Effect of Prenatal Opioid Exposure on the Human Placental Methylome

Prenatal exposure to addictive drugs can lead to placental epigenetic modifications, but a methylome-wide evaluation of placental DNA methylation changes after prenatal opioid exposure has not yet been performed. Placental tissue samples were collected at delivery from 19 opioid-exposed and 20 unexposed control full-term pregnancies. Placental DNA methylomes were profiled using the Illumina Infinium HumanMethylationEPIC BeadChip. Differentially methylated CpG sites associated with opioid exposure were identified with a linear model using the ‘limma’ R package. To identify differentially methylated regions (DMRs) spanning multiple CpG sites, the ‘DMRcate’ R package was used. The functions of genes mapped by differentially methylated CpG sites and DMRs were further annotated using Enrichr. Differentially methylated CpGs (n = 684, unadjusted p < 0.005 and |∆β| ≥ 0.05) were mapped to 258 genes (including PLD1, MGAM, and ALCS2). Differentially methylated regions (n = 199) were located in 174 genes (including KCNMA1). Enrichment analysis of the top differentially methylated CpG sites and regions indicated disrupted epigenetic regulation of genes involved in synaptic structure, chemical synaptic transmission, and nervous system development. Our findings imply that placental epigenetic changes due to prenatal opioid exposure could result in placental dysfunction, leading to abnormal fetal brain development and the symptoms of opioid withdrawal in neonates

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 \u3c .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P \u3c .01) and continued maternal substance use (P \u3c .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.

NCT01958476 } data-sheets-userformat= { 2 :33569153, 3 :{ 1 :0, 3 :1}, 10 :0, 11 :4, 14 :[null,2,0], 15 : Calibri , 16 :11, 28 :1} \u3eThis randomized clinical trial compares the safety and efficacy of methadone vs morphine for treatment of infants with neonatal abstinence syndrome using a weight-and sign-based treatment protocol. Key Points: Question: Does methadone or morphine have better safety and efficacy for the treatment of neonatal abstinence syndrome? Findings: In this randomized clinical trial, 117 infants were randomized to treatment with methadone or morphine using a weight- and sign-based treatment protocol. Methadone was associated with reductions in length of hospital stay, length of hospital stay attributable to neonatal abstinence syndrome, and length of treatment after adjusting for study site and type of maternal opioid. Meaning: Methadone is more effective than morphine only in infants needing pharmacologic treatment for neonatal abstinence syndrome. 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: NCT0195847

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