Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal: A Post Hoc Subgroup Analysis of the ESC-NOW Randomized Clinical Trial.

Importance: The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. Objective: To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. Design, Setting, and Participants: This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Exposure: Opioid treatment for NOWS and the ESC care approach. Main Outcomes and Measures: For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. Results: In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). Conclusion and Relevance: When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Characteristics and outcomes of neonatal opioid withdrawal syndrome in preterm infants: a retrospective cohort study in the current era.

OBJECTIVE: Compare Neonatal Opioid Withdrawal Syndrome (NOWS) in preterm and term infants. STUDY DESIGN: Single center, retrospective chart review of all in-utero opioid exposed infants born between 2014 and 2019. Withdrawal symptoms were assessed using Modified Finnegan Assessment Tool. RESULTS: Thirteen preterm (PT), 72 late preterm (LPT), and 178 term infants were included. Preterm and LPT compared to term infants had lower peak Finnegan scores (9/9 vs. 12) and received less pharmacologic treatment (23.1/44.4 vs. 66.3%). Similar onset, peak symptoms, and treatment duration was observed in LPT and term infants. CONCLUSIONS: Preterm and LPT infants have lower Finnegan scores and require less pharmacologic therapy for NOWS. It is unclear if this is because our current assessment tool does not capture their symptoms or if they truly have less withdrawal. Onset of NOWS is similar in LPT and term infant, thus LPT infants do not require prolonged hospital monitoring for NOWS.

Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

Quality Improvement Initiative to Improve Healthcare Providers' Attitudes towards Mothers with Opioid Use Disorder.

INTRODUCTION: Individuals with opioid use disorder often report feelings of shame and describe feeling judged negatively. These feelings are especially true for pregnant women with opioid use disorder. The Ohio Perinatal Quality Collaborative conducted a multimodal quality improvement initiative for infants born with Neonatal Abstinence Syndrome (NAS). An important component of the project was focused on improving staff attitudes toward mothers of infants with NAS. METHODS: The Ohio Perinatal Quality Collaborative implemented an education program for healthcare providers at 39 participating hospital units regarding opioid use as a chronic disease and principles of nonjudgmental, trauma-informed care. Healthcare providers partnered with the mother of infants with NAS in the care of the infant and connected with local community resources. This work was a subcomponent of an overall multimodal quality improvement project. Healthcare provider attitudes were measured with the "Attitude Measurement: Brief Scales" questionnaire anonymously, at 3 different time points throughout the project. Attitude change was measured by pretraining and posttraining scores. ANOVA methods were used to compare individual items and a summary score across the 3 surveys. RESULTS: Summary scores improved significantly from 18.99 at baseline (January-March 2014) to 19.94 (P < 0.0001) in February 2015 and were maintained at 20.05 in July 2016. CONCLUSIONS: A nonjudgmental attitude toward mothers of infants with NAS is an important component of compassionate care. Improving healthcare provider attitudes can benefit a mother of an infant with NAS and help preserve the mother-infant dyad.

Phenobarbital and Clonidine as Secondary Medications for Neonatal Opioid Withdrawal Syndrome.

BACKGROUND AND OBJECTIVES: Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS. METHODS: We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders. RESULTS: Of 563 infants with NOWS treated with morphine, 32% (n = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, P < .0001). CONCLUSIONS: Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS.

Early antenatal counseling in the outpatient setting for high-risk pregnancies: a randomized control trial.

OBJECTIVES: Determine if antenatal counseling delivered in the outpatient setting improves parental knowledge and satisfaction without contributing to anxiety. STUDY DESIGN: Randomized control trial at a large academic institution. Mothers at risk for preterm delivery were enrolled following routine maternal-fetal medicine (MFM) visits and randomized to early antenatal counseling of prematurity or standard counseling by MFM providers. The primary outcome was parental knowledge of prematurity. Secondary outcomes included parental satisfaction, anxiety scores, and compliance with recommended follow-up. RESULTS: Seventy-six women were enrolled, 38 in each group. Early counseling group had higher knowledge scores (86.3 vs 64.3, p = <0.001) and parental satisfaction (p = 0.003). Anxiety scores were similar between the two groups (38.2 vs 40.4, p = 0.53). No difference was noted in compliance with follow-up. CONCLUSIONS: Antenatal counseling in the high-risk outpatient setting improved parental knowledge and satisfaction without leading to increased anxiety.

Orchestrated Testing of Formula Type to Reduce Length of Stay in Neonatal Abstinence Syndrome.

BACKGROUND: Despite the standardization of care, formula feeding varied across sites of the Ohio Perinatal Quality Collaborative (OPQC). We used orchestrated testing (OT) to learn from this variation and improve nonpharmacologic care of infants with neonatal abstinence syndrome (NAS) requiring pharmacologic treatment in Ohio. METHODS: To test the impact of formula on length of stay (LOS), treatment failure, and weight loss among infants hospitalized with NAS, we compared caloric content (high versus standard) and lactose content (low versus standard) using a 22 factorial design. During October 2015 to June 2016, OPQC sites joined 1 of 4 OT groups. We used response plots to examine the effect of each factor and control charts to track formula use and LOS. We used the OT results to revise the nonpharmacologic bundle and implemented it during 2017. RESULTS: Forty-seven sites caring for 546 NAS infants self-selected into the 4 OT groups. Response plots revealed the benefit of high-calorie formula (HCF) on weight loss, treatment failure, and LOS. The nonpharmacologic treatment bundle was updated to recommend HCF when breastfeeding was not possible. During implementation, HCF use increased, and LOS decreased from 17.1 to 16.4 days across the OPQC. CONCLUSIONS: OT revealed that HCF was associated with shorter LOS in OPQC sites. Implementation of a revised nonpharmacologic care bundle was followed by additional LOS improvement in Ohio. Despite some challenges in the implementation of OT, our findings support its usefulness for learning in improvement networks.

Ohio Perinatal Quality Collaborative Improves Care of Neonatal Narcotic Abstinence Syndrome.

OBJECTIVES: Neonatal abstinence syndrome (NAS) after an infant's in-utero exposure to opioids has increased dramatically in incidence. No treatment standards exist, leading to substantial variations in practice, degree of opioid exposure, and hospital length of stay. METHODS: The Ohio Perinatal Quality Collaborative conducted an extensive multi-modal quality improvement initiative with the goal to (1) standardize identification, nonpharmacologic and pharmacologic treatment in level-2 and 3 NICUs in Ohio, (2) reduce the use of and length of treatment with opioids, and (3) reduce hospital length of stay in pharmacologically treated newborns with NAS. RESULTS: Fifty-two of 54 (96%) Ohio NICUs participated in the collaborative. Compliance with the nonpharmacologic bundle improved from 37% to 59%, and the pharmacologic bundle improved from 59% to 68%. Forty-eight percent of the 3266 opioid-exposed infants received pharmacologic treatment of symptoms of NAS, and this rate did not change significantly across the time period. Regardless of the opioid used to pharmacologically treat infants with NAS, the length of treatment decreased from 13.4 to 12.0 days, and length of stay decreased from 18.3 to 17 days. CONCLUSIONS: Standardized approaches to the identification and nonpharmacologic and pharmacologic care were associated with a reduced length of opioid exposure and hospital stay in a large statewide collaborative. Other states and institutions treating opioid-exposed infants may benefit from the adoption of these practices.

Adult Outcomes After Newborn Respiratory Failure Treated With Extracorporeal Membrane Oxygenation.

OBJECTIVE: To describe the outcome of young adults treated for hypoxemic respiratory failure with extracorporeal membrane oxygenation as neonates. DESIGN: The study was designed as a multisite, cross sectional survey. SETTING: The survey was completed electronically or on paper by subjects and stored in a secure data base. SUBJECTS: Subjects were surviving neonatal extracorporeal membrane oxygenation patients from eight institutions who were18 years old or older. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A questionnaire modified from the 2011 Behavioral Risk Factor Surveillance System and the 2011 National Health Interview Survey with additional unique questions was completed by subjects. Results were compared to age-matched national Behavioral Risk Factor Surveillance System and National Health Interview Survey data. One hundred and forty-six subjects participated (8.9% of eligible candidates). The age at questionnaire submission was 23.7 ± 2.89 years. Subjects differed statistically from national cohorts by being more satisfied with life (93% vs 84.2%); more educated (some college or degree; 80.1% vs 57.7%); more insured for healthcare (89.7% vs 72.3%); less frequent users of healthcare in the last 12 months (47.3% vs 58.2%); more limited because of physical, mental, and developmental problems (19.9% vs 10.9%); and having more medical complications. Furthermore, learning problems occurred in 29.5% of the study cohort. The congenital diaphragmatic hernia group was generally less healthy and less well educated, but equally satisfied with life. Perinatal variables contributed little to outcome prediction. CONCLUSIONS: Most young adult survivors in this study cohort treated with extracorporeal membrane oxygenation as neonates are satisfied with their lives, working and/or in college, in good health and having families. These successes are occurring despite obstacles involving health issues such as asthma, attention deficit disorder, learning difficulties, and vision and hearing problems; this is especially evident in the congenital diaphragmatic hernia cohort. Selection bias inherent in such a long-term study may limit generalizability, and it is imperative to note that our sample may not be representative of the whole.

Implementation of a Neonatal Abstinence Syndrome Weaning Protocol: A Multicenter Cohort Study.

OBJECTIVES: To evaluate the generalizability of stringent protocol-driven weaning in improving total duration of opioid treatment and length of inpatient hospital stay after treatment of neonatal abstinence syndrome (NAS). METHODS: We conducted a retrospective cohort analysis of 981 infants who completed pharmacologic treatment of NAS with methadone or morphine from January 2012 through August 2014. Before July 2013, 3 of 6 neonatology provider groups (representing Ohio's 6 children's hospitals) directed NAS nursery care by using group-specific treatment protocols containing explicit weaning guidelines. In July 2013, a standardized weaning protocol was adopted by all 6 groups. Statistical analysis was performed to identify effects of adoption of the multicenter weaning protocol on total duration of opioid treatment and length of hospital stay at the protocol-adopting sites and at the sites with preexisting protocol-driven weaning. RESULTS: After adoption of the multicenter protocol, infants treated by the 3 groups previously without stringent weaning guidelines experienced shorter duration of opioid treatment (23.0 vs 34.0 days, P < .001) and length of inpatient hospital stay (23.7 vs 31.6 days, P < .001). Protocol-adopting sites also experienced a lower rate of adjunctive drug therapy (5% vs 21%, P = .004). Outcomes were sustained by the 3 groups who initially had specific weaning guidelines after multicenter adoption (duration of treatment = 17.0 days and length of hospital stay = 23.3 days). CONCLUSIONS: Adoption of a stringent weaning protocol resulted in improved NAS outcomes, demonstrating generalizability of the protocol-driven weaning approach. Opportunity remains for additional protocol refinement.

A multicenter cohort study of treatments and hospital outcomes in neonatal abstinence syndrome.

OBJECTIVES: To compare pharmacologic treatment strategies for neonatal abstinence syndrome (NAS) with respect to total duration of opioid treatment and length of inpatient hospital stay. METHODS: We conducted a cohort analysis of late preterm and term neonates who received inpatient pharmacologic treatment of NAS at one of 20 hospitals throughout 6 Ohio regions from January 2012 through July 2013. Physicians managed NAS using 1 of 6 regionally based strategies. RESULTS: Among 547 pharmacologically treated infants, we documented 417 infants managed using an established NAS weaning protocol and 130 patients managed without protocol-driven weaning. Regardless of the treatment opioid chosen, when we accounted for hospital variation, infants receiving protocol-based weans experienced a significantly shorter duration of opioid treatment (17.7 vs. 32.1 days, P < .0001) and shorter hospital stay (22.7 vs. 32.1 days, P = .004). Among infants receiving protocol-based weaning, there was no difference in the duration of opioid treatment or length of stay when we compared those treated with morphine with those treated with methadone. Additionally, infants treated with phenobarbital were treated with the drug for a longer duration among those following a morphine-based compared with methadone-based weaning protocol. (P ≤ .002). CONCLUSIONS: Use of a stringent protocol to treat NAS, regardless of the initial opioid chosen, reduces the duration of opioid exposure and length of hospital stay. Because the major driver of cost is length of hospitalization, the implications for a reduction in cost of care for NAS management could be substantial.

Rehospitalization during the first year of life by insurance status.

OBJECTIVE: To assess the association of insurance status on infant rehospitalization in a population-based setting. METHODS: In this longitudinal retrospective study, hospitalizations were tracked for 1 year after birth discharge for 203 031 infants born in hospitals during 2008 using data from the New York State Inpatient Database. Relative risk was estimated using multivariable negative binomial regression models. RESULTS: Rehospitalization occurred in 9010 infants (4.4%). Medicaid coverage and being uninsured were strong predictors of rehospitalizations after adjustment for birth weight and other factors. Medicaid also bears a disproportionate share of the economic burden. Normal birth weight infants have the lowest risk, but comprise the majority of costs. Jaundice and acute bronchiolitis were the leading causes of rehospitalization within 30 days and 1 year, respectively. DISCUSSION: Future research can explore the preventability of rehospitalizations, and evaluate novel strategies for discharge and postnatal care coordination especially for uninsured and Medicaid-enrolled infants.

A hemoglobin variant associated with neonatal cyanosis and anemia.

Globin-gene mutations are a rare but important cause of cyanosis. We identified a missense mutation in the fetal Gγ-globin gene (HBG2) in a father and daughter with transient neonatal cyanosis and anemia. This new mutation modifies the ligand-binding pocket of fetal hemoglobin by means of two mechanisms. First, the relatively large side chain of methionine decreases both the affinity of oxygen for binding to the mutant hemoglobin subunit and the rate at which it does so. Second, the mutant methionine is converted to aspartic acid post-translationally, probably through oxidative mechanisms. The presence of this polar amino acid in the heme pocket is predicted to enhance hemoglobin denaturation, causing anemia.

A rational approach to red blood cell transfusion in the neonatal ICU.

PURPOSE OF REVIEW: There have been several recent randomized controlled trials collectively aimed at either the prevention or the management of anemia of prematurity. We aim to summarize evidence on prevention, management and long-term outcomes. RECENT FINDINGS: Current guidelines for red blood cell transfusion are based on expert opinion and vary. Conservative transfusion policies can reduce the number of transfusions, but other benefits are more uncertain. Delivery room prevention by using delayed cord clamping or cord milking is promising, but requires long-term outcome assessments in preterms. Some measures of hypoxemia to guide 'need' for transfusion have potential, but are not yet ready for general use. Pragmatic management trials have compared a 'restrictive' with a 'liberal' policy with respect to effects on clinically relevant outcomes by neonatal ICU discharge, but conclusions have differed. Follow-up data to 24 months is available for only one study, which showed no benefit in the primary outcome of death and or neurodisability. However, an a-priori subgroup analysis shows benefit in the cognitive Bayley scores, favoring high hemoglobins. SUMMARY: This field is plagued by lack of replication, small studies and speculative findings. Hence, the risk-benefit ratio of blood transfusions for preterms still needs adequate definition. Evidence suggests that a restrictive hemoglobin, hematocrit threshold or both for transfusion decreases the number of blood transfusions in preterm infants. However, uncertainty remains on long-term outcomes. Large randomized controlled trials are needed to clarify the safety of a lower threshold or the longer-term benefit of a high threshold.