Severe Neonatal Abstinence Syndrome Research Articles

Gestational buprenorphine-naloxone exposure and fetal neurobehavior

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

Do small for gestational age infants have less severe neonatal abstinence syndrome?

Small for gestational age (SGA) infants are likely to have decreased placental transfer of opioids and other substances and lower amounts of fat deposition, hence less severe neonatal abstinence syndrome (NAS). The goal of this study is to correlate SGA status and severity of NAS in infants admitted to the neonatal intensive care unit (NICU). This is a retrospective analysis of term and late-preterm infants (≥35 weeks gestation) exposed to in-utero substances, born between September 2006 and May 2021, and admitted to an inner-city NICU for medical therapy for NAS. Indicators of the severity of NAS (duration of medical treatment, duration of hospitalization, use of phenobarbital, and use of clonidine) were compared between infants characterized as SGA (birth weight <10th percentile for gestational age) to those not categorized as SGA (non-SGA). A total of 992 infants met the study criteria; 205 (20.7%) in the SGA group and 787 (79.3%) in the non-SGA group. The median duration of medical treatment was significantly lower in infants in the SGA group (22 days vs. 26 days, p = 0.04) and they were less likely to be treated with phenobarbital (19% vs. 26.8%, p = 0.02). SGA infants displayed less severe NAS symptoms as indicated by shorter a duration of medical treatment and decreased need for phenobarbital. Our findings may impact decisions around identifying the optimum treatment protocols catered to SGA infants with NAS.

Neonatal Outcomes after Combined Opioid and Nicotine Exposure in Utero: A Scoping Review.

Background: The majority of women who are pregnant with opioid use disorder (OUD) also smoke tobacco but are rarely offered tobacco cessation counseling. While the effects of exposure to opioids and nicotine in utero are well-understood separately, understanding the impact of the combined exposure to these substances on neonatal outcomes is lacking. Methods: A scoping review was conducted using PubMed and Scopus databases for studies addressing the combined exposure to opioids and nicotine during pregnancy published between 1 January 1980 and 9 July 2019. A total of 29 papers met the eligibility criteria for inclusion, with nine being identified as clinical trials (three from the MOTHER study) and two as secondary data analysis of clinical trial data. Results: Neonatal outcomes for infants who had a combined exposure to opioids and nicotine in utero indicated a reduction in birth weight and birth length. Findings in infants exposed to both nicotine and opioids were mixed with regard to the duration of neonatal abstinence syndrome (NAS), the likelihood of treatment for NAS, doses of medicine used to treat NAS, and NAS scores when compared with infants who had opioid exposure without nicotine. Conclusions: The combined exposure to nicotine and opioids during pregnancy may lead to a reduction in neonatal birth weight and birth length and more severe NAS signs, compared with opioid use alone, but more research is necessary to identify the minimum dosage and length of nicotine exposure to accurately predict these outcomes.

Nail disease in neonatal abstinence syndrome.

Neonatal abstinence syndrome (NAS) incidence continues to rise in the United States due to increasing opioid use disorder in pregnancy. While cutaneous excoriations have been noted in NAS, there is a paucity of literature regarding abnormal nail findings in NAS. A retrospective, observational case series was conducted of twelve patients with NAS and abnormal nail findings who were admitted to the neonatal intensive care unit between January 1, 2018, and May 1, 2020. Twelve neonates (10 male, 2 female, mean gestational age at birth 38.1weeks) with NAS diagnosis and abnormal nail findings were identified between January 1, 2018, and May 1, 2020. NAS was diagnosed by elevated Modified Finnegan Neonatal Abstinence Syndrome Tool (M-FNAST) scores. All patients required pharmacologic treatment for NAS with seven (58.3%) requiring phenobarbital in addition to first-line morphine. Common nail findings included periungual erythema, yellow crusting, desquamation of the proximal and/or distal lateral nail folds and sheared distal nail edges. Two patients (16.7%) required antibiotic treatment for paronychia. Peak M-FNAST scores were positively correlated with number of abnormal nail findings (r=.58, P=.047). Twelve neonates with severe NAS demonstrated similar nail abnormalities, likely secondary to NAS agitation and motor hyperactivity. Nail exams, therefore, are important in the setting of suspected or confirmed NAS to limit continued nail trauma and infection. Our findings also introduce an association between NAS severity and abnormal nail findings, which will require larger studies for further confirmation.

Body composition during the first 4 months in infants affected by neonatal abstinence syndrome: a pilot study.

Newborns with neonatal abstinence syndrome (NAS) display symptoms related to neurologic excitability and autonomic dysfunction that result in increased metabolic demands. These infants also exhibit feeding difficulties and/or hyperphagia. Because the effects of these symptoms and behaviors on growth are unknown, we sought to measure serial body composition measurements over the first 4 months in infants with NAS requiring pharmacologic treatment using air displacement plethysmography. Fourteen infants of singleton birth with appropriate-for-gestational-age (AGA) weight and a gestational age of ≥35 weeks and <42 weeks were evaluated. In mixed-effects models, per week, infants increased in mean fat percent by 1.1% (95% confidence interval [CI]: 0.85-1.43), fat mass by 90 g (CI: 70-100), and fat-free mass by 140 g (CI: 130-150). The subgroup of infants (N = 5) requiring multidrug therapy for symptom control had lower mean fat percent (-1.2%, CI: -5.2-2.1), fat mass (-60 g, CI: -25-13), and fat-free mass (-270 g, CI: -610-80) across time compared to infants requiring monotherapy. We are the first to report how body composition measures change over time in a small group of patients with NAS. Infants with NAS were smaller and leaner in the first several weeks compared to previously reported body composition measurements in term infants, but grew similarly to their healthy counterparts by 16 weeks. Infants with more severe NAS may be at risk for abnormalities in longer term growth.

Pharmacometric Evaluation of Umbilical Cord Blood Concentration-Based Early Initiation of Treatment in Methadone-Exposed Preterm Neonates.

In methadone-exposed preterm neonates, early identification of those at risk of severe neonatal abstinence syndrome (NAS) and use of a methadone dosing regimen that can provide effective and safe drug exposure are two important aspects of optimal care. To this end, we reviewed 17 methadone dosing recommendations in the international guidelines and literature and explored their variability in key dosing strategies. We selected three of the reviewed dosing regimens for their pharmacokinetics (PK) characteristics and their exposure–response relationship in three gestational age groups of preterm neonates (28, 32 and 36 gestational age weeks) at risk for development of severe NAS (defined as an umbilical cord methadone concentration of ≤60 ng/mL, following fetal exposure). We applied early (12 h after birth) vs. typical (36 h after birth) initiation of treatment. We observed that use of universally recommended dosing regimens in preterm neonates can result in under- or over-exposure. Use of a PK-guided dosing regimen resulted in effective target exposures within 24 h after birth with early initiation of treatment (12 h after birth). Future prospective studies should explore the incorporation of umbilical cord methadone concentrations for early identification of preterm neonates at risk of developing severe NAS and investigate the use of a PK-guided methadone dosing regimen, so that treatment failure, prolonged length of stay and opioid over-exposure can be avoided.

Is Maternal Methadone Dose Associated with the Severity of Neonatal Abstinence Syndrome?

The aim of the study is to assess the correlation between maternal methadone dose and severity of neonatal abstinence syndrome (NAS) in infants that required pharmacological treatment for NAS. This is a retrospective analysis of 574 infants ≥35 weeks' gestation exposed to methadone in utero, born between August 2006 and May 2018, and who required pharmacological therapy for NAS. Indicators of NAS severity (duration of morphine treatment, maximum morphine dose, use of phenobarbital, and length of hospitalization) were compared between infants exposed to high (≥200 mg), intermediate (100-199 mg), and low doses (<100 mg) of methadone. Logistic and linear regression models were used to adjust for the covariates. Median (interquartile range) duration of medical treatment with morphine was higher in infants exposed to higher doses of methadone (low dose 23 [14-37] days, intermediate dose 31 [18-45] days, and high dose 35 [20-48] days, p < 0.001). Higher methadone doses were also predictive of longer duration of hospitalization, higher maximum morphine dose, and increased likelihood of treatment with phenobarbital. The association between maternal methadone dose and the severity of NAS persisted in multivariable regression models. Infants exposed to higher methadone doses displayed more severe NAS, as indicated by longer durations of treatment, higher maximum morphine dose, longer duration of hospitalization, and increased likelihood of phenobarbital use. · Methadone maintenance therapy is used during pregnancy to control maternal withdrawal symptoms.. · Relationship between maternal methadone dose and severity of NAS is not adequately investigated.. · Increased doses of methadone during pregnancy correlate with increased severity of NAS..

Do Maternal Pharmacogenetics Impact the Neonatal Abstinence Syndrome Following In Utero Exposure to Antidepressant Medications?

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly used medications for mood and anxiety disorders in women. Many women need to continue or initiate these medications during pregnancy, but there is concern about potential withdrawal effects in the newborn, referred to as neonatal abstinence syndrome (NAS). The reason why some infants remain asymptomatic while others are affected has not been elucidated. The objective of this study was to examine whether genetic differences in maternal drug metabolism influence the incidence of NAS. Women who took Selective serotonin reuptake inhibitors s/SNRIs during pregnancy were recruited from obstetrical clinics. DNA was extracted from saliva samples for genetic analyses of cytochrome P450 (CYP) enzyme polymorphisms. Delivery and NAS data were collected from electronic medical records. Ninety-five women participated. The overall NAS rate was 16.2%. Mild NAS was seen in 13.8% of neonates and severe NAS, in 2%. One-quarter (25%) of the neonates with mild withdrawal symptoms were born to mothers with polymorphisms associated with slower metabolism of their particular antidepressant, but this association was not statistically significant. Importantly, the overall rate of NAS in our study was lower than previously reported. Maternal CYP polymorphisms did not affect the rate of NAS in neonates exposed to SSRIs/SNRIs in utero. This study lends added assurance to patients requiring SSRIs or SNRIs during pregnancy.

Patterns of Neonatal Co-Exposure to Gabapentin and Common Drugs of Abuse Observed in Umbilical Cord Tissue

Abstract Background Gabapentin is a structural analogue of gamma-aminobutyric acid approved by the U.S. Food and Drug Administration (FDA) for the treatment of postherpetic neuralgia and partial-onset seizures. Gabapentin is thought to have low abuse potential and is currently not scheduled as a controlled substance by the Drug Enforcement Administration (DEA). However, recent reports indicate that gabapentin is increasingly being abused by people with opioid use disorder in an attempt to potentiate the euphoric effects from opioids and other CNS depressants. (1) In 2018, Gabapentin was the sixth most commonly prescribed medication in the United States with 67 million prescriptions dispensed. (2) The frequency of non-prescribed gabapentin misuse reported at a reference laboratory increased by 40% between 2017 and 2018. (3) It is now recognized that combination of Gabapentin with opioids and other CNS depressants increases risk of respiratory depression. (4) Of particular concern are reports showing prolonged and more severe neonatal abstinence syndrome in infants with prenatal co-exposure to gabapentin and opioids. (5) Method This retrospective study evaluated the positivity rates of 13,609 umbilical cord tissues submitted for newborn drug testing at ARUP Laboratories. The umbilical cord drug detection assay is designed to detect 49 specific drugs and drug metabolites from commonly abused drug classes including opioids, stimulants, sedative-hypnotics and hallucinogens. Reverse phase liquid chromatography coupled with triple quadrupole mass spectrometry was used for semi-quantitative measurement of the drug analytes and metabolites. Results A positive result for at least one of the measured drugs or drug metabolites was found in 3,891 (29%) out of the 13,609 analyzed umbilical cord tissues. Norbuprenorphine had the highest positivity rate (874, 6%) followed by Amphetamine (764, 6 %) and Morphine (683, 5%). Gabapentin had a positivity rate of 2% with 302 positive results. Of the 302 positive Gabapentin samples, 216 (72%) also had a positive result for at least one other drug or drug metabolite. Co-positivity with Gabapentin was highest for Norbuprenorphine (105, 35%) followed by Amphetamine (41, 14%). The median Gabapentin concentration in umbilical cord tissues that were co-positive for Norbuprenorphine and Amphetamine is 3,762 ng/g (range = 13 - 40,997 ng/g) and 1,045 ng/g (range = 15 - 40,997 ng/g) respectively. Discussion This retrospective data analysis show that there is high neonatal co-exposure rate to Gabapentin and Buprenorphine / Norbuprenorphine. Buprenorphine is a partial mu-opioid receptor agonist and co-medication with Gabapentin might be used as a strategy to enhance the feeling of euphoria from Buprenorphine in pregnant women undergoing opioid substitution therapy.

Patterns of Neonatal Co-Exposure to Gabapentin and Commonly Abused Drugs Observed in Umbilical Cord Tissue.

Gabapentin was thought to have low abuse potential, but it is increasingly being abused by people with substance use disorder in an attempt to potentiate the euphoric effects from opioids and other CNS depressants. Additionally, infants co-exposed to gabapentin and opioids during pregnancy tend to exhibit prolonged and more severe neonatal abstinence syndrome. In this study, we describe positivity rates among commonly abused drugs and rates of co-medication with gabapentin in a large dataset of umbilical cord tissue specimens (n = 25,422) submitted for routine newborn drug testing at a national clinical reference laboratory (ARUP Laboratories, Salt Lake City, UT, USA). Detection of prenatal drug exposure in umbilical cord tissue specimens was accomplished using a semi-quantitative liquid chromatography-tandem mass spectrometry assay designed to detect 47 specific drugs and drug metabolites including opioids, stimulants, sedative-hypnotics and hallucinogens. A positive result for at least one of the measured drugs or drug metabolites was reported in 7,054 (28%) of the umbilical cord tissues analyzed. Gabapentin had a positivity rate of ~2% with 562 positive results. Of the 562 gabapentin-positive samples, 395 (70%) also had a positive result for at least one other drug or drug metabolite, with the highest co-positivity rate observed for norbuprenorphine (32%, n = 182) followed by amphetamine (15%, n = 84), buprenorphine (13%, n = 74), methamphetamine (12%, n = 68), morphine (11%, n = 64), fentanyl (10%, n = 54) and naloxone (10%, n = 54). Notably, the concentration of gabapentin in gabapentin-positive umbilical cord specimens was higher in buprenorphine-containing specimens as compared to specimens containing other opioids, stimulants or benzodiazepines. Identification of neonatal co-exposure to gabapentin and opioids, particularly buprenorphine, may guide clinicians in rapid initiation of monitoring and intervention for neonatal abstinence syndrome.

Neonatal Abstinence Syndrome Severity Index Predicts 18-Month Neurodevelopmental Outcome in Neonates Randomized to Morphine or Methadone

To develop an index to determine which opioid-exposed neonates have the most severe neonatal abstinence syndrome (NAS). Full-term neonates with NAS (n=116) from mothers maintained on methadone or buprenorphine were enrolled from 8 sites into a randomized clinical trial of morphine vs methadone. Ninety-nine (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale (NNNS). At 18months, 83 of 99 (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and 77 of 99 (77.7%) were evaluated with the Child Behavior Checklist (CBCL). Cluster analysis was used to define high (n=21) and low (n=77) NAS severity. Compared with infants in the low NAS severity cluster, infants in the high NAS severity cluster had a longer length of stay (P<.001), longer length of stay due to NAS (P<.001), longer duration of treatment due to NAS (P<.001), and higher total dose of the study drug (P<.001) and were more likely to have received phenobarbital (P<.001), to have been treated with morphine (P=.020), and to have an atypical NNNS profile (P=.005). The 2 groups did not differ in terms of maximum Finnegan score. At 18months, in unadjusted analyses, compared with the high-severity cluster, the low-severity cluster had higher scores on the Bayley-III Cognitive (P=.013), Language (P<.001), and Motor (P=.041) composites and less total behavior problems on the CBCL (P=.028). In adjusted analyses, the difference in the Bayley-III Language composite remained (P=.013). Presumptive measures of NAS severity can be aggregated to develop an index that predicts developmental outcomes at age 18months.

Maternal buprenorphine treatment during pregnancy and maternal physiology

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

The effect of maternal antidepressants on third trimester uteroplacental hemodynamics and the neonatal abstinence syndrome: a retrospective cohort study.

The objective of this study is to determine whether maternal antidepressant use during pregnancy influences uteroplacental hemodynamics, thereby affecting fetal growth and gestational age at delivery. The secondary aim was to determine the incidence of neonatal abstinence syndrome (NAS) among infants exposed to antidepressant medications. The charts of women who received obstetrical care and had a history of depression from January 2014 to December 2016 at Mount Sinai Hospital in Toronto, Canada, were reviewed. Exclusion criteria were substance abuse; narcotic or lithium use at the time of delivery.In total, 205 women met the inclusion criteria (92 took antidepressants; 113 women did not). There were no significant differences in umbilical artery pulsatility index (PI), gestational age at delivery, or birth weight when comparing women based on antidepressant use. A small proportion (18%) of neonates had mild withdrawal symptoms; one baby had a score (≥ 8) consistent with severe NAS. In women with a history of depression, there was no difference in uteroplacental hemodynamics as measured by third trimester Doppler ultrasonography when comparing women who took antidepressant medication versus those who did not. The large majority of babies who were exposed to antidepressants in utero did not show withdrawal symptoms. These results lend support for the relative safety of antidepressants during pregnancy.

Influence of dietary trans fat on the amphetamine preference in rats

To determine the effects of auditory stimulus on skin conductance (SC) in infants with severe neonatal abstinence syndrome (NAS) that required morphine treatment (MT) compared with NAS infants that did not require morphine treatment (non-MT). We prospectively enrolled opiate-exposed term infants without polysubstance exposure. Skin conductance responses to an auditory stimulus (ringing a bell for 3 s) near the time of discharge were obtained. Skin conductance was measured before, during, and after the stimulus. Non-parametric tests were used to determine between group and within phase differences. Infants were off MT at the time of SC measurement in response to an auditory stimulus. In a 2-group comparison of MT vs. non-MT infants, there was significantly higher SC responsivity to an auditory stimulus (p < 0.05) in the MT group as compared with the non-MT group near discharge. The mean +SE peak morphine dose was 0.85 + 0.20 mg/kg/day in the MT group. The mean Length of Stay (LOS) was 32 vs. 7 (p < 0.05) days respectively, for the MT vs. the non-MT group. Our preliminary data suggest that in infants with severe NAS symptoms, higher sympathetic arousal in response to an auditory stimulus persists at discharge, underscoring the need for ongoing evaluation and specialized care at home.

Severe Brief Resolved Unexplained Event in a Newborn Infant in Association with Maternal Sertralin Treatment during Pregnancy

Background: Selective serotonin reuptake inhibitors are a very common choice of antidepressive drug-therapy during pregnancy. In up to 30% of cases, they have been found to cause neonatal abstinence syndrome in newborn infants. Although often both time-limiting and self-limiting, severe symptoms of neonatal abstinence syndrome (NAS) can occur. Methods/Results: We report a term male infant suffering from a severe brief resolved unexplained event caused by his mother’s sertraline intake during pregnancy. Conclusions: Newborn infants exposed to selective serotonine reuptake inhibitors (SSRIs) during pregnancy should be evaluated very carefully concerning NAS and monitored for NAS symptoms for a minimum of 72–96 h, or until symptoms have fully recovered using standardized protocols. There is a risk of severe NAS symptoms which might occur, and this circumstance should be discussed with the parents and taken into account before administering the drug.

Epigenetic variation in OPRM1 gene in opioid-exposed mother-infant dyads.

Neonatal abstinence syndrome (NAS) due to in-utero opioid exposure has significant variability of severity. Preliminary studies have suggested that epigenetic variation within the μ-opioid receptor (OPRM1) gene impacts NAS. We aimed to determine if DNA methylation in OPRM1 within opioid-exposed mother-infant dyads is associated with differences in NAS severity in an independent cohort. Full-term opioid-exposed newborns and their mothers (N = 68 pairs) were studied. A DNA sample was obtained and then assessed for level of DNA methylation at 20 CpG sites within the OPRM1 promoter region by next-generation sequencing. Infants were monitored for NAS and treated with replacement opioids according to institutional protocol. The association between DNA methylation level at each CpG site with NAS outcome measures was evaluated using linear and logistic regression models. Higher methylation levels within the infants at the -18 (11.4% vs 4.4%, P = .0001), -14 (46.1% vs 24.0%, P = .002) and +23 (26.3% vs 12.9%, P = .008) CpG sites were associated with higher rates of infant pharmacologic treatment. Higher levels of methylation within the mothers at the -169 (R = 0.43, P = .008), -152 (R = 0.40, P = .002) and +84 (R = 0.44, P = .006) sites were associated point-wise with longer infant length of stay. Maternal associations remained significant point-wise for -169 (β = 0.07, P = .007) and on an experiment-wise level for +84 (β = -0.10, P = .003) using regression models. These results suggest an association of higher levels of OPRM1 methylation at specific CpG sites and increased NAS severity, replicating prior findings. These findings have important implications for personalized treatment regimens for infants at high risk for severe NAS.

Maternal Buprenorphine Treatment and Fetal Neurobehavioral Development

(Am J Obstet Gynecol. 2017;216(5):529.e1–529.e8) Opioid usage is increasing among pregnant mothers in the United States, which can lead to neonatal abstinence syndrome in their children. Previous studies have shown less severe neonatal abstinence syndrome in infants whose mothers were treated for opioid use with buprenorphine rather than methadone. This study looked at the effects of buprenorphine on fetal activity and development.

Maternal buprenorphine treatment and infant outcome

Background and objectivesMaternal buprenorphine maintenance predisposes the infant to exhibit neonatal abstinence syndrome (NAS), but there is insufficient published information regarding the nature of NAS and factors that contribute to its severity in buprenorphine-exposed infants. MethodsThe present study evaluated forty-one infants of buprenorphine-maintained women in comprehensive substance use disorder treatment who participated in an open-label study examining the effects of maternal buprenorphine maintenance on infant outcomes. Modifiers of the infant outcomes, including maternal treatment and substance use disorder parameters, were also evaluated. ResultsFifty-nine percent of offspring exhibited NAS that required pharmacologic management. Both maternal buprenorphine dose as well as prenatal polysubstance exposure to illicit substance use/licit substance misuse were independently associated with NAS expression. Polysubstance exposure was associated with more severe NAS expression after controlling for the effects of buprenorphine dose. Other exposures, including cigarette smoking and SRI use, were not related to outcomes. Maternal buprenorphine dose was positively associated with lower birth weight and length. ConclusionsPolysubstance exposure was the most potent predictor of NAS severity in this sample of buprenorphine-exposed neonates. This finding suggests the need for interventions that reduce maternal polysubstance use during medication assisted treatment for opioid use disorder, and highlights the necessity of a comprehensive approach, beyond buprenorphine treatment alone, for the optimal care for pregnant women with opioid use disorders.

Transitioning from methadone to buprenorphine maintenance in management of opioid use disorder during pregnancy

ABSTRACTBackground: Opioid use disorder during pregnancy is a growing health concern. Methadone maintenance is the treatment of choice but emerging data indicate buprenorphine is a viable alternative. Due to costs and limited accessibility of methadone, pregnant women may require transition from methadone to buprenorphine for maintenance treatment. Objectives: To assess safety and effectiveness of transitioning from methadone to buprenorphine when necessary during pregnancy. Methods: A standardized protocol using low buprenorphine doses to minimize emergent withdrawal symptoms under careful obstetric and psychiatric monitoring was implemented in 20 pregnant women. Outpatient maternal and neonatal outcomes were assessed. Results: Women maintained on an average methadone dose of 44 ± 4.77 (20–100) mg/day (mean±standard error mean (SEM); range) were successfully transitioned to 12.60 ± 0.8 (8–16) mg/day (mean±SEM; range) of buprenorphine. Within 4 weeks of transition, 15% had illicit drugs detected in urine drug screens. Ninety percent of women maintained outpatient follow-up until delivery. At delivery, 38.9% of mothers were exclusively adherent to buprenorphine (without use of illicit substances and/or other psychotropic medications); this resulted in significantly lower rates of neonatal abstinence syndrome (NAS) and shorter hospital stays. Discussion: Pregnant women transitioned from methadone to buprenorphine maintenance showed maternal and neonatal outcomes comparable to studies of women on buprenorphine throughout pregnancy. Infants born to buprenorphine-maintained women who abstained from illicit substances and other prescribed psychotropic medications experienced less severe NAS and shorter hospitalizations compared with women with illicit substance use and other psychotropic medications. These findings suggest women can safely be transitioned from methadone to buprenorphine during pregnancy.

Heightened sympathetic arousal is demonstrated by skin conductance responsivity to auditory stimuli in a small cohort of neonates with opiate withdrawal

To determine the effects of auditory stimulus on skin conductance (SC) in infants with severe neonatal abstinence syndrome (NAS) that required morphine treatment (MT) compared with NAS infants that did not require morphine treatment (non-MT). We prospectively enrolled opiate-exposed term infants without polysubstance exposure. Skin conductance responses to an auditory stimulus (ringing a bell for 3s) near the time of discharge were obtained. Skin conductance was measured before, during, and after the stimulus. Non-parametric tests were used to determine between group and within phase differences. Infants were off MT at the time of SC measurement in response to an auditory stimulus. In a 2-group comparison of MT vs. non-MT infants, there was significantly higher SC responsivity to an auditory stimulus (p <0.05) in the MT group as compared with the non-MT group near discharge. The mean +SE peak morphine dose was 0.85+0.20mg/kg/day in the MT group. The mean Length of Stay (LOS) was 32 vs. 7 (p <0.05) days respectively, for the MT vs. the non-MT group. Our preliminary data suggest that in infants with severe NAS symptoms, higher sympathetic arousal in response to an auditory stimulus persists at discharge, underscoring the need for ongoing evaluation and specialized care at home.