Ondansetron Pharmacokinetics in Pregnant Women and Neonates: Towards a New Treatment for Neonatal Abstinence Syndrome

Background Untreated opioid dependence in pregnant women is associated with adverse birth outcomes. Buprenorphine and methadone are options for opioid agonist medication-assisted treatment during pregnancy. Objective The aim of this study was to describe adverse birth outcomes observed with buprenorphine or methadone treatment compared to the general population in Sweden. Methods Pregnant women and their corresponding births during 2005–2011 were identified in the Swedish Medical Birth Register. Data on stillbirth, neonatal/infant death, mode of delivery, gestational age at birth, Apgar score, growth outcomes, neonatal abstinence syndrome, and congenital malformations were examined. Frequencies were compared using two-sided Fisher's exact tests. Unadjusted estimates of birth outcomes for women treated with buprenorphine or methadone were compared to the registered general population. Results A total of 746,257 pregnancies among 538,178 unique women resulted in 746,485 live births. Among the 194 women treated with buprenorphine ( N = 176) or methadone ( N = 52), no stillbirths or neonatal/infant deaths occurred. Neonatal abstinence syndrome developed in 23.3% and 38.5% of infants born to mothers treated with buprenorphine and methadone, respectively. The frequency of the selected adverse birth outcomes assessed in women treated with buprenorphine as compared to the general population was not significantly different. However, a significantly higher frequency of preterm birth and congenital malformations was observed in women treated with methadone as compared to the general population. Compared with the general population, methadone-treated women were significantly older than buprenorphine-treated women, and both treatment groups began prenatal care later, were more likely to smoke cigarettes, and did not cohabitate with the baby's father. Conclusions An increased frequency of the selected adverse birth outcomes was not observed with buprenorphine treatment during pregnancy. Twofold increased frequency of preterm birth [2.21 (1.11, 4,41)] and congenital malformations [2.05 (1.08, 3.87)] was observed in the methadone group, which may be partly explained by older average maternal age and differences in other measured and unmeasured confounders.

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Development and Implementation of a Mobile Tool for High-Risk Pregnant Women to Deliver Effective Caregiving for Neonatal Abstinence Syndrome: Protocol for a Mixed Methods Study (Preprint)

10.2196/preprints.27382 ◽

2021 ◽

Author(s):

Ekaterina Burduli ◽

Hendrée E Jones ◽

Olivia Brooks ◽

Celestina Barbosa-Leiker ◽

Ron Kim Johnson ◽

...

Keyword(s):

Mixed Methods ◽

High Risk ◽

Data Collection ◽

Pregnant Women ◽

The United States ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Semistructured Interviews ◽

Stage 1 ◽

Perinatal Women

BACKGROUND The United States continues to experience an alarming rise in opioid use that includes women who become pregnant and related neonatal abstinence syndrome (NAS) in newborns. Most newborns experiencing NAS require nonpharmacological care, which entails, most importantly, maternal involvement with the newborn. To facilitate positive maternal-newborn interactions, mothers need to learn effective caregiving NAS strategies when they are pregnant; however, an enormous gap exists in the early education of mothers on the symptoms and progression of NAS, partly because no education, training, or other interventions exist to prepare future mothers for the challenges of caring for their newborns at risk for NAS. OBJECTIVE In this paper, we describe a mixed methods, multistage study to adapt an existing mobile NAS tool for high-risk pregnant women and assess its usability, acceptability, and feasibility in a small randomized controlled trial. METHODS Stage 1 will include 20 semistructured interviews with a panel of neonatology experts, NAS care providers, and mothers with experience caring for NAS-affected newborns to gather their recommendations on the management of NAS and explore their perspectives on the care of these newborns. The findings will guide the adaptation of existing mobile NAS tools for high-risk pregnant women. In stage 2, we will test the usability, acceptability, and feasibility of the adapted mobile tool via surveys with 10 pregnant women receiving opioid agonist therapy (OAT). Finally, in stage 3, we will randomize 30 high-risk pregnant women receiving OAT to either receive the adapted mobile NAS caregiving tool or usual care. We will compare these women on primary outcomes—maternal drug relapse and OAT continuation—and secondary outcomes—maternal-newborn bonding; length of newborn hospital stays; readmission rates; breastfeeding initiation and duration; and postpartum depression and anxiety at 4, 8, and 12 weeks postpartum. RESULTS This project was funded in July 2020 and approved by the institutional review board in April 2020. Data collection for stage 1 began in December 2020, and as of January 2021, we completed 18 semistructured interviews (10 with NAS providers and 8 with perinatal women receiving OAT). Common themes from all interviews will be analyzed in spring 2021 to inform the adaptation of the NAS caregiving tool. The results from stage 1 are expected to be published in summer 2021. Stage 2 data collection will commence in fall 2021. CONCLUSIONS The findings of this study have the potential to improve NAS care and maternal-newborn outcomes and lead to commercialized product development. If effective, our new tool will be well suited to tailoring for other high-risk perinatal women with substance use disorders. CLINICALTRIAL ClinicalTrials.gov NCT04783558; https://clinicaltrials.gov/ct2/show/NCT04783558 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/27382

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Opioid Use in Pregnant Women and the Increase in Neonatal Abstinence Syndrome

Journal of Addiction Medicine ◽

10.1097/adm.0000000000000122 ◽

2015 ◽

Vol 9 (3) ◽

pp. 222-225 ◽

Cited By ~ 8

Author(s):

Kay Roussos-Ross ◽

Gary Reisfield ◽

Iain Elliot ◽

Susan Dalton ◽

Mark Gold

Keyword(s):

Pregnant Women ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Opioid Use

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Neonatal Abstinence Syndrome: Strategies for Care of the Drug-Exposed Infant

Neonatal Network The Journal of Neonatal Nursing ◽

10.1891/0730-0832.22.4.15 ◽

2003 ◽

Vol 22 (4) ◽

pp. 15-24 ◽

Cited By ~ 15

Author(s):

Carol Greene ◽

Michael Goodman

Keyword(s):

Pregnant Women ◽

Clinical Condition ◽

State Of The Art ◽

Clinical Care ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Psychoactive Substances ◽

Polydrug Use ◽

Clinical Issue ◽

Exposed Infant

Neonatal abstinence syndrome (NAS), a clinical condition that has been recognized for over 30 years, remains a significant clinical issue, although our knowledge of abstinence, its treatment, and outcome continues to grow. The condition is now complicated by polydrug use (which is becoming more prevalent) as well as concomitant use of tobacco, and psychoactive substances that are frequently prescribed to pregnant women. This article reviews the neonatal effects of a variety of substances, discusses the state of the art for clinical care of drug-exposed infants, including NAS patients, and updates the reader on areas of current research.

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A retrospective, observational study on medication for opioid use disorder during pregnancy and risk for neonatal abstinence syndrome

Family Practice ◽

10.1093/fampra/cmab121 ◽

2021 ◽

Author(s):

Ayesha Sujan ◽

Emma Cleary ◽

Edie Douglas ◽

Rubin Aujla ◽

Lisa Boyars ◽

...

Keyword(s):

Pregnant Women ◽

Clinical Sample ◽

Opioid Use Disorder ◽

Additional Benefit ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Opioid Use ◽

Relative Safety ◽

Increased Risk ◽

Exposure During Pregnancy

Abstract Objectives The prevalence of opioid use disorder (OUD) among pregnant women is increasing. Research consistently demonstrates the efficacy of medications for OUD (MOUD); however, researchers have called for additional studies evaluating the safety of MOUD during pregnancy, particularly the relative safety of two commonly used MOUD medications—methadone and buprenorphine. This study aimed to evaluate the consequences of MOUD exposure during pregnancy on risk for neonatal abstinence syndrome (NAS). Methods In a clinical sample of infants born to women with OUD, we evaluated the risk of NAS among those exposed to (i) methadone and (ii) buprenorphine compared with those unexposed to MOUD, as well as the risk of NAS among those exposed to (i) methadone compared with those exposed to (ii) buprenorphine. Results Compared with buprenorphine-exposed infants (n = 37), methadone-exposed infants (n = 27) were at increased risk for NAS (odds ratio [OR] = 4.67, 95% confidence interval [CI]: 1.03, 21.17). Compared with unexposed infants (n = 43), buprenorphine-exposed infants were at decreased risk for NAS (OR = 0.45, 95% CI: 0.14, 1.39) and methadone-exposed infants were at increased risk for NAS (OR = 2.64, 95% CI: 0.79, 8.76), though these associations were not statistically significant. Conclusions Our study suggests that when methadone and buprenorphine are equally appropriate options for the treatment of OUD in pregnant women, buprenorphine may add the additional benefit of reduced risk of newborn NAS.

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566: Co-prescription of opioids and psychotropics among commercially insured US pregnant women and neonatal abstinence syndrome

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2018.11.588 ◽

2019 ◽

Vol 220 (1) ◽

pp. S377

Author(s):

Kartik K. Venkatesh ◽

Virginia Pate ◽

Kim A. Boggess ◽

Michele Funk ◽

Marcela Smid

Keyword(s):

Pregnant Women ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome

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Neonatal Abstinence Syndrome and Ethical Approaches to the Identification of Pregnant Women Who Use Drugs

Obstetrics and Gynecology ◽

10.1097/aog.0000000000001781 ◽

2017 ◽

Vol 129 (1) ◽

pp. 164-167 ◽

Cited By ~ 18

Author(s):

Mishka Terplan ◽

Howard Minkoff

Keyword(s):

Pregnant Women ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Ethical Approaches ◽

Women Who Use Drugs

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Opioid Utilization by Pregnant Women with Sickle Cell Disease and the Risk of Neonatal Abstinence Syndrome

Journal of the National Medical Association ◽

10.1016/j.jnma.2017.04.002 ◽

2018 ◽

Vol 110 (2) ◽

pp. 163-168 ◽

Cited By ~ 3

Author(s):

Aisha Nnoli ◽

Neil S. Seligman ◽

Kevin Dysart ◽

Jason K. Baxter ◽

Samir K. Ballas

Keyword(s):

Sickle Cell Disease ◽

Pregnant Women ◽

Sickle Cell ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Cell Disease

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Association of Maternal Buprenorphine or Methadone Dose with Fetal Growth Indices and Neonatal Abstinence Syndrome

American Journal of Perinatology ◽

10.1055/s-0039-1694729 ◽

2019 ◽

Vol 38 (01) ◽

pp. 028-036

Author(s):

Carol C. Coulson ◽

Erin Lorencz ◽

Katelyn Rittenhouse ◽

Melinda Ramage ◽

Kathleen Lorenz ◽

...

Keyword(s):

Pregnant Women ◽

Fetal Growth ◽

Neonatal Outcomes ◽

Neonatal Abstinence Syndrome ◽

High Dose ◽

Abstinence Syndrome ◽

Opioid Use ◽

Moderate Dose ◽

Medication Assisted Treatment ◽

Opioid Use Disorders

Abstract Objective Our objective was to compare fetal growth and incidence of neonatal abstinence syndrome requiring treatment across pregnant women with opioid use disorders on two types and two dose categories of medication-assisted treatment. Study Design A retrospective cohort study was conducted in a comprehensive, perinatal program in western North Carolina comparing growth percentiles on third-trimester ultrasound and at birth, and diagnosis of neonatal abstinence syndrome requiring treatment. Singletons were exposed in utero to low- to moderate-dose buprenorphine (≤16 mg/day; n = 70), high-dose buprenorphine (≥17 mg/day; n = 36), low- to moderate-dose methadone (≤89 mg/day; n = 41), or high-dose methadone (≥90 mg/day; n = 74). Multivariate analysis of variance with posthoc Bonferroni comparisons (p ≤ 0.01) and multinomial logistic regressions (adjusted odds ratio, 99% confidence interval) were conducted. Results Differences in neonatal outcomes reached statistical significance for larger head circumference for buprenorphine doses (p = 0.01) and for longer length (p < 0.01) and lower odds of neonatal abstinence syndrome requiring treatment (p < 0.01) with low- to moderate-dose buprenorphine versus high-dose methadone. Conclusion Among pregnant women using medication-assisted treatment for opioid use disorders, low- to moderate-dose buprenorphine (≤16 mg/day) was associated with the most favorable neonatal outcomes. However, more rigorous control of confounders with a larger sample is necessary to determine if low- to moderate-dose buprenorphine is the better treatment choice.

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2421 Development and validation of a translational rat model of neonatal abstinence syndrome

Journal of Clinical and Translational Science ◽

10.1017/cts.2018.63 ◽

2018 ◽

Vol 2 (S1) ◽

pp. 9-9

Author(s):

Lisa Brents ◽

Bryce A. Griffin ◽

Caitlin Caperton ◽

Lauren Russell ◽

Christian Cabanlong ◽

...

Keyword(s):

Pregnant Women ◽

Rat Model ◽

Maternal Blood ◽

Positive Control ◽

Neonatal Abstinence Syndrome ◽

Abstinence Syndrome ◽

Blood Concentrations ◽

Pregnant Rat ◽

Withdrawal Signs ◽

Buprenorphine Treatment

OBJECTIVES/SPECIFIC AIMS: Rodent models can be used to study neonatal abstinence syndrome (NAS), but the applicability of findings from the models to NAS in humans is not well understood. The objective of this study was to develop a rat model of norbuprenorphine-induced NAS and validate its translational value by comparing blood concentrations in the norbuprenorphine-treated pregnant rat to those previously reported in pregnant women undergoing buprenorphine treatment. METHODS/STUDY POPULATION: Pregnant Long-Evans rats were implanted with 14-day osmotic minipumps containing vehicle, morphine (positive control), or norbuprenorphine (0.3–3 mg/kg/d) on gestation day 9. Within 12 hours of delivery, pups were tested for spontaneous or precipitated opioid withdrawal by injecting them with saline (10 mL/kg, i.p.) or naltrexone (1 or 10 mg/kg, i.p), respectively, and observing them for well-validated neonatal withdrawal signs. Blood was sampled via indwelling jugular catheters from a subset of norbuprenorphine-treated dams on gestation day 8, 10, 13, 17, and 20. Norbuprenorphine concentrations in whole blood samples were quantified using LC/MS/MS. RESULTS/ANTICIPATED RESULTS: Blood concentrations of norbuprenorphine in rats exposed to 1–3 mg/kg/d of norbuprenorphine were similar to levels previously reported in pregnant women undergoing buprenorphine treatment. Pups born to dams treated with these doses exhibited robust withdrawal signs. Blood concentrations of norbuprenorphine decreased across gestation, which is similar to previous reports in humans. DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that dosing dams with 1–3 mg/kg/day norbuprenorphine produces maternal blood concentrations and withdrawal severity similar to those previously reported in humans. This provides evidence that, at these doses, this model is useful for testing hypotheses about norbuprenorphine that are applicable to NAS in humans.

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