Effects of Pharmacologic Treatment for Neonatal Abstinence Syndrome on DNA Methylation and Neurobehavior: A Prospective Cohort Study.

OBJECTIVE: To determine whether pharmacologic treatment for neonatal abstinence syndrome (NAS) is associated with changes in DNA methylation (DNAm) of the mu-opioid receptor gene (OPRM1) and improvements in neonatal neurobehavior. STUDY DESIGN: Buccal swabs were collected from 37 neonates before and after morphine treatment for NAS. Genomic DNA was extracted, and DNAm was examined at 4 cytosine-phosphate-guanine (CpG) sites within the OPRM1 gene. Assessment with the NICU Network Neurobehavioral Scales (NNNS) was also performed before and after NAS treatment. Changes in DNAm (DNAmpost-tx - DNAmpre-tx) and NNNS summary scores (NNNSpost-tx - NNNSpre-tx) were then calculated. Path analysis was used to examine associations among pharmacologic treatment (length of treatment [LOT] and total dose of morphine), changes in DNAm, and changes in NNNS summary scores. RESULTS: DNAm was significantly decreased from pretreatment to post-treatment at 1 of 4 CpG sites within the OPRM1 gene. Neonates also demonstrated decreased excitability, hypertonia, lethargy, signs of stress and abstinence, and increased quality of movement and regulation from pretreatment to post-treatment. Longer LOT and higher morphine dose were associated with greater decreases in DNAm; greater decreases in DNAm were associated with greater decreases in excitability and hypertonia on the NNNS. CONCLUSIONS: Pharmacologic treatment of NAS is associated with decreased DNAm of the OPRM1 gene and improved neonatal neurobehavior. Epigenetic changes may play a role in these changes in neonatal neurobehavior.

Improving the Assessment of Neonatal Abstinence Syndrome (NAS).

Neonatal Abstinence Syndrome (NAS) is a public health problem of epidemic proportions. The Finnegan Neonatal Abstinence Scoring System (FNASS) is the tool most widely used to evaluate NAS. However, it is limited by its lack of interrater reliability and standardized approach. Surveys to evaluate the FNASS were distributed to nurses at the Women and Infants Hospital in Providence, RI, USA. Infants (n = 78) treated for NAS and born to methadone-maintained mothers were examined to compare items administered from the FNASS and the NICU Network Neurobehavioral Scale (NNNS). All nurses reported that the FNASS was somewhat to very subjective. More than half reported that it was somewhat to not accurate and a new scoring method is needed to accurately diagnose NAS. Correlations between FNASS items and NNNS items showed 9 of 32 (28.1%) correlations were strong (rs > 0.5), 5 of 32 (15.6%) were moderate (0.3 < rs < 0.5), and 10 of 32 (31.3%) were weak (0.1 < rs < 0.3). Principal component factor analysis (PCA) of the NNNS explained more variance (35.1%) than PCA of NNNS and FNASS items combined (33.1%). The nursing survey supported the need for developing a more objective exam to assess NAS. NNNS exam items may be used to improve the evaluation of NAS.

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

OBJECTIVE: To develop an index to determine which opioid-exposed neonates have the most severe neonatal abstinence syndrome (NAS). STUDY DESIGN: 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 18 months, 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). RESULTS: 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 18 months, 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). CONCLUSIONS: Presumptive measures of NAS severity can be aggregated to develop an index that predicts developmental outcomes at age 18 months.

Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome.

OBJECTIVE: To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial. STUDY DESIGN: Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL). RESULTS: Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01). CONCLUSIONS: Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958476.

Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial.

Importance: Although opioids are used to treat neonatal abstinence syndrome (NAS), the best pharmacologic treatment has not been established. Objective: To compare the safety and efficacy of methadone and morphine in NAS. Design, Setting, and Participants: In this randomized, double-blind, intention-to-treat trial, term infants from 8 US newborn units whose mothers received buprenorphine, methadone, or opioids for pain control during pregnancy were eligible. A total of 117 infants were randomized to receive methadone or morphine from February 9, 2014, to March 6, 2017. Mothers who declined randomization could consent to data collection and standard institutional treatment. Interventions: Infants were assessed with the Finnegan Neonatal Abstinence Scoring System every 4 hours and treated with methadone or placebo every 4 hours or morphine every 4 hours. Infants with persistently elevated Finnegan scores received dose increases. Infants who exceeded a predetermined opioid dose received phenobarbital. Dose reductions occurred every 12 to 48 hours when signs of NAS were controlled with therapy, stopping at 20% of the original dose. Main Outcomes and Measures: The primary end point was length of hospital stay (LOS). The secondary end points were LOS attributable to NAS and length of drug treatment (LOT). Results: A total of 183 mothers consented to have their infants in the study; 117 infants required treatment. Because 1 parent withdrew consent, data were analyzed on 116 infants (mean [SD] gestational age, 39.1 [1.1] weeks; mean [SD] birth weight, 3157 [486] g; 58 [50%] male). Demographic variables and risk factors were similar except for more prenatal cigarette exposure in infants who received methadone. Adjusting for study site and maternal opioid type, methadone was associated with decreased mean number of days for LOS by 14% (relative number of days, 0.86; 95% CI, 0.74-1.00; P = .046), corresponding to a difference of 2.9 days; 14% reduction in LOS attributable to NAS (relative number of days, 0.86; 95% CI, 0.77-0.96; P = .01), corresponding to a difference of 2.7 days; and 16% reduction in LOT (relative number of days, 0.84; 95% CI, 0.73-0.97; P = .02), corresponding to a difference of 2.3 days. Methadone was also associated with reduced median LOS (16 vs 20 days, P = .005), LOS attributable to NAS (16 vs 19 days, P = .005), and LOT (11.5 vs 15 days, P = .009). Study infants had better short-term outcomes than 170 nonrandomized infants treated with morphine per standard institutional protocols. Conclusions and Relevance: With use of weight- and sign-based treatment for NAS, short-term outcomes were better in infants receiving methadone compared with morphine. Assessment of longer-term outcomes is ongoing. Trial Registration: ClinicalTrials.gov Identifier: NCT01958476.