Neonatal Abstinence Syndrome Severity Index Predicts 18-Month Neurodevelopmental Outcome in Neonates Randomized to Morphine or Methadone.
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ABSTRACT: 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.
SUBMITTER: Flannery T
PROVIDER: S-EPMC7731918 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial.Study designEight 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).ResultsPrimary 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).ConclusionsInfants 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 registrationClinicalTrials.gov: NCT01958476.
| S-EPMC7161698 | biostudies-literature
Project description:To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine-exposed infants.Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined.For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (methadone = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition.Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine-exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine-exposed infants (36 versus 59 hours postnatal, respectively).The profile of neonatal abstinence syndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome.
| S-EPMC4165073 | biostudies-literature
Project description:BackgroundMethadone, a full mu-opioid agonist, is the recommended treatment for opioid dependence during pregnancy. However, prenatal exposure to methadone is associated with a neonatal abstinence syndrome (NAS) characterized by central nervous system hyperirritability and autonomic nervous system dysfunction, which often requires medication and extended hospitalization. Buprenorphine, a partial mu-opioid agonist, is an alternative treatment for opioid dependence but has not been extensively studied in pregnancy.MethodsWe conducted a double-blind, double-dummy, flexible-dosing, randomized, controlled study in which buprenorphine and methadone were compared for use in the comprehensive care of 175 pregnant women with opioid dependency at eight international sites. Primary outcomes were the number of neonates requiring treatment for NAS, the peak NAS score, the total amount of morphine needed to treat NAS, the length of the hospital stay for neonates, and neonatal head circumference.ResultsTreatment was discontinued by 16 of the 89 women in the methadone group (18%) and 28 of the 86 women in the buprenorphine group (33%). A comparison of the 131 neonates whose mothers were followed to the end of pregnancy according to treatment group (with 58 exposed to buprenorphine and 73 exposed to methadone) showed that the former group required significantly less morphine (mean dose, 1.1 mg vs. 10.4 mg; P<0.0091), had a significantly shorter hospital stay (10.0 days vs. 17.5 days, P<0.0091), and had a significantly shorter duration of treatment for the neonatal abstinence syndrome (4.1 days vs. 9.9 days, P<0.003125) (P values calculated in accordance with prespecified thresholds for significance). There were no significant differences between groups in other primary or secondary outcomes or in the rates of maternal or neonatal adverse events.ConclusionsThese results are consistent with the use of buprenorphine as an acceptable treatment for opioid dependence in pregnant women. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00271219.).
| S-EPMC3073631 | biostudies-literature
Project description: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.
| S-EPMC6142918 | biostudies-literature
Project description:Medical management of newborn infants often necessitates recurrent painful procedures, which may alter nociceptive pathways during a critical developmental period and adversely effect neuropsychological outcomes. To mitigate the effects of repeated painful stimuli, opioid administration for peri-procedural analgesia and ICU (intensive care unit) sedation is common in the NICU (neonatal intensive care unit). A growing body of basic and animal evidence suggests potential long-term harm associated with neonatal opioid therapy. Morphine increases apoptosis in human microglial cells, and animal studies demonstrate long-term changes in behavior, brain function, and spatial recognition memory following morphine exposure. This comprehensive review examines existing preclinical and clinical evidence on the long-term impacts of neonatal pain and opioid therapy.
| S-EPMC4101480 | biostudies-literature
Project description:ObjectiveThis pilot study evaluated the relationship between maternal and neonatal R- and S-methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) exposure and the severity of neonatal abstinence syndrome (NAS). The use of dried blood spots (DBS) as an alternative for plasma in assessing methadone and EDDP was also assessed.Study designWomen receiving methadone for medication assisted treatment of opioid use disorder during pregnancy were eligible for recruitment. Plasma and DBS samples were collected from mothers during labor, from cord blood, and from newborns during genetic screen. R-/S-methadone and EDDP were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS). Associations between methadone exposure, neonatal morphine requirements, and severity of NAS were examined.ResultsTwenty women and infants completed the study. Maternal methadone dose at delivery was 112 mg/day (range = 60-180 mg/day). Sixteen neonates experienced NAS requiring morphine; three also required phenobarbital. Higher cord blood concentrations of R-methadone, R- and S-EDDP were associated with higher maximum doses of morphine (p < 0.05).ConclusionMaternal methadone and cord blood concentration at delivery are variable and may be potential markers of neonatal abstinence syndrome.
| S-EPMC9393850 | biostudies-literature
Project description:ObjectivesThe purpose of this study was to investigate early markers of risk for neurobehavioral compromise in survivors with congenital heart disease (CHD).MethodsPregnant women in whom a fetal CHD had been diagnosed before 24 weeks' gestational age (GA) were enrolled in this prospective pilot study for serial Doppler ultrasound assessment of the fetal middle cerebral artery (MCA) and umbilical arteries. The cerebral-to-placental resistance ratio (CPR) and MCA pulsatility index (PI) Z-scores for GA were calculated. After birth, subjects underwent high-density (128-lead) electroencephalography (EEG), and beta frequency (12-24 Hz) band EEG power, a measure of local neural synchrony, was analyzed. Neurodevelopment was assessed at 18 months with the Bayley Scales of Infant Development (BSID)-III.ResultsThirteen subjects were enrolled: four with hypoplastic left heart syndrome (HLHS), four with transposition of the great arteries (TGA) and five with tetralogy of Fallot (TOF). Compared with subjects with normal CPR, those with CPR < 1 (n = 7) had lower mean BSID cognitive scores (91.4 ± 4.8 vs. 99.2 ± 3.8, P = 0.008). Fetal MCA-PI Z-score also correlated with BSID cognitive score (r = 0.589, P = 0.03) as did neonatal EEG left frontal polar (r = 0.58, P = 0.037) and left frontal (r = 0.77, P = 0.002) beta power. Furthermore, fetal Doppler measures were associated with EEG power: fetuses with CPR < 1 had lower left frontal polar (t = 2.36, P = 0.038) and left frontal (t = 2.85, P = 0.016) beta power as newborns than did fetuses with normal CPR, and fetal MCA-PI Z-score correlated with neonatal EEG left frontal polar (r = 0.596, P = 0.04) and left frontal (r = 0.598, P = 0.04) beta power.ConclusionIn fetuses with HLHS, TGA and TOF, abnormal cerebrovascular resistance predicts decreased neonatal EEG left frontal beta power and lower 18-month cognitive development scores.
| S-EPMC3612978 | biostudies-literature
Project description:BACKGROUND:Our objective was to estimate the association between methadone and neonatal abstinence syndrome compared with buprenorphine using a probabilistic bias analysis to account for unmeasured confounding by severity of addiction. METHODS:We used a cohort of live-born infants exposed in utero to methadone or buprenorphine for maternal opioid maintenance therapy at Magee-Womens Hospital in Pittsburgh, PA, from 2013 to 2015 (n = 716). We determined exposure and outcome status using pharmacy billing claims. We used log-binomial regression models to assess association of treatment with neonatal abstinence syndrome after adjusting for parity, maternal race, age, delivery year, employment, hepatitis c, smoking, marital, and insurance status. We implemented probabilistic bias analysis, informed by an internal validation study, to assess the impact of unmeasured confounding by severity of addiction. RESULTS:Infants exposed to methadone in utero were more likely to experience neonatal abstinence syndrome compared with those exposed to buprenorphine (RR, 1.3; 95% CI, 1.2, 1.5). After adjustment, infants exposed to methadone were more likely (adjusted RR, 1.3; 95% CI, 1.1, 1.5) than infants exposed to buprenorphine to have the syndrome. In the validation cohort (n = 200), severe addiction was more common in methadone- versus buprenorphine-exposed deliveries (77% vs. 32%). However, adjustment for severe addiction in the bias analysis only slightly attenuated the association (RR, 1.2; 95% CI, 1.0, 1.4), supporting conventional analysis. CONCLUSIONS:Methadone is associated with increased risk of neonatal abstinence syndrome compared with buprenorphine in infants exposed in utero. This association is subject to minimal bias due to unmeasured confounding by severity of addiction.
| S-EPMC5792296 | biostudies-literature
Project description:BackgroundTherapeutic hypothermia (TH) is standard of care for moderate to severe neonatal hypoxic ischemic encephalopathy (HIE) but many survivors still suffer lifelong disabilities and benefits of TH for mild HIE are under active debate. Development of objective diagnostics, with sensitivity to mild HIE, are needed to select, guide, and assess response to treatment. The objective of this study was to determine if cerebral oxygen metabolism (CMRO2) in the days after TH is associated with 18-month neurodevelopmental outcomes as the first step in evaluating CMRO2's potential as a diagnostic for HIE. Secondary objectives were to compare associations with clinical exams and characterise the relationship between CMRO2 and temperature during TH.MethodsThis was a prospective, multicentre, observational, cohort study of neonates clinically diagnosed with HIE and treated with TH recruited from the tertiary neonatal intensive care units (NICUs) of Boston Children's Hospital, Brigham and Women's Hospital, and Beth Israel Deaconess Medical Center between December 2015 and October 2019 with follow-up to 18 months. In total, 329 neonates ≥34 weeks gestational age admitted with perinatal asphyxia and suspected HIE were identified. 179 were approached, 103 enrolled, 73 received TH, and 64 were included. CMRO2 was measured at the NICU bedside by frequency-domain near-infrared and diffuse correlation spectroscopies (FDNIRS-DCS) during the late phases of hypothermia (C), rewarming (RW) and after return to normothermia (NT). Additional variables were body temperature and clinical neonatal encephalopathy (NE) scores, as well as findings from magnetic resonance imaging (MRI) and spectroscopy (MRS). Primary outcome was the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) at 18 months, normed (SD) to 100 (15).FindingsData quality for 58 neonates was sufficient for analysis. CMRO2 changed by 14.4% per °C (95% CI, 14.2-14.6) relative to its baseline at NT while cerebral tissue oxygen extraction fraction (cFTOE) changed by only 2.2% per °C (95% CI, 2.1-2.4) for net changes from C to NT of 91% and 8%, respectively. Follow-up data for 2 were incomplete, 33 declined and 1 died, leaving 22 participants (mean [SD] postnatal age, 19.1 [1.2] month; 11 female) with mild to moderate HIE (median [IQR] NE score, 4 [3-6]) and 21 (95%) with BSID-III scores >85 at 18 months. CMRO2 at NT was positively associated with cognitive and motor composite scores (β (SE) = 4.49 (1.55) and 2.77 (1.00) BSID-III points per 10-10 moL/dl × mm2/s, P = 0.009 and P = 0.01 respectively; linear regression); none of the other measures were associated with the neurodevelopmental outcomes.InterpretationPoint of care measures of CMRO2 in the NICU during C and RW showed dramatic changes and potential to assess individual response to TH. CMRO2 following TH outperformed conventional clinical evaluations (NE score, cFTOE, and MRI/MRS) at predicting cognitive and motor outcomes at 18 months for mild to moderate HIE, providing a promising objective, physiologically-based diagnostic for HIE.FundingThis clinical study was funded by an NIH grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States (R01HD076258).
| S-EPMC10338207 | biostudies-literature
Project description:To characterize the population pharmacokinetics of oral methadone in neonates requiring pharmacologic treatment of neonatal abstinence syndrome and to develop a pharmacokinetic (PK) model toward an evidence-based treatment protocol.Based on a methadone dosing protocol, serum concentrations of methadone and its metabolites were assessed by high performance liquid chromatography-tandem mass spectrometry from dried blood spots. Population PK analysis was performed to determine the volume of distribution and clearance of oral methadone. Methadone plasma concentration-time profiles were simulated from the deduced PK model to optimize the dosing regimen.There was substantial interindividual variability in methadone concentrations. Blood concentrations of methadone were best described by a 1-compartment model with first-order absorption. The population mean estimates (coefficient of variation percentage) for oral clearance and volume of distribution were 8.94 (103%) L/h/70 kg and 177 (133%) L/70 kg, respectively. Optimized dosing strategies were developed based on the simulated PK profiles. We suggest a starting dose of 0.1 mg/kg per dose every 6 hours for most patients requiring pharmacologic treatment of neonatal abstinence syndrome followed by an expedited weaning phase.The proposed dosing regimen may reduce the cumulative dose of opioid and shorten the length of hospitalization. Future studies should aim to validate the simulated dosing schemes with clinical data and expand our understanding of the between-patient PK variability.ClinicalTrials.gov: NCT01754324.
| S-EPMC4662899 | biostudies-literature