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.

Motivations for and against Participation in Neonatal Research: Insights from Interviews of Diverse Parents Approached for Neonatal Research in the US.

OBJECTIVE: To describe parents' motivations for and against participation in neonatal research, including the views of those who declined participation. STUDY DESIGN: We performed 44 semi-structured, qualitative interviews of parents approached for neonatal research. Here we describe their motivations for and against participation. RESULTS: Altruism was an important reason parents chose to participate. Some hoped participation in research would benefit their infant. Burdens of participation to the family, such as transportation to follow up (distinct from risks/burdens to the infant), were often deciding factors among those who declined participation. Perceived risks to the infant were reasons against participation, but parents often did not differentiate between baseline risks and incremental risk of study participation. Concerns regarding their infant being treated like a "guinea pig" were common among those who declined. Finally, historical abuses and institutional racism were reported as important concerns by some research decliners from minoritized populations. CONCLUSIONS: Within a diverse sample of parents approached to enroll their infant in neonatal research, motivations for and against participation emerged, which may be targets of future interventions. These motivations included reasons for participation which we may hope to encourage, such as altruism. They also included reasons against participation, which we may hope to, as feasible, eliminate, mitigate, or at least acknowledge. These findings can help clinical trialists, regulators, and funders attempting to improve neonatal research recruitment processes.

Social distancing and extremely preterm births in the initial COVID-19 pandemic period.

HYPOTHESIS: Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period. STUDY DESIGN: Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (220/7-286/7 weeks) and extremely preterm intrapartum stillbirths (EPIS) rates during the pandemic period (March-July, weeks 9-30 of 2020) with the reference period (same weeks in 2018 and 2019), correlating with state-specific social distancing index (SDI). RESULTS: EPLB and EPIS percentages did not significantly decrease (1.58-1.45%, p = 0.07, and 0.08-0.06%, p = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = -0.12, 0.71) or EPIS (CC = -0.23, 95% CI = -0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91). CONCLUSIONS: Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births. GOV ID: Generic Database: NCT00063063.

A Prospective Multi-Institutional Study Comparing the Brain Development in the Third Trimester between Opioid-Exposed and Nonexposed Fetuses Using Advanced Fetal MR Imaging Techniques.

BACKGROUND AND PURPOSE: While the adverse neurodevelopmental effects of prenatal opioid exposure on infants and children in the United States are well described, the underlying causative mechanisms have yet to be fully understood. This study aims to compare quantitative volumetric and surface-based features of the fetal brain between opioid-exposed fetuses and unexposed controls by using advanced MR imaging processing techniques. MATERIALS AND METHODS: This is a multi-institutional IRB-approved study in which pregnant women with and without opioid use during the current pregnancy were prospectively recruited to undergo fetal MR imaging. A total of 14 opioid-exposed (31.4 ± 2.3 weeks of gestation) and 15 unexposed (31.4 ± 2.4 weeks) fetuses were included. Whole brain volume, cortical plate volume, surface area, sulcal depth, mean curvature, and gyrification index were computed as quantitative features by using our fetal brain MR imaging processing pipeline. RESULTS: After correcting for gestational age, fetal sex, maternal education, polysubstance use, high blood pressure, and MR imaging acquisition site, all of the global morphologic features were significantly lower in the opioid-exposed fetuses compared with the unexposed fetuses, including brain volume, cortical volume, cortical surface area, sulcal depth, cortical mean curvature, and gyrification index. In regional analysis, the opioid-exposed fetuses showed significantly decreased surface area and sulcal depth in the bilateral Sylvian fissures, central sulci, parieto-occipital fissures, temporal cortices, and frontal cortices. CONCLUSIONS: In this small cohort, prenatal opioid exposure was associated with altered fetal brain development in the third trimester. This adds to the growing body of literature demonstrating that prenatal opioid exposure affects the developing brain.

Prenatal Opioid Exposure and Risk for Adverse Brain and Motor Outcomes in Infants Born Premature.

OBJECTIVE: To compare brain magnetic resonance imaging (MRI) biomarkers and neurodevelopmental test scores in infants born preterm with and without prenatal opioid exposure (POE). STUDY DESIGN: We examined 395 preterm infants (≤32 weeks gestational age) who had term-equivalent brain MRIs, composite scores from the Bayley Scales of Infant and Toddler Development-III at 2 years corrected age, and POE data. MRI parameters included total/regional brain volumes and severe punctate white matter lesions (PWMLs). We conducted bivariable analysis and multivariable logistic regression analyses. RESULTS: The mean ± SD gestational age was 29.3 ± 2.5 weeks; 35 (8.9%) had POE and 20 (5.1%) had severe PWML. Compared with unexposed infants, those with POE exhibited higher rates of severe PWML (17.1% vs 3.9%, respectively; P = .002); findings remained significant with an OR of 4.16 (95% CI, 1.26-13.68) after adjusting for confounders. On mediation analysis, the significant relationship between POE and severe PWML was not indirectly mediated through preterm birth/gestational age (OR, 0.93; 95% CI, 0.78-1.10), thus suggesting the association was largely driven by a direct adverse effect of POE on white matter. In multivariable analyses, POE was associated with a significantly lower score by -6.2 (95% CI, -11.8 to -0.6) points on the Bayley Scales of Infant and Toddler Development-III Motor subscale compared with unexposed infants. CONCLUSIONS: POE was associated with severe PWML; this outcome may be a direct effect of POE rather than being mediated by premature birth. POE was also associated with worse motor development. Continued follow-up to understand the long-term effects of POE is warranted.

Experiences and preferences for learning about neonatal research: insights from parent interviews.

INTRODUCTION: Parents struggle with being asked to participate in neonatal research. Past work has largely failed to include views of minoritized parents, low-socioeconomic status parents, and those who declined research. We aimed to describe parents' preferences related to learning about eligibility for neonatal research. METHODS: Qualitative interviews of parents who were asked to enroll their infant in neonatal research. Themes related to parental experiences and preferences for learning about neonatal research were identified using content analysis. RESULTS: Many parents desired greater involvement of their clinical team. Emotions at the time of recruitment were critically important to parents' experience, where were deeply impacted by interpersonal relationships with research staff. DISCUSSION: Increased involvement of the clinical team and greater sensitivity to the stressors around parent and infant conditions at the time of recruitment for neonatal research should be considered by those attempting to improve recruitment for neonatal research.

Correlation of NICU anthropometry in extremely preterm infants with brain development and language scores at early school age.

Growth in preterm infants in the neonatal intensive care unit (NICU) is associated with increased global and regional brain volumes at term, and increased postnatal linear growth is associated with higher language scores at age 2. It is unknown whether these relationships persist to school age or if an association between growth and cortical metrics exists. Using regression analyses, we investigated relationships between the growth of 42 children born extremely preterm (< 28 weeks gestation) from their NICU hospitalization, standardized neurodevelopmental/language assessments at 2 and 4-6 years, and multiple neuroimaging biomarkers obtained from T1-weighted images at 4-6 years. We found length at birth and 36 weeks post-menstrual age had positive associations with language scores at 2 years in multivariable linear regression. No growth metric correlated with 4-6 year assessments. Weight and head circumference at 36 weeks post-menstrual age positively correlated with total brain volume and negatively with global cortical thickness at 4-6 years of age. Head circumference relationships remained significant after adjusting for age, sex, and socioeconomic status. Right temporal cortical thickness was related to receptive language at 4-6 years in the multivariable model. Results suggest growth in the NICU may have lasting effects on brain development in extremely preterm children.

Use of term reference infants in assessing the developmental outcome of extremely preterm infants: lessons learned in a multicenter study.

OBJECTIVE: Extremely preterm (EP) impairment rates are likely underestimated using the Bayley III norm-based thresholds scores and may be better assessed relative to concurrent healthy term reference (TR) infants born in the same hospital. STUDY DESIGN: Blinded, certified examiners in the Neonatal Research Network (NRN) evaluated EP survivors and a sample of healthy TR infants recruited near the 2-year assessment age. RESULTS: We assessed 1452 EP infants and 183 TR infants. TR-based thresholds showed higher overall EP impairment than Bayley norm-based thresholds (O.R. = 1.86; [95% CI 1.56-2.23], especially for severe impairment (36% vs. 24%; p ≤ 0.001). Difficulty recruiting TR patients at 2 years extended the study by 14 months and affected their demographics. CONCLUSION: Impairment rates among EP infants appear to be substantially underestimated from Bayley III norms. These rates may be best assessed by comparison with healthy term infants followed with minimal attrition from birth in the same centers. GOV ID: Term Reference (under the Generic Database Study): NCT00063063.

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.).

Neonatal Opioid Withdrawal Syndrome: An Update on Developmental Outcomes.

Infants and children with prenatal opioid exposure generally have development within the normal range; however, they seem to be at risk for behavioral problems and for lower scores on cognitive, language, and motor assessments than children without prenatal opioid exposure. It is as of yet unclear whether prenatal opioid exposure itself causes issues with development and behavior, or whether it is simply correlated, due to other confounding factors.

The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: (1) To evaluate the direct (un-mediated) and indirect (mediated) relationship between antenatal exposure to opioid agonist medication as treatment for opioid use disorder (MOUD) and the severity of neonatal opioid withdrawal syndrome (NOWS), and (2) to understand the degree to which mediating factors influence the direct relationship between MOUD exposure and NOWS severity. METHODS: This cross-sectional study includes data abstracted from the medical records of 1294 opioid-exposed infants (859 MOUD exposed and 435 non-MOUD exposed) born at or admitted to one of 30 US hospitals from July 1, 2016, to June 30, 2017. Regression models and mediation analyses were used to evaluate the relationship between MOUD exposure and NOWS severity (i.e., infant pharmacologic treatment and length of newborn hospital stay (LOS)) to identify potential mediators of this relationship in analyses adjusted for confounding factors. RESULTS: A direct (un-mediated) association was found between antenatal exposure to MOUD and both pharmacologic treatment for NOWS (aOR 2.34; 95%CI 1.74, 3.14) and an increase in LOS (1.73 days; 95%CI 0.49, 2.98). Delivery of adequate prenatal care and a reduction in polysubstance exposure were mediators of the relationship between MOUD and NOWS severity and as thus, were indirectly associated with a decrease in both pharmacologic treatment for NOWS and LOS. CONCLUSIONS FOR PRACTICE: MOUD exposure is directly associated with NOWS severity. Prenatal care and polysubstance exposure are potential mediators in this relationship. These mediating factors may be targeted to reduce the severity of NOWS while maintaining the important benefits of MOUD during pregnancy.

MRI Findings in Third-Trimester Opioid-Exposed Fetuses, With Focus on Brain Measurements: A Prospective Multicenter Case-Control Study.

BACKGROUND. The opioid epidemic has profoundly affected infants born in the United States, as in utero opioid exposure increases the risk of cognitive and behavioral problems in childhood. Scarce literature has evaluated prenatal brain development in fetuses with opioid exposure in utero (hereafter opioid-exposed fetuses). OBJECTIVE. The purpose of this study is to compare opioid-exposed fetuses and fetuses without opioid exposure (hereafter unexposed fetuses) in terms of 2D biometric measurements of the brain and additional pregnancy-related assessments on fetal MRI. METHODS. This prospective case-control study included patients in the third trimester of pregnancy who underwent investigational fetal MRI at one of three U.S. academic medical centers from July 1, 2020, through December 31, 2021. Fetuses were classified as opioid exposed or unexposed in utero. Fourteen 2D biometric measurements of the fetal brain were manually assessed and used to derive four indexes. Measurements and indexes were compared between the two groups by use of multivariable linear regression models, which were adjusted for gestational age (GA), fetal sex, and nicotine exposure. Additional pregnancy-related findings on MRI were evaluated. RESULTS. The study included 65 women (mean age, 29.0 ± 5.5 [SD] years). A total of 28 fetuses (mean GA at the time of MRI, 32.2 ± 2.5 weeks) were opioid-exposed, and 37 fetuses (mean GA at the time of MRI, 31.9 ± 2.7 weeks) were unexposed. In the adjusted models, seven measurements were smaller (p < .05) in opioid-exposed fetuses than in unexposed fetuses: cerebral frontooccipital diameter (93.8 ± 7.4 vs 95.0 ± 8.6 mm), bone biparietal diameter (79.0 ± 6.0 vs 80.3 ± 7.1 mm), brain biparietal diameter (72.9 ± 7.7 vs 74.1 ± 8.6 mm), corpus callosum length (37.7 ± 4.0 vs 39.4 ± 3.7 mm), vermis height (18.2 ± 2.7 vs 18.8 ± 2.6 mm), anteroposterior pons measurement (11.6 ± 1.4 vs 12.1 ± 1.4 mm), and transverse cerebellar diameter (40.4 ± 5.1 vs 41.4 ± 6.0 mm). In addition, in the adjusted model, the frontoocccipital index was larger (p = .02) in opioid-exposed fetuses (0.04 ± 0.02) than in unexposed fetuses (0.04 ± 0.02). Remaining measures and indexes were not significantly different between the two groups (p > .05). Fetal motion, cervical length, and deepest vertical pocket of amniotic fluid were not significantly different (p > .05) between groups. Opioid-exposed fetuses, compared with unexposed fetuses, showed higher frequencies of both breech position (21% vs 3%, p = .03) and increased amniotic fluid volume (29% vs 8%, p = .04). CONCLUSION. Fetuses with opioid exposure in utero had a smaller brain size and altered fetal physiology. CLINICAL IMPACT. The findings provide insight into the impact of prenatal opioid exposure on fetal brain development.

The critical importance of follow-up to school age: Contributions of the NICHD Neonatal Research Network.

Follow-up studies are essential for understanding outcomes and informing the care of infants with high risk for medical and developmental consequences because of extreme prematurity or perinatal illness. Studies that extend to school age often identify sequelae that go unrecognized in neonatal or short-term follow-up studies. Many critical neurocognitive, behavioral, functional, and health outcomes are best assessed beginning at school age. The Eunice Kennedy Shriver National Institute of Child Health and Development Neonatal Research Network (NRN) has performed comprehensive school age evaluations of several key trial cohorts. This manuscript summarizes the important contributions of school age follow-up studies in the NRN, both historically and in ongoing research. We describe in detail the clinical questions that have been answered by the completed studies and new questions about the outcomes of high-risk infants that must be addressed by ongoing and future studies.

Neural alterations in opioid-exposed infants revealed by edge-centric brain functional networks.

Prenatal opioid exposure has been linked to adverse effects spanning multiple neurodevelopmental domains, including cognition, motor development, attention, and vision. However, the neural basis of these abnormalities is largely unknown. A total of 49 infants, including 21 opioid-exposed and 28 controls, were enrolled and underwent MRI (43 ± 6 days old) after birth, including resting state functional MRI. Edge-centric functional networks based on dynamic functional connections were constructed, and machine-learning methods were employed to identify neural features distinguishing opioid-exposed infants from unexposed controls. An accuracy of 73.6% (sensitivity 76.25% and specificity 69.33%) was achieved using 10 times 10-fold cross-validation, which substantially outperformed those obtained using conventional static functional connections (accuracy 56.9%). More importantly, we identified that prenatal opioid exposure preferentially affects inter- rather than intra-network dynamic functional connections, particularly with the visual, subcortical, and default mode networks. Consistent results at the brain regional and connection levels were also observed, where the brain regions and connections associated with visual and higher order cognitive functions played pivotal roles in distinguishing opioid-exposed infants from controls. Our findings support the clinical phenotype of infants exposed to opioids in utero and may potentially explain the higher rates of visual and emotional problems observed in this population. Finally, our findings suggested that edge-centric networks could better capture the neural differences between opioid-exposed infants and controls by abstracting the intrinsic co-fluctuation along edges, which may provide a promising tool for future studies focusing on investigating the effects of prenatal opioid exposure on neurodevelopment.

Extracallosal Structural Connectivity Is Positively Associated With Language Performance in Well-Performing Children Born Extremely Preterm.

Children born extremely preterm (<28 weeks gestation) are at risk for language delay or disorders. Decreased structural connectivity in preterm children has been associated with poor language outcome. Previously, we used multimodal imaging techniques to demonstrate that increased functional connectivity during a stories listening task was positively associated with language scores for preterm children. This functional connectivity was supported by extracallosal structural hyperconnectivity when compared to term-born children. Here, we attempt to validate this finding in a distinct cohort of well-performing extremely preterm children (EPT, n = 16) vs. term comparisons (TC, n = 28) and also compare this to structural connectivity in a group of extremely preterm children with a history of language delay or disorder (EPT-HLD, n = 8). All participants are 4-6 years of age. We perform q-space diffeomorphic reconstruction and functionally-constrained structural connectometry (based on fMRI activation), including a novel extension enabling between-groups comparisons with non-parametric ANOVA. There were no significant differences between groups in age, sex, race, ethnicity, parental education, family income, or language scores. For EPT, tracks positively associated with language scores included the bilateral posterior inferior fronto-occipital fasciculi and bilateral cerebellar peduncles and additional cerebellar white matter. Quantitative anisotropy in these pathways accounted for 55% of the variance in standardized language scores for the EPT group specifically. Future work will expand this cohort and follow longitudinally to investigate the impact of environmental factors on developing language networks and resiliency in the preterm brain.

Brain microstructural antecedents of visual difficulties in infants born very preterm.

Infants born very preterm (VPT) are at risk of later visual problems. Although neonatal screening can identify ophthalmologic abnormalities, subtle perinatal brain injury and/or delayed brain maturation may be significant contributors to complex visual-behavioral problems. Our aim was to assess the micro and macrostructural antecedents of early visual-behavioral difficulties in VPT infants by using diffusion MRI (dMRI) at term-equivalent age. We prospectively recruited a cohort of 262 VPT infants (≤32 weeks gestational age [GA]) from five neonatal intensive care units. We obtained structural and diffusion MRI at term-equivalent age and administered the Preverbal Visual Assessment (PreViAs) questionnaire to parents at 3-4 months corrected age. We used constrained spherical deconvolution to reconstruct nine white matter tracts of the visual pathways with high reliability and performed fixel-based analysis to derive fiber density (FD), fiber-bundle cross-section (FC), and combined fiber density and cross-section (FDC). In multiple logistic regression analyses, we related these tract metrics to visual-behavioral function. Of 262 infants, 191 had both high-quality dMRI and completed PreViAs, constituting the final cohort: mean (SD) GA was 29.3 (2.4) weeks, 90 (47.1%) were males, and postmenstrual age (PMA) at MRI was 42.8 (1.3) weeks. FD and FC of several tracts were altered in infants with (N = 59) versus those without retinopathy of prematurity (N = 132). FDC of the left posterior thalamic radiations (PTR), left inferior longitudinal fasciculus (ILF), right superior longitudinal fasciculus (SLF), and left inferior fronto-occipital fasciculus (IFOF) were significantly associated with visual attention scores, prior to adjusting for confounders. After adjustment for PMA at MRI, GA, severe retinopathy of prematurity, and total brain volume, FDC of the left PTR, left ILF, and left IFOF remained significantly associated with visual attention. Early visual-behavioral difficulties in VPT infants are preceded by micro and macrostructural abnormalities in several major visual pathways at term-equivalent age.

Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018.

IMPORTANCE: Despite improvement during recent decades, extremely preterm infants continue to contribute disproportionately to neonatal mortality and childhood morbidity. OBJECTIVE: To review survival, in-hospital morbidities, care practices, and neurodevelopmental and functional outcomes at 22-26 months' corrected age for extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: Prospective registry for extremely preterm infants born at 19 US academic centers that are part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. The study included 10 877 infants born at 22-28 weeks' gestational age between January 1, 2013, and December 31, 2018, including 2566 infants born before 27 weeks between January 1, 2013, and December 31, 2016, who completed follow-up assessments at 22-26 months' corrected age. The last assessment was completed on August 13, 2019. Outcomes were compared with a similar cohort of infants born in 2008-2012 adjusting for gestational age. EXPOSURES: Extremely preterm birth. MAIN OUTCOMES AND MEASURES: Survival and 12 in-hospital morbidities were assessed, including necrotizing enterocolitis, infection, intracranial hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia. Infants were assessed at 22-26 months' corrected age for 12 health and functional outcomes, including neurodevelopment, cerebral palsy, vision, hearing, rehospitalizations, and need for assistive devices. RESULTS: The 10 877 infants were 49.0% female and 51.0% male; 78.3% (8495/10848) survived to discharge, an increase from 76.0% in 2008-2012 (adjusted difference, 2.0%; 95% CI, 1.0%-2.9%). Survival to discharge was 10.9% (60/549) for live-born infants at 22 weeks and 94.0% (2267/2412) at 28 weeks. Survival among actively treated infants was 30.0% (60/200) at 22 weeks and 55.8% (535/958) at 23 weeks. All in-hospital morbidities were more likely among infants born at earlier gestational ages. Overall, 8.9% (890/9956) of infants had necrotizing enterocolitis, 2.4% (238/9957) had early-onset infection, 19.9% (1911/9610) had late-onset infection, 14.3% (1386/9705) had severe intracranial hemorrhage, 12.8% (1099/8585) had severe retinopathy of prematurity, and 8.0% (666/8305) had severe bronchopulmonary dysplasia. Among 2930 surviving infants with gestational ages of 22-26 weeks eligible for follow-up, 2566 (87.6%) were examined. By 2-year follow-up, 8.4% (214/2555) of children had moderate to severe cerebral palsy, 1.5% (38/2555) had bilateral blindness, 2.5% (64/2527) required hearing aids or cochlear implants, 49.9% (1277/2561) had been rehospitalized, and 15.4% (393/2560) required mobility aids or other supportive devices. Among 2458 fully evaluated infants, 48.7% (1198/2458) had no or mild neurodevelopmental impairment at follow-up, 29.3% (709/2419) had moderate neurodevelopmental impairment, and 21.2% (512/2419) had severe neurodevelopmental impairment. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants born in 2013-2018 and treated at 19 US academic medical centers, 78.3% survived to discharge, a significantly higher rate than for infants born in 2008-2012. Among infants born at less than 27 weeks' gestational age, rehospitalization and neurodevelopmental impairment were common at 2 years of age.

Neonatal opioid withdrawal syndrome: a review of the science and a look toward the use of buprenorphine for affected infants.

Neonates born to mothers taking opioids during pregnancy are at risk for neonatal opioid withdrawal syndrome (NOWS), for which there is no recognized standard approach to care. Nonpharmacologic treatment is typically used as a first-line approach for management, and pharmacologic treatment is added when clinical signs are not responding to nonpharmacologic measures alone. Although morphine and methadone are the most commonly used pharmacotherapies for NOWS, buprenorphine has emerged as a treatment option based on its pharmacologic profile and results from initial single site clinical trials. The objective of this report is to provide an overview of NOWS including a summary of ongoing work in the field and to review the state of the science, knowledge gaps, and practical considerations specific to the use of buprenorphine for the treatment of NOWS as discussed by a panel of experts during a virtual workshop hosted by the National Institutes of Health.