Neonatal Abstinence Syndrome Research Articles

Behandeling van opioïdverslaafde zwangere vrouwen met buprenorfine: invloed op de foetus en de pasgeborene

Treatment of opioid addiction in pregnancy with buprenorphine: implications for the fetus and newborn The aim of this article is to summarize the actual knowledge on the use of buprenorphine for the treatment of opioid addiction in pregnancy. Buprenorphine is a semisynthetic thebaine derivative, increasingly used instead of methadone for the treatment of opioid-dependent pregnant women. Fetuses exposed to buprenorphine have a more favorable biophysical profile compared to methadone. The neonatal abstinence syndrome (NAS) occurs less in comparison to methadone-exposed neonates. Treatment is not always indicated and, if necessary, morphine is administered. Buprenorphine is a promising alternative to methadone in the treatment of pregnant women with opioid addiction.

Prenatal Opioid Exposure and Immune-Related Conditions in Children

Prenatal opioid exposure (POE) may alter with fetal development of the immune system, which may influence long-term health and susceptibility to immune-related conditions. To compare the risk of hospitalization and emergency department presentation for immune-related conditions in children with and without POE. This retrospective, population-based cohort study used linked administrative health records of all children born in Western Australia between January 1, 2003, and December 31, 2018 (N = 401 462). Prenatal exposure to prescription opioids (overall and by trimester), neonatal abstinence syndrome diagnosis, and opioid indication (pain or opioid use disorder [OUD]). The main outcome was hospital admissions and emergency department presentations during which a child was diagnosed with an immune-related condition, including infections, conditions associated with an overactive immune system (eg, asthma, eczema, and allergy and anaphylaxis), and autoimmune diseases diagnosed before age 5 years or June 30, 2020. Data were analyzed between August 30, 2022, and February 27, 2023. Neonates with POE (1656 [0.4%]; mean [SD] gestational age, 37.7 [2.1] weeks; 836 females [50.5%]; 820 males [49.5%]) were more likely to be born preterm, have low birth weight for gestational age, and be coexposed to cigarette smoke compared with nonexposed neonates. Perinatal opioid exposure was associated with an increased risk of perinatal infection (adjusted odds ratio [AOR], 1.62; 95% CI, 1.38-1.90) and eczema and dermatitis (AOR, 11.91; 95% CI, 9.84-14.41) compared with nonexposure. Neonatal abstinence syndrome was also associated with both conditions (AOR, 2.91 [95% CI, 2.36-3.57] and 31.11 [95% CI, 24.64-39.28], respectively). Prenatal opioid exposure was also associated with an increased risk of childhood asthma (adjusted hazard ratio [AHR], 1.44; 95% CI, 1.16-1.79), but not allergies and anaphylaxis. It was also associated with an increased risk of childhood eczema and dermatitis, but only in children with POE from opioids used to treat OUD (AHR, 1.47; 95% CI, 1.08-1.99) rather than pain. In contrast, POE from opioids used for pain was associated with an increased risk of infection (AHR, 1.44; 95% CI, 1.32-1.58), but POE to opioids used to treat OUD was not. Autoimmune conditions were rare and were not observed to be associated with POE. In this cohort study, POE was associated with an increased risk of infection, eczema and dermatitis, and asthma, but not allergies and anaphylaxis or autoimmune conditions. These findings highlight the importance of further study of opioid-induced immune changes during pregnancy, the potential impact on long-term health in exposed children, and the mechanisms of opioid-induced immune dysregulation.

The Risks of “Getting High” on Over-the-Counter Drugs during Pregnancy

Easy access to over-the-counter (OTC) drugs makes it possible to procure active substances that normally used in therapeutic doses do not raise health problems. The use of high doses of OTC drugs containing codeine, loperamide, pseudoephedrine, diphenhydramine or dimenhydrinate, as well as the use of benzidamine systemically raises concerns regarding the increase in units sold. These drugs are used for recreational or euphorizing purposes, including by young women of childbearing age, psychoactive substance users representing a risk group in terms of the possibility of an unplanned pregnancy. Abusive consumption of OTC products during pregnancy is harmful, with consequences for both fetal and late development that can occur in the infant. This literature review presents the risks (teratogenicity, fetal toxicity, neonatal abstinence syndrome, etc.) associated with the use of potentially psychoactive OTC drugs to emphasize the importance of re-evaluating OTC classification and dispensing.

Neonatal Withdrawal Syndrome, Management Difficulties: About Two Cases

Neonatal Withdrawal Syndrome, Management Difficulties: About Two Cases

The association between gestational age at delivery and neonatal abstinence syndrome: A systematic review and meta-analysis

Objectives: Some evidence suggests that infants born at later gestational age (GA) are at higher risk of developing neonatal abstinence syndrome (NAS). This systematic review estimated the association between GA at delivery and development of NAS in infants born to women on opioid agonist therapy (OAT).
 Methods: MEDLINE/PubMed, Scopus, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials were searched from January 2000 to April 2023. Studies reporting data on the association between GA and NAS among pregnant women being treated with OAT were eligible for inclusion. Random effects meta-analysis was used to estimate the mean difference in GA between infants affected by NAS and unaffected infants; odds ratio (OR) for the association between preterm birth and NAS; and OR for the association between gestational week and NAS.
 Results: Of 966 records identified, 38 studies were eligible for this review. The pooled mean difference in GA between infants affected by NAS and unaffected infants was 0.62 weeks (95% CI: 0.08–1.16, I2=90.7%). The odds of developing NAS were estimated to increase by 3% per gestational week (OR 1.03, 95% CI: 0.997-1.06, I2=84.2%). The OR for the association between preterm birth and developing NAS was estimated to be 0.87 (95% CI: 0.63-1.21, I2=85.7%).
 Conclusions: The data included in this review demonstrate that higher GA is unlikely to be associated with an increased risk of NAS, although poor study quality and significant study heterogeneity were observed.

Placental cytochrome P450 methylomes in infants exposed to prenatal opioids: exploring the effects of neonatal opioid withdrawal syndrome on health horizons.

Background: Neonatal opioid withdrawal syndrome (NOWS), arises due to increased opioid use during pregnancy. Cytochrome P450 (CYP) enzymes play a pivotal role in metabolizing a wide range of substances in the human body, including opioids, other drugs, toxins, and endogenous compounds. The association between CYP gene methylation and opioid effects is unexplored and it could offer promising insights. Objective: To investigate the impact of prenatal opioid exposure on disrupted CYPs in infants and their anticipated long-term clinical implications. Study Design: DNA methylation levels of CYP genes were analyzed in a cohort of 96 placental tissues using Illumina Infinium MethylationEPIC (850k) BeadChips. This involved three groups of placental tissues: 32 from mothers with infants exposed to opioids prenatally requiring pharmacologic treatment for NOWS, 32 from mothers with prenatally opioid-exposed infants not needing NOWS treatment, and 32 from unexposed control mothers. Results: The study identified 20 significantly differentially methylated CpG sites associated with 17 distinct CYP genes, with 14 CpGs showing reduced methylation across 14 genes (CYP19A1, CYP1A2, CYP4V2, CYP1B1, CYP24A1, CYP26B1, CYP26C1, CYP2C18, CYP2C9, CYP2U1, CYP39A1, CYP2R1, CYP4Z1, CYP2D7P1 and), while 8 exhibited hypermethylation (CYP51A1, CYP26B1, CYP2R1, CYP2U1, CYP4X1, CYP1A2, CYP2W1, and CYP4V2). Genes such as CYP1A2, CYP26B1, CYP2R1, CYP2U1, and CYP4V2 exhibited both increased and decreased methylation. These genes are crucial for metabolizing eicosanoids, fatty acids, drugs, and diverse substances. Conclusion: The study identified profound methylation changes in multiple CYP genes in the placental tissues relevant to NOWS. This suggests that disruption of DNA methylation patterns in CYP transcripts might play a role in NOWS and may serve as valuable biomarkers, suggesting a future pathway for personalized treatment. Further research is needed to confirm these findings and explore their potential for diagnosis and treatment.

Weaning buprenorphine in pregnant patients#

Objective Evaluate maternal and neonatal outcomes after buprenorphine wean compared to patients maintained on buprenorphine throughout pregnancy. Methods Prospective cohort study of pregnant patients with opioid use disorder enrolled in a multidisciplinary treatment program between 2015 and 2022. All patients were offered Medications to treat Opioid Use Disorder (MOUD) primarily with buprenorphine. Patients had at least 2 prenatal visits and negative urine drug tests (UDT) prior to weaning. The experimental group underwent a buprenorphine wean greater than 20% of their baseline dose. The control group was maintained on buprenorphine throughout the pregnancy. Relapse was defined as patient reported use or positive UDT during weekly assessments. Mass spectrophotometer was used for detection of drugs in samples. Fisher’s exact tests were used to compare outcomes in weaned and control groups. Results 334 of 456 (73%) patients were treated with buprenorphine during pregnancy, with 39 in the experimental group and 295 in the control group. The mean dose for buprenorphine was similar between the groups (wean: 10.6 mg ± 5.6 vs. control: 10.3 mg ± 4.6, p = 0.76) but was significantly lower at delivery (wean: 4.4 ± 4.6 mg vs. control: 13.0 ± 4.7, p < 0.0001). Mean gestational age at initiation of the buprenorphine wean was 22.7 weeks. 10 of 39 (26%) who weaned were able to completely discontinue buprenorphine prior to delivery. Demographic data was similar between the groups, including overdose history. Overdose history at time of enrollment had a higher trend in the non-weaning group. neonatal opioid withdrawal syndrome (NOWS) treatment was significantly lower in the wean group (23 vs. 47%, p = 0.006), as was highest Finnegan score (9.6 ± 4.5 vs. 12.3 ± 4.0, p = 0.0003). Birthweight percentile was significantly higher in the wean group (44.3 ± 29.9 vs. 34.8 ± 24.4, p = 0.03). Gestational age at delivery, mode of delivery, and complications (HTN, DM, preterm labor, or short cervix) at delivery did not significantly differ between the groups. Conclusion Despite counseling to stay on buprenorphine, there are patients who desire to wean. The NOWS rate in the weaned cohort was significantly lower than the controls with no observed increase in maternal or neonatal morbidity. There were no maternal overdoses or deaths during the pregnancy. Larger studies are needed to evaluate this approach.

Eat, Sleep, Console model for neonatal opioid withdrawal syndrome: a meta-analysis.

The rising incidence of drug abuse among pregnant women has rendered neonatal opioid withdrawal syndrome a significant global health concern. Databases including PubMed, Web of Science, the Cochrane Library, Embase, Elton B. Stephens. Company (EBSCO), China National Knowledge Infrastructure (CNKI), and Wanfang were searched for comparative studies of the Eat, Sleep, Console model vs. traditional assessment tools for neonatal opioid withdrawal syndrome. Two reviewers conducted literature searches, screened according to the inclusion criteria, extracted data, and independently verified accuracy. All meta-analyses were conducted using Review Manager Version 5.4. In total, 18 studies involving 4,639 neonates were included in the meta-analysis. The Eat, Sleep, Console model demonstrated superior outcomes in assessing neonatal opioid withdrawal syndrome, significantly reducing the need for pharmacological treatment [risk ratio = 0.44, 95% confidence interval (CI) = 0.34-0.56, P < 0.001], decreasing the length of hospital stay [standard mean difference (SMD) = -2.10, 95% CI = -3.43 to -0.78, P = 0.002], and shortening the duration of opioid treatment (SMD = -1.33, 95% CI = -2.22 to -0.45, P = 0.003) compared to the Finnegan Neonatal Abstinence Scoring System. The Eat, Sleep, Console model is more effective than the Finnegan Neonatal Abstinence Scoring System in improving the assessment and management of neonatal opioid withdrawal syndrome.

A REFLECTIVE ACCOUNT – NON-PHARMACOLOGICAL MANAGEMENT OF NEONATAL ABSTINENCE SYNDROME

This reflection will use Gibbs’ Reflective Cycle to undertake a critical account of my experience as a student midwife on a busy postnatal ward caring for a woman and her newborn baby who was being assessed for neonatal abstinence syndrome. My reflection focuses on the assessment of neonatal abstinence syndrome and how newborns can be supported through withdrawal with the use of nonpharmacological methods. The use of strength-based approaches by midwives to provide effective care and support of newborn babies, and the importance of interdisciplinary working when caring for vulnerable women and families is also highlighted.

565 Association between neonatal abstinence syndrome and access to obstetric delivery facilities

565 Association between neonatal abstinence syndrome and access to obstetric delivery facilities

Inpatient Growth in Infants Requiring Pharmacologic Treatment for Neonatal Opioid Withdrawal Syndrome.

Aim: To assess inpatient growth parameter trajectories and to identify the type of opioid exposure and treatment characteristics influencing growth parameters of infants admitted to the newborn intensive care unit (NICU) for pharmacological treatment of neonatal opioid withdrawal syndrome (NOWS). Methods: Charts of term infants with NOWS admitted to NICU from 2012 to 2019, who received pharmacologic treatment, were reviewed. Intake (volume: mL/kg/day; calorie: kcal/kg/day) and growth parameter trajectories (weight, head circumference, and length) were analyzed based on the type of prenatal opioid exposure (short-acting opioids (SAOs), long-acting opioids (LAOs), and polysubstance), pharmacologic treatment, and sex. Growth measurement patterns over time were compared between groups using longitudinal mixed-effects models. Results: One hundred nineteen infants were included in the study with median birth weight Z-score of -0.19 at birth and decreased to a median of -0.72 at discharge. Exposure to SAO was associated with an increase in Z-scores nearing discharge across all growth parameters (Z-score for weight p = 0.03). Polysubstance exposure was associated with a decrease in Z-scores for length and head circumference throughout hospitalization. Infants with adjunct clonidine treatment had an increase in Z-score for weight trends. Male infants had a decrease in Z-scores for weight (male -0.96, female -0.59, interaction p = 0.06) and length (male -1.17, female -0.57, interaction p = 0.003) at Day 28. Despite the difference in growth trajectories, intake in terms of amount (mL/kg/day) and calorie intake (kcal/kg/day) was similar based on prenatal exposure, treatment, and sex. Conclusion: Infants with NOWS requiring pharmacologic treatment have a decrease in Z-scores for weight, length, and head circumference at birth and at hospital discharge. Infants with prenatal polysubstance exposure were at particular risk for poorer inpatient growth relative to infants exposed to SAO and LAO, indicated by lower Z-scores for length and occipital frontal circumference (OFC).

Buprenorphine Induction Using Microdosing for the Management of Opioid Use Disorder in Pregnancy

Abstract Background Conventional buprenorphine inductions require patients to abstain from full agonist opioids until they experience mild-to-moderate opioid withdrawal. We described a successful buprenorphine induction case in a pregnant patient using microdosing, which avoided withdrawal symptoms. Case Presentation The patient is a 29-year-old G2P1001 at 18 2/7 weeks of gestation, who desired a switch from methadone to buprenorphine to minimize neonatal opioid withdrawal syndrome (NOWS), which complicated her last pregnancy. She was given increasing microdoses of buprenorphine over a 7-day period, while continuing her daily dose of methadone. She discontinued the methadone on day 8. She did well during the week of buprenorphine microdosing, with no complaints of withdrawal or cravings. She was engaged in her prenatal care. Her dose of buprenorphine was increased to 8 mg twice daily in the third trimester for some withdrawal symptoms in the evening consisting of new onset nausea and vomiting.The patient underwent an elective 39-week induction of labor and had a spontaneous vaginal delivery of an appropriately grown male fetus. Only nonpharmacologic interventions were used. Conclusion Buprenorphine microdosing was well tolerated in this patient and avoided withdrawal symptoms in the mothers, and NOWS. A microdosing study in pregnancy is indicated

Current Research on Opioid Use Disorder (OUD) in Pregnancy with Emphasis on Medication Assisted Treatment (MAT)

Substance use disorder in pregnancy is a major obstetric issue, with significant maternal and fetal morbidity and mortality. The incidence of opioid use disorder has risen substantially in the United States, with overdose now a leading contributor to pregnancy related deaths. Medication assisted treatment for opioid use disorder can improve pregnancy outcomes, with Methadone, and more recently Buprenorphine becoming the mainstays of treatment. There is decreased incidence of neonatal abstinence syndrome with maternal Buprenorphine use, as well as possible decreased association with neonatal low birth weight. Despite the known benefits of treatment, there remain barriers to medication assisted treatment, including clinician stigma and lack of familiarity with pharmacology. The American College of Obstetrics and Gynecology maintains a firm stance on the benefits of treatment during pregnancy, in order to avoid the known adverse outcomes associated with substance abuse during pregnancy. Pregnancy is period when most women routinely seek healthcare, and thus allows the opportunity for obstetrical providers to optimize maternal well-being. The goals during pregnancy remain the same as those outside of pregnancy: For medication treatment to assist in the prevention of a chronic and remitting condition that can result in overdose, and provide a gateway towards long-term recovery.

Avaliação do Eletroencefalograma de Amplitude Integrada em recém-nascidos maiores que 35 semanas de idade gestacional expostos ao crack e/ou cocaína no pré-natal

OBJECTIVE: To evaluate the findings of video aEEG/EEG brain monitoring in newborns of mothers who used cocaine and/or crack during pregnancy and to describe the epidemiological profile of these mothers and infants. METHODS: Descriptive prospective study carried out from August 2019 to February 2020. We included newborns with a gestational age = 35 weeks and a history of maternal use of crack or cocaine during pregnancy. Newborns underwent video aEEG/EEG monitoring for 24 hours in the first 48 hours of life. The assessment of neonatal abstinence syndrome was performed using the Finnegan Score. Demographic and clinical data were analyzed. The Intergrowth-21 curve was used to classify the anthropometric measurements described. Capurro and New-Ballard methods were standardized for determining gestational age in newborns. RESULTS: 12 newborns met the criteria; all scored from 0 to 7 according to the Finnigan score in the first 6 hours of life. In the 30th hour of life, 10 (91%) scored between 0 and 7 and 1 neonate between 8 and 11, considered altered with the need for treatment. At 72 hours of life, the 12 newborns evaluated had scores between 0 and 7. The background electroencephalographic activity pattern in the first 48 hours of life was continuous, with the presence of a sleep-wake cycle in all cases. CONCLUSIONS: Newborns of drug-using mothers may have an early maturation pattern on electroencephalographic assessment. More studies are needed to assess this relationship better.

Modulation of intestinal TLR4 expression in infants with neonatal opioid withdrawal syndrome

ObjectiveNeonatal Opioid Withdrawal Syndrome (NOWS) has been associated with the development of necrotizing enterocolitis (NEC) in term and late-preterm neonates. In this study, we used stool gene expression to determine if an increase in baseline inflammation in the intestine of infants with NOWS is associated with these findings.Study designStool samples were prospectively collected between days 1–3 and days 4–9 after delivery for opioid-exposed ( n = 9) or non-exposed neonates (n = 8). Stool gene expression for TLR4 and HMGB1 was determined via real-time PCR.ResultsTLR4 expression was higher in the stool of the non-exposed group in both time periods, between days 1–3 (P < 0.0001) and days 4–9 (P < 0.05) after delivery. No significant difference in HMGB1 expression was found at either time point (P > 0.05).ConclusionThese findings point to an important interplay between opioid exposure and/or NOWS and the inflammatory milieu of the neonatal intestine.

Methadone and neonatal abstinence syndrome (NAS): what we think we know, but do not.

Since the first use of methadone to treat OUD in pregnancy in the 1970s, there has been a long, controversial, and confusing history of studies, regulatory actions, and practice changes that have clouded an accurate perception of methadone's use in pregnancy. This review will trace this history with a focus on the effect of methadone exposure during pregnancy on neonatal abstinence syndrome (NAS). A new laboratory measure, the serum methadone/metabolite ratio (MMR), has provided a tool for documenting the profoundly dynamic nature of perinatal metabolism. Continuous induction of metabolic enzymes during pregnancy requires dose adjustments and dose frequency changes. The concept of "fetal methadone dosing" emphasizes that relative stability of methadone levels in the fetus is an important consideration for methadone dosing in pregnancy. Finally, the effects of the societal "war on drugs" on pediatric management of neonatal withdrawal risks will be discussed, as well as the importance of comprehensive services for mother and child including the "rooming-in" approach of neonatal care which has considerably replaced the older NICU care model of maternal/infant separation.

Implementation of a Nurse-Driven Eat-Sleep-Console (ESC) Treatment Pathway at a Community Hospital for Treatment of Neonatal Opioid Withdrawal Syndrome in an Effort to Improve Short-term Outcomes.

The Chandler Regional Medical Center (CRMC) neonatal intensive care unit (NICU) began a phased implementation of Eat-Sleep-Console (ESC) for the management of those at risk for neonatal opioid withdrawal syndrome (NOWS). The purpose of this initiative is to track short-term outcomes as well as the program's effect on nursing workflow and job performance rating/satisfaction. A retrospective review of the ESC implementation process at CRMC from the years 2018-2020. The study consisted of 3 epochs: (1) traditional pharmacologic management; (2) parent-led ESC management; and (3) parent/nurse-led ESC management. Length of stay (LOS), treatment pathway assignment, and proportion of infants treated with pharmacologic agents were compared between epochs. In addition, a survey of NICU nursing staff was distributed to measure nurses' perceptions and attitudes towards the ESC program and the management of infants with NOWS. The proportion of infants treated via ESC increased (0%, 53%, and 100%), with an associated decrease in LOS (18.4, 10.5, and 9.3 days) during each epoch of the study period. Thirty-seven nurses completed the survey, with 94% of nurses reporting being comfortable caring for ESC patients and 89% feeling supported in their ESC nursing assignments, with only 11% stating that caring for ESC patients significantly alters their other nursing care processes. Implementation of an ESC treatment program for infants with NOWS significantly decreased LOS and the proportion of infants treated pharmacologically. This phased implementation process was not associated with self-reported negative nursing perceptions of the program and its treatment goals/outcomes.

Implicit Racial Bias in Evaluation of Neonatal Opioid Withdrawal Syndrome.

To assess implicit bias by administrating the Modified Finnegan Score (MFS) for quantifying neonatal opioid withdrawal and to evaluate risk of decreased opioid treatment of Black versus White infants. Study participants were nurses recruited from a large tertiary care center who received three clinical vignettes portraying withdrawing infants and were randomized to receive an accompanying photo of either a Black or White infant. MFS results were compared for identical vignettes based on race of infant photo. Out of 275 nurses, 70 completed the survey. In vignette 2, nurses aged ≤35 years scored Black infants lower than White infants (MFS=8.3 ± 2 vs. 9.5 ± 1.2, p=0.012). Nurses with <5 years of experience and ≤10 years of experience also scored Black infants lower for the same vignette (8.2 ± 2.3 vs. 9.6 ± 1.2, p=0.032 and 8.3 ± 2 vs. 9.5 ± 1.2, p=0.0083). Implicit bias may contribute to the difference in opioid treatment.

Opioid, methamphetamine, and polysubstance use: perinatal outcomes for the mother and infant.

The escalation in opioid pain relief (OPR) medications, heroin and fentanyl, has led to an increased use during pregnancy and a public health crisis. Methamphetamine use in women of childbearing age has now eclipsed the use of cocaine and other stimulants globally. Recent reports have shown increases in methamphetamine are selective to opioid use, particularly in rural regions in the US. This report compares the extent of our knowledge of the perinatal outcomes of OPRs, heroin, fentanyl, two long-acting substances used in the treatment of opioid use disorders (buprenorphine and methadone), and methamphetamine. The methodological limitations of the current research are examined, and two important initiatives that will address these limitations are reviewed. Current knowledge of the perinatal effects of short-acting opioids, OPRs, heroin, and fentanyl, is scarce. Most of what we know about the perinatal effects of opioids comes from research on the long-acting opioid agonist drugs used in the treatment of OUDs, methadone and buprenorphine. Both have better perinatal outcomes for the mother and newborn than heroin, but the uptake of these opioid substitution programs is poor (<50%). Current research on perinatal outcomes of methamphetamine is limited to retrospective epidemiological studies, chart reviews, one study from a treatment center in Hawaii, and the US and NZ cross-cultural infant Development, Environment And Lifestyle IDEAL studies. Characteristics of pregnant individuals in both opioid and MA studies were associated with poor maternal health, higher rates of mental illness, trauma, and poverty. Infant outcomes that differed between opioid and MA exposure included variations in neurobehavior at birth which could complicate the diagnosis and treatment of neonatal opioid withdrawal (NOWs). Given the complexity of OUDs in pregnant individuals and the increasing co-use of these opioids with MA, large studies are needed. These studies need to address the many confounders to perinatal outcomes and employ neurodevelopmental markers at birth that can help predict long-term neurodevelopmental outcomes. Two US initiatives that can provide critical research and treatment answers to this public health crisis are the US Environmental influences on Child Health Outcomes (ECHO) program and the Medication for Opioid Use Disorder During Pregnancy Network (MAT-LINK).

Salivary therapeutic monitoring of methadone toxicity in neonates after transplacental transfer from parturient mothers treated with oral methadone guided by PBPK modeling

Opioid use disorders (OUD) during pregnancy are related to neonatal opioid withdrawal syndrome (NOWS). R,S-methadone used to treat OUD and NOWS can penetrate the placenta. High neonatal brain extracellular fluid (bECF) levels of R,S-methadone can induce respiratory depression in newborns. The purpose of this work was to estimate neonatal bECF and saliva levels to establish the neonatal R,S-methadone salivary thresholds for respiratory depression after maternal oral dosing despite the sparse data in pregnancy and newborn populations. An adult physiologically-based pharmacokinetic (PBPK) model for R,S-methadone after intravenous and oral administration was constructed, vetted, and scaled to newborn and pregnancy populations. The pregnancy model predicted the R-methadone and S-methadone doses transplacentally transferred to newborns. Then, the newborn PBPK model was used to estimate newborn exposure after such doses. After maternal oral dosing of R,S-methadone (43.8 mg/day), the neonatal plasma levels were below the respiratory depression threshold. Further, the bECF levels were above the analgesia threshold for more than 96 h. The salivary thresholds for the analgesic effects of R-methadone, S-methadone, and R,S-methadone were estimated herein at 1.7, 43, and 16 ng/mL, respectively. Moreover, the salivary thresholds for the respiratory depression of R-methadone and R,S-methadone were estimated at 58 and 173 ng/mL, respectively. Using neonatal salivary monitoring of methadone can be useful in ensuring newborns' safety during maternal OUD treatment.