR, relative to BUP-SL. A second aim is to determine the relative economic value of utilizing BUP-XR.

Approximately 300 pregnant women with an estimated gestational age (EGA) of 6–30 weeks, recruited from 12 sites, will be randomized in a 1:1 ratio to BUP-XR or BUP-SL, balancing on site, EGA, and BUP-SL status (taking/not taking) at the time of randomization. Participants will be provided with study medication and attend weekly medication visits through 12 months postpartum. Participants will be invited to participate in two sub-studies to evaluate the: 1) mechanisms by which BUP-XR may improve mother and infant outcomes; and 2) effects of prenatal exposure to BUP-XR versus BUP-SL on infant neurodevelopment.

Conclusions: This paper describes the key design decisions for the main trial made during protocol development. This Investigational New Drug (IND) trial uniquely uses pragmatic features where feasible in order to maximize external validity, hence increasing the potential to inform clinical practice guidelines and address multiple knowledge gaps for treatment of this patient population.

Related protocols: CTN-0080