Sex-Related Differences in the Severity of Neonatal Opioid Withdrawal Syndrome: A Single-Center, Retrospective Cohort Study.

OBJECTIVE: Factors associated with the development and expression of Neonatal Opioid Withdrawal Syndrome (NOWS) are poorly understood. There are conflicting data on the role of infant sex in NOWS. Some studies have suggested that infant sex predicts NOWS severity and adverse outcomes, with male infants being more vulnerable. This study aimed to analyze if infant sex is associated with the severity of NOWS among those who require pharmacologic treatment. STUDY DESIGN: This is a retrospective cohort study of term and late-preterm infants (≥35 weeks gestation) exposed to in utero opioids, born between September 2006 and August 2022, and required pharmacologic treatment for NOWS. Maternal and infant demographics were collected. Indicators of the severity of NOWS (duration of medical treatment (DOT), duration of hospitalization, maximum dose of opioid treatment, and use of secondary medications) were compared between male and female infants. Standard statistical tests and regression analysis were used to establish the differences in outcomes after accounting for confounders and baseline differences. RESULTS: Out of the 1,074 infants included in the study, 47.9% were female, and 52.1% were male. There was no significant difference in demographic and baseline clinical characteristics between groups except for anthropometry (birth weight, head circumference, and length) and Apgar score at 5 minutes. The median DOT (25 days [14, 39] vs. 23 days [13, 39], p = 0.57), length of hospital stay (31.5 days [20, 44] vs. 28 days [20, 44], p = 0.35), treatment with phenobarbital (24.7 vs. 26.3%, p = 0.56), and clonidine (3.9 vs. 3.8%, p = 0.9) were similar in both groups. The differences remained nonsignificant after adjusting for birth anthropometric measurements, gestational age, 5-minute Apgar score, small for gestational age status, and maternal exposure to benzodiazepines. CONCLUSION: In this cohort of neonates, sex-related differences were not identified to influence the severity of NOWS among those who required pharmacological treatment. KEY POINTS: · Vulnerability to NOWS is multifactorial.. · The role of infant sex in the severity of NOWS is not concrete.. · We noted that sex did not impact NOWS severity in those treated..

Buprenorphine vs. morphine: impact on neonatal opioid withdrawal syndrome (NOWS) outcomes in a single center retrospective study.

OBJECTIVES: To compare clinical outcomes for infants with neonatal opioid withdrawal syndrome (NOWS) treated with buprenorphine or morphine. STUDY DESIGN: Retrospective study of infants born ≥35 weeks' gestation and admitted to the NICU for NOWS treatment between 2011 and 2022. Length of treatment, length of stay in the hospital, and the need for secondary medications were compared between buprenorphine and morphine treated neonates. Multiple regression analysis was performed, adjusting for baseline differences and confounders. RESULTS: 417 neonates were treated with morphine and 232 with buprenorphine. The buprenorphine group had shorter treatment days [-10.8 days; 95% CI: -8.08 to -13.53] and shorter hospital stay [-11.8 days; 95% CI: -8.83 to -14.78]. The buprenorphine group was no more likely to receive phenobarbital or clonidine (26% vs. 29%). CONCLUSION: In this large single-center study, buprenorphine was associated with shorter lengths of treatment and hospital stay in the treatment of NOWS compared to morphine.

Abstinence scoring algorithms for treatment of neonatal opioid withdrawal syndrome (NOWS).

OBJECTIVE: Chervoneva et al. (2020) developed an abbreviated score (sMNAS-9) derived from full modified Finnegan MOTHER NAS scale (MNAS) for evaluating severity of NOWS. We sought to develop NOWS treatment algorithms for clinical decision rules based on scores utilizing the shorter sMNAS. STUDY DESIGN: This was a retrospective study of 373 infants with NOWS scored with MNAS and treated with morphine between 2007 and 2016. The infants were randomly split into training/test sets. The training set was used to derive optimized cutoff values for sMNAS-9 scores. The independent set evaluated the sMNAS-9 clinical decision rules based on full MNAS in NOWS morphine and buprenorphine treatment algorithms. RESULT: Clinical decision rules based on sMNAS-9 yielded sensitivities of 88% or higher and specificities of 85% or higher for predicting the respective rules based on full MNAS. CONCLUSION: The sMNAS-9 scoring instrument is expected to yield similar clinical decisions in treatment of NOWS.

Acute Kidney Injury and Abnormalities on Brain Magnetic Resonance Imaging or Death in Infants with Hypoxic-Ischemic Encephalopathy: A Case-Control Study.

OBJECTIVE: This study aimed to analyze the association between acute kidney injury (AKI) and abnormalities on brain magnetic resonance imaging (MRI) or death in neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: This is a retrospective case-control analysis of 380 neonates born at ≥35 weeks' gestation treated with therapeutic hypothermia for HIE. Death or abnormal brain MRI using the basal ganglia watershed scoring system was compared between neonates with and without AKI. RESULTS: A total of 51 (13.4%) neonates had AKI. Infants with AKI had higher rates of the composite of death or abnormal brain MRI (74.5 vs. 38.3%; p < 0.001). Rate of death (21.6 vs. 5.5%; p < 0.001) and severe abnormalities on MRI or death (43.1 vs. 19.1%; p < 0.001) were also higher in neonates with AKI. CONCLUSION: AKI is strongly associated with abnormalities on brain MRI or death in neonates with HIE. Identification of AKI in this patient population may be helpful in guiding clinical management and predicting potential neurodevelopmental impairment. KEY POINTS: · Neonates with HIE are at increased risk for AKI.. · AKI is associated with hypoxic-ischemic injury on brain MRI or death among neonates with HIE.. · Identification of AKI in infants with HIE may help predict neurodevelopmental impairment..

Polygenic risk scores and the need for pharmacotherapy in neonatal abstinence syndrome.

BACKGROUND: The aim of this study was to identify genetic variants associated with NAS through a genome-wide association study (GWAS) and estimate a Polygenic Risk Score (PRS) model for NAS. METHODS: A prospective case-control study included 476 in utero opioid-exposed term neonates. A GWAS of 1000 genomes-imputed genotypes was performed to identify variants associated with need for pharmacotherapy for NAS. PRS models for estimating genetic predisposition were generated via a nested cross-validation approach using 382 neonates of European ancestry. PRS predictive ability, discrimination, and calibration were assessed. RESULTS: Cross-ancestry GWAS identified one intergenic locus on chromosome 7 downstream of SNX13 exhibiting genome-wide association with need for pharmacotherapy. PRS models derived from the GWAS for a subset of the European ancestry neonates reliably discriminated between need for pharmacotherapy using cis variant effect sizes within validation sets of European and African American ancestry neonates. PRS were less effective when applying variant effect sizes across datasets and in calibration analyses. CONCLUSIONS: GWAS has the potential to identify genetic loci associated with need for pharmacotherapy for NAS and enable development of clinically predictive PRS models. Larger GWAS with additional ancestries are needed to confirm the observed SNX13 association and the accuracy of PRS in NAS risk prediction models. IMPACT: Genetic associations appear to be important in neonatal abstinence syndrome. This is the first genome-wide association in neonates with neonatal abstinence syndrome. Polygenic risk scores can be developed examining single-nucleotide polymorphisms across the entire genome. Polygenic risk scores were higher in neonates receiving pharmacotherapy for treatment of their neonatal abstinence syndrome. Future studies with larger cohorts are needed to better delineate these genetic associations.

Ondansetron to reduce neonatal opioid withdrawal severity a randomized clinical trial.

OBJECTIVE: To determine if treatment with a 5-HT3 antagonist (ondansetron) reduces need for opioid therapy in infants at risk for neonatal opioid withdrawal syndrome (NOWS). STUDY DESIGN: A multicenter, randomized, placebo controlled, double blind clinical trial of ninety (90) infants. The intervention arms were intravenous ondansetron or placebo during labor followed by a daily dose of ondansetron or placebo in infants for five days. RESULTS: Twenty-two (49%) ondansetron-treated and 26 (63%) placebo-treated infants required pharmacologic treatment (p > 0.05). The Finnegan score was lower in the ondansetron-treated group (4.6 vs. 5.6, p = 0.02). A non-significant trend was noted for the duration of hospitalization. There was no difference in need for phenobarbital or clonidine therapy, or total dose of morphine in the first 15 days of NOWS treatment. CONCLUSIONS: Ondansetron treatment reduced the severity of NOWS symptoms; and there was an indication that it could reduce the length of stay. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT01965704.

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

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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. KEY POINTS: · 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..

Growth failure in infants with neonatal abstinence syndrome in the neonatal intensive care unit.

OBJECTIVE: To assess if infants with neonatal abstinence syndrome (NAS) are smaller at birth and have decreased growth parameters between birth and discharge from the neonatal intensive care unit (NICU). METHODS: Retrospective data analysis of term/late-preterm neonates with NAS at a single-center NICU between September 2006 and May 2018. Growth parameters (weight, length, HC) were measured at birth and discharge. Z scores and percentiles were calculated using WHO standard growth curves. RESULTS: A total of 864 infants ≥35 weeks were admitted for NAS. At birth, median percentiles were weight 30%, HC 23%, and length 37%; these decreased significantly (p < 0.001) at discharge to 12%, 6.5%, and 13%, respectively. The percentage of infants <3rd percentile increased significantly (p < 0.001) in all growth parameters from birth to discharge. CONCLUSION: Infants with NAS are smaller at birth and have significant growth retardation in all growth parameters at discharge. An ongoing long-term growth follow-up study will discern the impact of growth restriction in NAS infants.

Pharmacometric dose optimization of buprenorphine in neonatal opioid withdrawal syndrome.

Results from Blinded Buprenorphine OR Neonatal morphine solution (BBORN), a previous phase III trial in infants with neonatal opioid withdrawal syndrome (NOWS), demonstrated that sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than the comparator, oral morphine. Objectives of Buprenorphine Pharmacometric Open Label Research study of Drug Exposure (BPHORE), a new trial with buprenorphine in a similar population, were to (1) optimize initial dose, up-titration to achieve symptom control and weaning steps of pharmacologic treatment and (2) investigate safety of the revised regimen. A pharmacodynamic model linked buprenorphine exposure to NOWS symptom scores. Adaptive dose regimens were simulated using BBORN results to compare dosing regimens for times to stabilization, weaning, and cessation. A clinical trial using model informed doses (BPHORE), was conducted. Simulations indicated benefits in time to stabilization and weaning when up-titration rates increased to 30%. Stabilization time was not greatly impacted by the starting dose. Time to wean and time to cessation were dose dependent. A weaning rate of 25% shortened time to cessation. Ten infants were enrolled in BPHORE using buprenorphine starting dose of 24 µg/kg/day, 33% titration, and 15% wean rate. Five subjects required adjuvant therapy. Half-maximal effective concentration (EC50 ) values indicated maximum buprenorphine doses did not generate maximal effect size, suggesting potential efficacy of a further increased dose if a goal was to reduce the use of adjunct agents. Simulations indicated that further benefits can be gained by increasing starting doses of buprenorphine and increasing wean rates. Use of a model-based analysis to provide focused guidelines for care can be used with goals of reducing treatment time and hospital stays in infants with NOWS.

Apgar Scores at 10 Minutes and Outcomes in Term and Late Preterm Neonates with Hypoxic-Ischemic Encephalopathy in the Cooling Era.

OBJECTIVE: To determine the short-term outcomes (abnormal brain magnetic resonance imaging [MRI]/death) in infants born with a 10-minute Apgar score of 0 who received therapeutic hypothermia and compare them with infants with higher scores. STUDY DESIGN: This is a retrospective review of 293 neonates (gestational age ≥ 35 weeks) born between November 2006 and October 2015 admitted with hypoxic-ischemic encephalopathy who received therapeutic hypothermia. Results of brain MRIs were assessed by the basal ganglia/watershed scoring system. Short-term outcomes were compared between infants with Apgar scores of 0, 1 to 4, and ≥5 at 10 minutes. RESULTS: Eight of 17 infants (47%) with an Apgar of 0 at 10 minutes survived, having 4 (24%) without abnormalities on the brain MRI and 7 (41%) without severe abnormalities. There was no significant difference in the combined outcomes of "death/abnormal MRI" and "death/severe abnormalities on the MRI" between infants with Apgar scores of 0 and 1 to 4. Follow-up data were available for six of eight surviving infants, and none had moderate or severe neurodevelopmental impairment. CONCLUSION: In the cooling era, 47% of infants with no audible heart rate at 10 minutes and who were admitted to the neonatal intensive care unit survived; 24% without abnormalities on the brain MRI and 41% without severe abnormalities.

The Pharmacokinetics and Pharmacodynamics of Buprenorphine in Neonatal Abstinence Syndrome.

Neonatal abstinence syndrome (NAS) is a condition affecting newborns that are exposed to an opioid in utero. In a randomized, controlled trial assessing the efficacy of buprenorphine and morphine in NAS, blood samples were analyzed from a subset of patients receiving buprenorphine along with NAS scores. The data were used to validate and adapt an existing model of buprenorphine in neonates and to identify relationships between buprenorphine or norbuprenorphine pharmacokinetics (PK) and efficacy or safety. The time to NAS stabilization was found to decrease with increasing buprenorphine exposure. This pharmacokinetic-pharmacodynamic (PK-PD) relationship was able to be quantified and adequately described with a mathematical model. The findings confirm a previous PK model of buprenorphine and extend the model to describe the PK of norbuprenorphine and to identify a novel PK-PD relationship of buprenorphine in NAS. This model will allow optimization of dosing strategies in future clinical trials.

Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome.

BACKGROUND: Current pharmacologic treatment of the neonatal abstinence syndrome with morphine is associated with a lengthy duration of therapy and hospitalization. Buprenorphine may be more effective than morphine for this indication. METHODS: In this single-site, double-blind, double-dummy clinical trial, we randomly assigned 63 term infants (≥37 weeks of gestation) who had been exposed to opioids in utero and who had signs of the neonatal abstinence syndrome to receive either sublingual buprenorphine or oral morphine. Infants with symptoms that were not controlled with the maximum dose of opioid were treated with adjunctive phenobarbital. The primary end point was the duration of treatment for symptoms of neonatal opioid withdrawal. Secondary clinical end points were the length of hospital stay, the percentage of infants who required supplemental treatment with phenobarbital, and safety. RESULTS: The median duration of treatment was significantly shorter with buprenorphine than with morphine (15 days vs. 28 days), as was the median length of hospital stay (21 days vs. 33 days) (P<0.001 for both comparisons). Adjunctive phenobarbital was administered in 5 of 33 infants (15%) in the buprenorphine group and in 7 of 30 infants (23%) in the morphine group (P=0.36). Rates of adverse events were similar in the two groups. CONCLUSIONS: Among infants with the neonatal abstinence syndrome, treatment with sublingual buprenorphine resulted in a shorter duration of treatment and shorter length of hospital stay than treatment with oral morphine, with similar rates of adverse events. (Funded by the National Institute on Drug Abuse; BBORN ClinicalTrials.gov number, NCT01452789 .).

Are outcomes and care processes for preterm neonates influenced by health insurance status?

OBJECTIVE: The purpose of this work was to compare the processes of care and to evaluate outcomes of premature neonates delivered to women with Medicaid managed care versus private insurance. DESIGN/METHODS: All of the infants born at <37 weeks' gestation between January 2001 and August 2005 in the ParadigmHealth database were included in these analyses (n = 24151). Infants were categorized by maternal health insurance status as private insurance or Medicaid managed care and analyzed for differences in demographic data and length of stay. For survivors, differences in respiratory care, nutritional, and maturational milestones were assessed. In addition, age to wean to open crib, weight gain, home oxygen, and apnea monitor use were compared. Adverse outcomes, including necrotizing enterocolitis, sepsis, severe intraventricular hemorrhage, severe retinopathy of prematurity, bronchopulmonary dysplasia, apnea, and mortality, were compared. Statistical tests used were Students t test, chi(2), and Kruskall-Wallis test. Multiple logistic regression was performed after controlling for demographic variables. RESULTS: Of the 24151 infants studied, 19046 (78.9%) had private insurance, and 5105 (21.1%) had Medicaid managed care. There were no differences in gestational age at birth; however, Medicaid managed care infants had lower birth weight, lower Apgar score at 5 minutes, increased incidence of necrotizing enterocolitis and bacterial sepsis, and longer length of stay. Of the surviving infants, more neonates with private insurance went home on oxygen and apnea monitors despite no differences found in the incidences of apnea or bronchopulmonary dysplasia between the groups. There were no differences in processes of care for feeding and respiratory milestones, but infants with Medicaid managed care weaned to an open crib later and had greater overall weight gain compared with infants with private insurance. CONCLUSIONS: We speculate that, in addition to the known impact of insurance status on well-being at birth, Medicaid managed care is independently associated with adverse neonatal outcomes in preterm infants, as well as differences in neonatal intensive care discharge processes.