Neonatal Opioid Withdrawal Syndrome Research Articles

Performance of Phenotype Algorithms for the Identification of Opioid-Exposed Infants.

Observational studies examining outcomes among opioid-exposed infants are limited by phenotype algorithms that may under identify opioid-exposed infants without neonatal opioid withdrawal syndrome (NOWS). We developed and validated the performance of different phenotype algorithms to identify opioid-exposed infants using electronic health record data. We developed phenotype algorithms for the identification of opioid-exposed infants among a population of birthing person-infant dyads from an academic health care system (2010-2022). We derived phenotype algorithms from combinations of 6 unique indicators of in utero opioid exposure, including those from the infant record (NOWS or opioid-exposure diagnosis, positive toxicology) and birthing person record (opioid use disorder diagnosis, opioid drug exposure record, opioid listed on medication reconciliation, positive toxicology). We determined the positive predictive value (PPV) and 95% confidence interval for each phenotype algorithm using medical record review as the gold standard. Among 41 047 dyads meeting exclusion criteria, we identified 1558 infants (3.80%) with evidence of at least 1 indicator for opioid exposure and 32 (0.08%) meeting all 6 indicators of the phenotype algorithm. Among the sample of dyads randomly selected for review (n = 600), the PPV for the phenotype requiring only a single indicator was 95.4% (confidence interval: 93.3-96.8) with varying PPVs for the other phenotype algorithms derived from a combination of infant and birthing person indicators (PPV range: 95.4-100.0). Opioid-exposed infants can be accurately identified using electronic health record data. Our publicly available phenotype algorithms can be used to conduct research examining outcomes among opioid-exposed infants with and without NOWS.

Development and verification of a full physiologically-based pharmacokinetic model for sublingual buprenorphine in healthy adult volunteers that accounts for nonlinear bioavailability.

Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome (NOWS). The study aimed to develop a full physiologically-based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e. untransformed or log-transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O ratios) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. Significance Statement The PBPK model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for fetomaternal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome (NOWS).

Maternal opioid use during pregnancy and the risk of neonatal opioid withdrawal syndrome in the offspring.

Neonatal opioid withdrawal syndrome (NOWS) is caused by sudden cessation from in utero exposure to opioids. The indications for opioid use during pregnancy are diverse including medication for opioid use disorder and analgesia. The opioid dose typically depends on the indication, with higher doses used for medication for opioid use disorder and lower doses used for analgesia. The aim of this study was to investigate the relationship between maternal opioid dose during pregnancy and the risk of NOWS. We conducted a historical multicenter cohort study of neonates prenatally exposed to opioids in Eastern Denmark during a six-year period from 2013 to 2018. The data was extracted from reviewing the individual's medical record(s), which were identified through a search of the Danish National Patient Register. Four groups (quartiles) according to maternal opioid dose during the last four weeks prior to delivery were compared. Unadjusted and adjusted logistic regression analyses were conducted to examine the risk of NOWS while controlling for relevant covariates. A total of 130 in utero opioid exposed neonates were included. The majority of the pregnant patients (88%) were treated with opioids for analgesic purposes. Overall, 52% of neonates developed NOWS. The cumulative incidence of NOWS was 21%, 28%, 67% and 91% at maternal average daily dose of morphine milligram equivalent during the last four weeks prior to delivery of 0.7-14 (group I), 14.3-38.6 (group II), 40-90 (group III) and 90.9-1440 (group IV), respectively. Compared to group I the adjusted odds (aOR) of NOWS increased significantly in group III (aOR 10.6 [2.9-39.1]) and group IV (aOR 37.8 [7.6-188.2]) but not in group II (aOR 1.5 [0.4-5.2]). No cases of NOWS were reported at maternal dose less than an average daily dose of five morphine milligram equivalent during the last four weeks prior to delivery. No significant changes in the incidence of NOWS were observed between 2013 and 2018. The odds of neonatal opioid withdrawal syndrome increased significantly as the maternal average daily dose of morphine milligram equivalent during the last four weeks prior to delivery surpassed 40.

Decreased Sonographic Head Circumference Is Found in Buprenorphine-Exposed Fetuses [ID 2683396

INTRODUCTION: Neonates diagnosed with neonatal opioid withdrawal syndrome (NOWS) have decreased head circumference compared to non-exposed newborns. This is the first study to evaluate fetal head circumference over time in a group of fetuses with intrauterine buprenorphine exposure. METHODS: Fetal anatomic surveys are commonly performed at around 20 weeks of gestation. Patients treated with medication-assisted therapy (MAT) for opioid use disorder commonly receive estimated fetal weight scans at around 32 weeks of gestation due to the risk of intrauterine growth restriction. Retrospective review of ultrasound reports for three groups of patients were performed. Group 1 (75 patients) was low-dose MAT; group 2 (73 patients) was traditional higher-dose MAT. Group 3 (104 patients) was a control group. The IRB approval was 1220.9e-ETSU, entitled “Effect of Maternal Buprenorphine on Fetal Head Circumference.” RESULTS: At the time of the approximately 20-week scan, no statistical difference was found between the groups. At the approximately 32-week growth scan, however, a comparison of the two buprenorphine groups together versus control group showed a statistically significant difference (P=.018) in head circumference. Although the low-dose group had larger head circumferences than the higher-dose group in the 32-week scan, the difference was not significant. CONCLUSION: Previous studies have shown decreased head circumference in newborns in association with maternal MAT. This is the first study to provide ultrasound confirmation of decreased head circumference in fetuses exposed to buprenorphine. Effects are pronounced in the third trimester; the possibility exists that interventions during pregnancy might preserve fetal brain volume. Further research is needed.

Evaluating a web-based training curriculum for disseminating best practices for the care of newborns with neonatal opioid withdrawal syndrome in a rural hospital, the NOWS-NM Program

BackgroundThe incidence of neonatal opiate withdrawal syndrome (NOWS) in the US has grown dramatically over the past two decades. Many rural hospitals not equipped to manage these patients transfer them to hospitals in bigger cities.MethodsWe created a curriculum, the NOWS-NM Program, a web-based curriculum training in best practices. To evaluate the curriculum, we conducted pre- and post-surveys of NOWS knowledge, attitudes, and care practices, plus post-curriculum interviews and focus groups.ResultsFourteen participants completed both pre- and post-curriculum surveys. They indicated an increase in knowledge and care practices. A small number of respondents expressed negative attitudes about parents of infants with NOWS at pre-test, the training curriculum appeared to have no impact on such attitudes at post-test. Sixteen participants participated in focus groups or interviews. Qualitative data reinforced the positive quantitative results and contradicted the negative survey results, respondents reported that the program did reduce stigma and improve provider/staff interactions with patients.ConclusionsThis curriculum demonstrated positive impacts on NOWS knowledge and care practices. Incorporating focus on core concepts of trauma-informed care and self-regulation in future iterations of the curriculum may strengthen the opportunity to change attitudes and address the needs expressed by participants and improve care of families and babies with NOWS.

Complementary Therapies For Mild to Moderate Neonatal Opioid Withdrawal Syndrome: A Mini-review

Introduction: Neonatal Opioid Withdrawal Syndrome, resulting from prenatal opioid exposure, is rising in prevalence and presents substantial health and developmental challenges for neonates. While standard treatments of opioids such as morphine have been traditionally employed for treatment, concerns about their long-term effects on neonatal development have spurred interest in alternative therapeutic strategies. This review seeks to highlight emerging non-opioid interventions for Neonatal Opioid Withdrawal Syndrome and their potential benefits. Methods: Utilizing the PRISMA framework, the database PubMed was systematically searched for complementary therapies for neonatal opioid withdrawal syndrome. The search was conducted on September 27th, 2023, and employed a combination of keywords targeting the condition and the treatment modalities. Cochrane risk of bias tool was utilized to evaluate study quality and classify studies based on their risk of bias. Data captured from these studies encompassed parameters such as study design, intervention, and outcomes, including length of stay and length of pharmacotherapy. Results: Among 71 identified articles, only five met the inclusion criteria. Three were randomized controlled trials, and two were quasi-experimental studies. Among the 5 included trials, 3 demonstrated potential benefits, while two revealed no differences in treatment duration or reliance on pharmacological support. The "Eat-Sleep-Console" method, acupuncture, and vibrating mattresses were associated with reduced morphine dosages and shorter hospital stays. Most trials showed moderate to high risk using the Cochrane RoB-2 tool. Discussion: This review underlines the growing concern of Neonatal Opioid Withdrawal Syndrome stemming from increased opioid use during pregnancy. While severe cases necessitate pharmaceutical treatments, there’s a pressing need for safer alternatives. "Eat-Sleep-Console" method and transcutaneous auricular neuromodulation might offer mild relief. Future efforts should adopt a multifaceted strategy, emphasizing further research to optimize treatments and outcomes. Conclusion: Although complementary therapies show promise, with limited evidence from three RCTs, their efficacy remains uncertain. Additional studies might clarify the role while combining it with pharmacological methods could enhance outcomes. Comprehensive research is essential to optimize treatments for NOWS-affected infants. Complementary therapies in mild to moderate cases of Neonatal Opioid Withdrawal Syndrome show promising results. So far, not enough data has been obtained to support the efficacy of observed therapies.

Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal

The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Opioid treatment for NOWS and the ESC care approach. For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. ClinicalTrials.gov Identifier: NCT04057820.

An epidemiological examination of neonatal opioid withdrawal syndrome and maternal and infant characteristics.

Analyze maternal and infant characteristics by Neonatal Opioid Withdrawal Syndrome (NOWS) status and examine the association between mothers with Hepatitis C Virus (HCV) and infants diagnosed with NOWS. Hospital discharge diagnoses of low-income women in Tennessee were used to identify NOWS cases (n = 1,369) in 2013 and 2014 and randomly selected controls (n = 1,369) were matched on county of residence and birth year. Maternal and infant characteristics were obtained by linking these data to birth certificate data. Of Tennessee's 683 cases of NOWS in 2013 and 686 in 2014, most (69%) occurred in Eastern Tennessee. Mothers of infants with NOWS were more likely to be older, unmarried, and white than mothers of infants without NOWS. Mothers of infants with NOWS also faced greater health risk: more smoking, HCV, herpes simplex diagnosis, and no or less frequent prenatal care (p < .0001). Infants with NOWS were more likely to present with infection, be admitted into the NICU, have lower birth weight, be enrolled in TennCare, but less likely to be breastfed than infants without NOWS (p < .0001). After adjusting for demographic factors and smoking, compared to mothers of infants without NOWS, mothers of infants with NOWS had an alarmingly increased odds of HCV [OR = 12.97 (95% CI 7.42, 22.66)]. This study emphasizes the complexity of challenges facing families impacted by NOWS, the importance of multifaceted prevention, and the need to conduct HCV testing in NOWS infants.

Short term outcomes of neonatal opioid withdrawal syndrome: a comparison of two approaches.

To evaluate outcomes in opioid exposed neonates (OENs) assessed by the Eat, Sleep, Console (ESC) tool compared to the Finnegan Neonatal Abstinence Scoring System (FNASS). Retrospective analysis of a statewide database of OENs from 2017 to 2020 with birthing hospitals classified based on the assessment tool used. Four main outcomes were examined using multivariable and Poisson logistic regression models. Of 2375 OENs, 42.1% received pharmacotherapy (PT) with a consistent decrease in PT, length of treatment (LOT), and length of stay (LOS) over the study period. There was no change in use of mother's own milk (MoM). While outcomes were significantly associated with several specific variables, there were no differences in outcomes between assessment methods. While there was a significant decrease over time in PT, LOT, and LOS, improvements were independent of the assessment tool used and likely related to the increased use of non-pharmacologic care.

Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US

High-risk infants, defined as newborns with substantial neonatal-perinatal morbidities, often undergo multiple procedures and require prolonged intubation, resulting in extended opioid exposure that is associated with poor outcomes. Understanding variation in opioid prescribing can inform quality improvement and best-practice initiatives. To examine regional and institutional variation in opioid prescribing, including short- and long-acting agents, in high-risk hospitalized infants. This retrospective cohort study assessed high-risk infants younger than 1 year from January 1, 2016, to December 31, 2022, at 47 children's hospitals participating in the Pediatric Health Information System (PHIS). The cohort was stratified by US Census region (Northeast, South, Midwest, and West). Variation in cumulative days of opioid exposure and methadone treatment was examined among institutions using a hierarchical generalized linear model. High-risk infants were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for congenital heart disease surgery, medical and surgical necrotizing enterocolitis, extremely low birth weight, very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and other abdominal surgery. Infants with neonatal opioid withdrawal syndrome, in utero substance exposure, or malignant tumors were excluded. Any opioid exposure and methadone treatment. Regional and institutional variations in opioid exposure. Overall, 132 658 high-risk infants were identified (median [IQR] gestational age, 34 [28-38] weeks; 54.5% male). Prematurity occurred in 30.3%, and 55.3% underwent surgery. During hospitalization, 76.5% of high-risk infants were exposed to opioids and 7.9% received methadone. Median (IQR) length of any opioid exposure was 5 (2-12) cumulative days, and median (IQR) length of methadone treatment was 19 (7-46) cumulative days. There was significant hospital-level variation in opioid and methadone exposure and cumulative days of exposure within each US region. The computed intraclass correlation coefficient estimated that 16% of the variability in overall opioid prescribing and 20% of the variability in methadone treatment was attributed to the individual hospital. In this retrospective cohort study of high-risk hospitalized infants, institution-level variation in overall opioid exposure and methadone treatment persisted across the US. These findings highlight the need for standardization of opioid prescribing in this vulnerable population.

Forecasting Fetal Buprenorphine Exposure through Maternal-Fetal Physiologically Based Pharmacokinetic Modeling.

Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal-fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal-fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal-fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity.

Intrauterine exposure to maternal opioid maintenance treatment and associated risk factors may impair child growth.

How maternal opioid maintenance treatment (OMT) affects children is under-researched. This population-based registry study investigated child growth and somatic health following intrauterine exposure to this treatment. Children born between 1 March 2011 and 30 May 2021 to mothers who used buprenorphine, buprenorphine-naloxone, or methadone throughout their pregnancies were followed for 2 years at the Helsinki University Hospital, Finland. Appropriate statistical tests were used to compare the treatment groups. Of the 67 neonates, 52% were male, 96% were born full-term and 63% were treated for neonatal opioid withdrawal syndrome. Otherwise, the children were predominantly healthy, although relatively small: 22% were small for gestational age, the methadone group children being the smallest. Foetal exposure to maternal methadone treatment, illicit drugs, hepatitis C and smoking were associated with small for gestational age; the former two were also associated with later slower growth, especially head growth and weight gain (p < 0.001). However, 29% were overweight at 2 years. Using child growth as the outcome, we found that buprenorphine-naloxone and buprenorphine-monotherapy had equal effects as forms of maternal OMT. Exposure to multiple risk factors may harm foetal and subsequent growth. We recommend long-term follow-up of children exposed to maternal OMT.

Neurobehavioral problems at age 2 years in children with prenatal opioid exposure.

To evaluate factors associated with borderline/clinical range Child Behavior Checklist (CBCL) scores in opioid-exposed children. Retrospective study of 94 children with prenatal opioid exposure evaluated with the CBCL at age 2 years. Twenty-eight children (30%) had borderline/clinical findings on the CBCL, with 27% scoring borderline/clinical for Externalizing Problems. In the multivariable model, lower Bayley-III motor scores and discharge home with mother with safety plan were associated with borderline/clinical Externalizing Problems. Medication treatment for neonatal opioid withdrawal syndrome (NOWS) was associated with normal Externalizing Problems scores. Treatment with clonidine or phenobarbital was associated with scores in the normal range in all broadband CBCL measures. Specific factors are associated with behavioral and emotional challenges measured by borderline/clinical CBCL scores among opioid-exposed children.

Neonatal Opioid Withdrawal Syndrome (NOWS) Monitoring Not Requiring NICU Admissions: Examining Rooming-in as Standard Care

ABSTRACT Objectives: Neonatal opioid withdrawal syndrome (NOWS) refers to the withdrawal symptoms a newborn may experience if exposed to opioids in utero. Traditional NOWS management involves pharmacological treatments, and admission to a high acuity unit such as a neonatal intensive care unit (NICU) for continuous cardiorespiratory monitoring due to the theoretical risk of respiratory depression and apnea. This quality assurance project aims to demonstrate that current clinical practices at the Families in Recovery (FIR) unit at BC Women’s Hospital + Health Centre for infants diagnosed with NOWS are safe and effective; namely, that NICU admission and/or continuous cardiorespiratory monitoring is not necessary for infants (&gt;35 weeks, without comorbidities) requiring morphine oral solution (MOS) to manage the symptoms of NOWS. Methods: A 5-year retrospective chart review of infants admitted to the FIR unit between 2014 and 2018 was conducted. All infants born/admitted to BC Women’s Hospital + Health Centre, diagnosed with NOWS, and given MOS to manage withdrawal symptoms were included. Data gathered included morphine treatment, associated respiratory status, and any reasons for NICU admission and subsequent length of stay. Results: Infants on MOS for NOWS management in NICU did not experience low respiratory rates with clinically significant oxygen desaturations. MOS management of NOWS on FIR is done successfully with Q4 vital assessment and additional supportive care when required. Conclusions: Infants requiring MOS for the treatment of NOWS, without comorbidities, can be safely managed without continuous cardiorespiratory monitoring outside the NICU setting, promoting the Rooming-in model of care and mitigating the financial burden on the health care system. Objectifs: Le Syndrome de Sevrage Néonatal aux Opioïdes (SSNO) désigne les symptômes de sevrage qu’un nouveau-né peut ressentir s’il est exposé à des opioïdes in utero. La prise en charge traditionnelle du SSNO comprend des traitements pharmacologiques et l’admission dans une Unité de Soins Intensifs Néonatals (USIN) pour une surveillance cardiorespiratoire continue en raison du risque théorique de dépression respiratoire et d’apnée. Ce projet d’assurance qualité vise à démontrer que les pratiques cliniques actuelles de l’unité Families in Recovery (FIR) du BC Women’s Hospital + Health Centre (BCWH) pour les nourrissons diagnostiqués avec un SSNO sont sûres et efficaces. L’admission en USIN et/ou la surveillance cardiorespiratoire continue n’est pas nécessaire pour les nourrissons (&gt;35 semaines, sans comorbidités) nécessitant une solution orale de morphine (SOM) pour gérer les symptômes du SSNO. Méthodes: Une étude rétrospective sur 5 ans des dossiers des nourrissons admis dans l’unité FIR entre 2014-2018 a été réalisée. Tous les nourrissons nés/admis au BCWH, diagnostiqués avec un SSNO et ayant reçu une SOM pour gérer les symptômes de sevrage ont été inclus. Les données recueillies comprenaient le traitement à la morphine, l'état respiratoire associé et toutes les raisons de l’admission à l’unité de soins intensifs néonatals (USIN) et de la durée de séjour subséquente. Résultats: Les nourrissons sous SOM pour la prise en charge du SSNO en USIN n’ont pas connu de faibles fréquences respiratoires avec des désaturations en oxygène cliniquement significatives. La prise en charge par SOM du SSNO dans l’unité FIR est réussie avec une évaluation des fonctions vitales au 4e trimestre et des soins de soutien supplémentaires si nécessaire. Conclusion: Les nourrissons nécessitant une SOM pour le traitement du SSNO, sans comorbidités, peuvent être pris en charge en toute sécurité sans surveillance cardiorespiratoire continue en dehors de l’USIN. Ceci favorise le modèle de soins Rooming-in et atténue le fardeau financier pour le système de soins de santé.

Maternal opioid use disorder and infant mortality in Wisconsin, United States, 2010–2018

ObjectiveThe difference in infant health outcomes by maternal opioid use disorder (OUD) status is understudied. We measured the association between maternal OUD during pregnancy and infant mortality and investigated whether this association differs by infant neonatal opioid withdrawal syndrome (NOWS) or maternal receipt of medication for OUD (MOUD) during pregnancy. MethodsWe sampled 204,543 Medicaid-paid births from Wisconsin, United States (2010–2018). The primary exposure was any maternal OUD during pregnancy. We also stratified this exposure on NOWS diagnosis (no OUD; OUD without NOWS; OUD with NOWS) and on maternal MOUD receipt (no OUD; OUD without MOUD; OUD with <90 consecutive days of MOUD; OUD with 90+ consecutive days of MOUD). Our outcome was infant mortality (death at age <365 days). Demographic-adjusted logistic regressions measured associations with odds ratios (OR) and 95% confidence intervals (CI). ResultsMaternal OUD was associated with increased odds of infant mortality (OR 1.43; 95% CI 1.02–2.02). After excluding infants who died <5 days post-birth (i.e., before the clinical presentation of NOWS), regression estimates of infant mortality did not significantly differ by NOWS diagnosis. Likewise, regression estimates did not significantly differ by maternal MOUD receipt in the full sample. ConclusionsMaternal OUD is associated with an elevated risk of infant mortality without evidence of modification by NOWS nor by maternal MOUD treatment. Future research should investigate potential mechanisms linking maternal OUD, NOWS, MOUD treatment, and infant mortality to better inform clinical intervention.

Abstinence scoring algorithms for treatment of neonatal opioid withdrawal syndrome (NOWS).

Chervoneva et al. (2020) developed an abbreviated score (sMNAS-9) derived from full modified Finnegan MOTHER NAS scale (MNAS) for evaluating severity of NOWS. We sought to develop NOWS treatment algorithms for clinical decision rules based on scores utilizing the shorter sMNAS. This was a retrospective study of 373 infants with NOWS scored with MNAS and treated with morphine between 2007 and 2016. The infants were randomly split into training/test sets. The training set was used to derive optimized cutoff values for sMNAS-9 scores. The independent set evaluated the sMNAS-9 clinical decision rules based on full MNAS in NOWS morphine and buprenorphine treatment algorithms. Clinical decision rules based on sMNAS-9 yielded sensitivities of 88% or higher and specificities of 85% or higher for predicting the respective rules based on full MNAS. The sMNAS-9 scoring instrument is expected to yield similar clinical decisions in treatment of NOWS.

Salivary Therapeutic Monitoring of Buprenorphine in Neonates After Maternal Sublingual Dosing Guided by Physiologically Based Pharmacokinetic Modeling.

Opioid use disorder (OUD) during pregnancy is associated with high mortality rates and neonatal opioid withdrawal syndrome (NOWS). Buprenorphine, an opioid, is used to treat OUD and NOWS. Buprenorphine active metabolite (norbuprenorphine) can cross the placenta and cause neonatal respiratory depression (EC50 = 35 ng/mL) at high brain extracellular fluid (bECF) levels. Neonatal therapeutic drug monitoring using saliva decreases the likelihood of distress and infections associated with frequent blood sampling. An adult physiologically based pharmacokinetic model for buprenorphine and norbuprenorphine after intravenous and sublingual administration was constructed, vetted, and scaled to newborn and pregnant populations. The pregnancy model predicted that buprenorphine and norbuprenorphine doses would be transplacentally transferred to the newborns. The newborn physiologically based pharmacokinetic model was used to estimate the buprenorphine and norbuprenorphine levels in newborn plasma, bECF, and saliva after these doses. After maternal sublingual administration of buprenorphine (4 mg/d), the estimated plasma concentrations of buprenorphine and norbuprenorphine in newborns exceeded the toxicity thresholds for 8 and 24 hours, respectively. However, the norbuprenorphine bECF levels were lower than the respiratory depression threshold. Furthermore, the salivary buprenorphine threshold levels in newborns for buprenorphine analgesia, norbuprenorphine analgesia, and norbuprenorphine hypoventilation were observed to be 22, 2, and 162 ng/mL. Using neonatal saliva for buprenorphine therapeutic drug monitoring can facilitate newborn safety during the maternal treatment of OUD using sublingual buprenorphine. Nevertheless, the suitability of using adult values of respiratory depression EC50 for newborns must be confirmed.

Case Series of Individuals Treated with Naltrexone during Pregnancy for Opioid and/or Alcohol Use Disorder.

There is a lack of knowledge about the relative safety and efficacy of naltrexone for the treatment of pregnant individuals with opioid and/or alcohol use disorder, including the range of outcomes, in both the pregnant individual and the infant, over the course of peripartum period. Our objective was to describe these outcomes in a cohort of pregnant individuals on naltrexone. In this prospective case series, 7 pregnant individuals with opioid use disorder (OUD) or alcohol use disorder (AUD) treated with naltrexone were followed from pregnancy through 12 months after delivery. Clinical treatment protocols and outcomes related to safety and efficacy during pregnancy, delivery, and the postpartum period are described. There were 4 pregnant individuals with OUD and 3 with AUD, of which 3 were managed with oral and 4 with extended-release naltrexone. The mean gestational age at study enrollment was 21.7 (SD, 12) weeks. Of the 7 participants, there was no return to nonprescribed opioid use and 2 who experienced a return to alcohol use over the course of the study. All individuals delivered vaginally at a mean of 37 weeks gestation without any peripartum pain difficulties. Five of the individuals (71.4%) remained on naltrexone 12 months after delivery. There were no reported fetal anomalies and one preterm delivery. None of the infants developed neonatal opioid withdrawal syndrome. For pregnant individuals with OUD or AUD treated with naltrexone, there were low rates of return to nonprescribed use and reassuring pregnant person and infant outcomes to 12 months postpartum.

County-level neonatal opioid withdrawal syndrome rates and real-world access to buprenorphine during pregnancy: An audit (“secret shopper”) study in Missouri

BackgroundAmid rising rates of neonatal opioid withdrawal syndrome (NOWS) worldwide and in many regions of the USA, we conducted an audit study (“secret shopper study”) to evaluate the influence of county-level buprenorphine capacity and rurality on county-level NOWS rates. MethodsIn 2019, up to three phone calls were made to buprenorphine prescribers in the state of Missouri (USA). County-level buprenorphine capacity was defined as the number of clinicians (across all specialties) accepting pregnant people divided by the number of births. Multivariable negative binomial regression models estimated associations between buprenorphine capacity, rurality, and county-level NOWS rates, controlling for potential confounders (i.e., poverty, unemployment, and physician shortages) that may correspond to higher rates of NOWS and lower rates of buprenorphine prescribing. Analyses were stratified using tertiles of county-level overdose rates (top, middle, and lowest 1/3 of overdose rates). ResultsOf 115 Missouri counties, 81(70 %) had no buprenorphine capacity, 17(15 %) were low-capacity (<0.5-clinicians/1,000 births), and 17(15 %) were high-capacity (≥0.5/1,000 births). The mean NOWS rate was 6.5/1,000 births. In Missouri counties with both the highest and lowest opioid overdose rates, higher buprenorphine capacity did not correspond to decreases in NOWS rates (incidence rate ratio[IRR]=1.23[95 %-confidence-interval[CI]=0.65–2.32] and IRR=1.57[1.21–2.03] respectively). Rurality did not correspond to greater NOWS burden in both Missouri counties with highest and lowest opioid overdose rates. ConclusionsThe vast majority of counties in Missouri have no capacity for buprenorphine prescribing during pregnancy. Rurality and lower buprenorphine capacity did not significantly predict elevated rates of NOWS.

The Bioavailability of CHF6563, an Ethanol-Free, Sublingual Neonatal Buprenorphine Formulation: A Bridging Study Conducted in Adults

OBJECTIVE Sublingual buprenorphine has demonstrated efficacy for treatment of the neonatal opioid withdrawal syndrome (NOWS), but the current formulation used in clinical practice contains 30% ethanol. Ethanol as a pharmacologically active excipient ideally should be removed from neonatal formulations. The objective of this study was to determine the relative bioavailability of a novel ethanol-free ­formulation (CHF6563) compared with the commonly used ethanolic solution in a phase I, open-label, 2-period, ­single-dose, crossover study in healthy adults. METHODS Eighteen adult opioid-naïve volunteers were administered one of the formulations in a randomized crossover treatment. After a 10-day washout period, subjects received the other formulation. Serial blood samples were drawn for pharmacokinetic analysis over 48 hours. RESULTS The geometric mean ratio (90% CIs) of the ethanol-free buprenorphine solution AUC0–last was 0.80 (0.65–0.99) and Cmax was 0.81 (0.66–0.99) compared with reference ethanolic formulation. The ­ethanol-free formulation had a greater degree of intersubject variability than the ethanol-containing ­reference formulation (coefficient of variation of 59% vs 31.5%, respectively, for AUC0–last). CONCLUSIONS In an adult population, a novel ethanol-free formulation of buprenorphine containing widely used excipients demonstrated a slight decrease in bioavailability when compared with an ethanolic solution. These results will inform those seeking to develop ethanol-free pediatric drug formulations.