Timing of Red Blood Cell Transfusions and Occurrence of Necrotizing Enterocolitis: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Observational studies often report that anemia and red blood cell (RBC) transfusions are associated with a higher risk of necrotizing enterocolitis (NEC) among extremely low-birthweight (ELBW) infants. Objective: To evaluate whether there is a temporal association between 72-hour hazard periods of exposure to RBC transfusions and NEC among ELBW infants randomized to either higher or lower hemoglobin transfusion thresholds. Design, Setting, and Participants: This post hoc secondary analysis of 1690 ELBW infants who survived to postnatal day 10 enrolled in the Transfusion of Prematures (TOP) randomized multicenter trial between December 1, 2012, and April 12, 2017, was performed between June 2021 and July 2023. Exposures: First, the distribution of RBC transfusions and the occurrence of NEC up to postnatal day 60 were examined. Second, 72-hour posttransfusion periods were categorized as hazard periods and the pretransfusion periods of variable duration as control periods. Then, the risk of NEC in posttransfusion hazard periods was compared with that in pretransfusion control periods, stratifying the risk based on randomization group (higher or lower hemoglobin transfusion threshold group). Main Outcomes and Measures: The primary outcome was incidence of NEC stage 2 or 3. Secondary outcomes included the incidence rates of NEC within five 10-day intervals, taking into account the number of days at risk. Results: Of 1824 ELBW infants randomized during the TOP trial, 1690 were included in the present analysis (mean [SD] gestational age, 26.0 [1.5] weeks; 899 infants [53.2%] were female). After categorizing 4947 hazard periods and 5813 control periods, we identified 133 NEC cases. Fifty-nine of these cases (44.4%) occurred during hazard periods. Baseline and clinical characteristics of infants with NEC during hazard periods did not differ from those of infants with NEC during control periods. The risk of NEC was 11.9 per 1000 posttransfusion hazard periods and 12.7 per 1000 control periods (adjusted risk ratio, 0.95; 95% CI, 0.68-1.32; P = .74). This risk did not differ significantly between randomization groups, but the incidence rate of NEC per 1000 days peaked between postnatal days 20 and 29 in the lower hemoglobin transfusion threshold group. Conclusions and Relevance: The findings of this post hoc analysis suggest that, among ELBW infants with the hemoglobin ranges occurring in the TOP trial, exposure to RBC transfusions was not temporally associated with a higher risk of NEC during 72-hour posttransfusion hazard periods. Given that the incidence rate of NEC peaked between postnatal days 20 and 29 among infants with lower hemoglobin values, a more in-depth examination of this at-risk period using larger data sets is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Neurodevelopmental Outcomes of Extremely Preterm Infants Fed Donor Milk or Preterm Infant Formula: A Randomized Clinical Trial.

Importance: Maternal milk feeding of extremely preterm infants during the birth hospitalization has been associated with better neurodevelopmental outcomes compared with preterm formula. For infants receiving no or minimal maternal milk, it is unknown whether donor human milk conveys similar neurodevelopmental advantages vs preterm formula. Objective: To determine if nutrient-fortified, pasteurized donor human milk improves neurodevelopmental outcomes at 22 to 26 months' corrected age compared with preterm infant formula among extremely preterm infants who received minimal maternal milk. Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 15 US academic medical centers within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants younger than 29 weeks 0 days' gestation or with a birth weight of less than 1000 g were enrolled between September 2012 and March 2019. Intervention: Preterm formula or donor human milk feeding from randomization to 120 days of age, death, or hospital discharge. Main Outcomes and Measures: The primary outcome was the Bayley Scales of Infant and Toddler Development (BSID) cognitive score measured at 22 to 26 months' corrected age; a score of 54 (score range, 54-155; a score of ≥85 indicates no neurodevelopmental delay) was assigned to infants who died between randomization and 22 to 26 months' corrected age. The 24 secondary outcomes included BSID language and motor scores, in-hospital growth, necrotizing enterocolitis, and death. Results: Of 1965 eligible infants, 483 were randomized (239 in the donor milk group and 244 in the preterm formula group); the median gestational age was 26 weeks (IQR, 25-27 weeks), the median birth weight was 840 g (IQR, 676-986 g), and 52% were female. The birthing parent's race was self-reported as Black for 52% (247/478), White for 43% (206/478), and other for 5% (25/478). There were 54 infants who died prior to follow-up; 88% (376/429) of survivors were assessed at 22 to 26 months' corrected age. The adjusted mean BSID cognitive score was 80.7 (SD, 17.4) for the donor milk group vs 81.1 (SD, 16.7) for the preterm formula group (adjusted mean difference, -0.77 [95% CI, -3.93 to 2.39], which was not significant); the adjusted mean BSID language and motor scores also did not differ. Mortality (death prior to follow-up) was 13% (29/231) in the donor milk group vs 11% (25/233) in the preterm formula group (adjusted risk difference, -1% [95% CI, -4% to 2%]). Necrotizing enterocolitis occurred in 4.2% of infants (10/239) in the donor milk group vs 9.0% of infants (22/244) in the preterm formula group (adjusted risk difference, -5% [95% CI, -9% to -2%]). Weight gain was slower in the donor milk group (22.3 g/kg/d [95% CI, 21.3 to 23.3 g/kg/d]) compared with the preterm formula group (24.6 g/kg/d [95% CI, 23.6 to 25.6 g/kg/d]). Conclusions and Relevance: Among extremely preterm neonates fed minimal maternal milk, neurodevelopmental outcomes at 22 to 26 months' corrected age did not differ between infants fed donor milk or preterm formula. Trial Registration: ClinicalTrials.gov Identifier: NCT01534481.

Social Determinants of Health and Redirection of Care for Infants Born Extremely Preterm.

Importance: Redirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding. Objective: To examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm. Design, Setting, and Participants: This is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks' gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic). Main Outcomes and Measures: The primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks' gestation, death and neurodevelopmental impairment at 22 to 26 months' corrected age. Results: Of the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type. Conclusions and Relevance: For infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

Association of maternal pre-pregnancy or first trimester body mass index with neurodevelopmental impairment or death in extremely low gestational age neonates.

OBJECTIVE: To compare the rates of death or survival with severe neurodevelopmental impairment (sNDI) at 2 years among extremely preterm infants in relation to pre-pregnancy or first-trimester maternal body mass index (BMI). METHODS: This retrospective cohort study included extremely preterm infants (gestational age 220/7-266/7 weeks). The study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. The primary outcome was death or sNDI at 2 years. RESULTS: Data on the primary outcome were available for 1208 children. Death or sNDI was not different among the three groups: 54.9% in normal, 56.1% in overweight, and 53.4% in obese group (p = 0.39). There was no significant difference in mortality, sNDI, moderate/severe cerebral palsy, Bayley Scales of Infant Development (BSID)-III cognitive composite score <70, BSID-III language composite score <70 in adjusted models. CONCLUSION: Neurodevelopmental outcome was not significantly associated with maternal pre-pregnancy BMI among extreme preterm infants.

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.

Secular Trends in Patent Ductus Arteriosus Management in Infants Born Preterm in the National Institute of Child Health and Human Development Neonatal Research Network.

We evaluated changes in patent ductus arteriosus (PDA) diagnosis and treatment from 2012 through 2021 in a network of US academic hospitals. PDA treatment decreased among infants born at 26-28 weeks but not among infants born at 22-25 weeks. Rates of indomethacin use and PDA ligation decreased while acetaminophen use and transcatheter PDA closure increased.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Importance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Serum ferritin values in neonates <29 weeks' gestation are highly variable and do not correlate with reticulocyte hemoglobin content.

OBJECTIVES: To compare serum ferritin and RET-He values among extremely low gestational age neonates ELGANs with other markers of iron-deficient erythropoiesis. STUDY DESIGN: This is a secondary analysis of the NICHD Darbepoetin Trial. Study data from placebo recipients who had a serum ferritin, a RET-He, and a mean corpuscular volume (MCV) measurement within a 24-hour period were analyzed for correlation. RESULTS: Mixed linear regression models showed no association between ferritin and RET-He at both early (ß = 0.0016, p = 0.40) and late (ß = -0.0001, p = 0.96) time points. Positive associations were observed between RET-He and MCV at baseline, early, and late time points (p < 0.01, =0.01, <0.001, respectively), while ferritin was not associated with MCV at any time point. CONCLUSIONS: Our study shows that RET-He is better correlated with MCV as a marker of iron-limited erythropoiesis than ferritin. The results suggest that ferritin is limited as a marker of iron sufficiency in premature infants. STUDY IDENTIFICATION: FDA IND Number 100138; ClinicalTrials.gov number NCT03169881; NRN ID number NICHD-NRN-0058 (Darbe).

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.

Red Blood Cell Transfusion Thresholds for Anemia of Prematurity.

Anemia of prematurity affects the majority of preterm infants, particularly extremely low birthweight infants. Anemia of prematurity arises from both innate and iatrogenic causes and results in more than 80% of extremely preterm infants receiving red blood cell transfusions during the first month after birth. Multiple randomized controlled trials were conducted to evaluate the effect of using lower versus higher transfusion thresholds based on hemoglobin levels. These trials showed no difference in the primary outcome of neurodevelopmental impairment at 2 years of age between lower and higher thresholds. However, some uncertainties about transfusion thresholds remain. This review elaborates the following: 1) the etiology, prevention, and treatment of anemia of prematurity with a focus on red blood cell transfusions, 2) the history of randomized controlled trials on the treatment of anemia of prematurity, and 3) limitations of the evidence and remaining questions about thresholds for red blood cell transfusions in preterm infants.

Early-Life Outcomes in Relation to Social Determinants of Health for Children Born Extremely Preterm.

OBJECTIVE: To characterize the relationships between social determinants of health (SDOH) and outcomes for children born extremely preterm. STUDY DESIGN: This is a cohort study of infants born at 22-26 weeks of gestation in National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2017) who survived to discharge. Infants were classified by 3 maternal SDOH: education, insurance, and race. Outcomes included postmenstrual age (PMA) at discharge, readmission, neurodevelopmental impairment (NDI), and death postdischarge. Regression analyses adjusted for center, perinatal characteristics, neonatal morbidity, ethnicity, and 2 SDOH (eg, group comparisons by education adjusted for insurance and race). RESULTS: Of 7438 children, 5442 (73%) had at least 1 risk-associated SDOH. PMA at discharge was older (adjusted mean difference 0.37 weeks, 95% CL 0.06, 0.68) and readmission more likely (aOR 1.27, 95% CL 1.12, 1.43) for infants whose mothers had public/no insurance vs private. Neither PMA at discharge nor readmission varied by education or race. NDI was twice as likely (aOR 2.36, 95% CL 1.86, 3.00) and death 5 times as likely (aOR 5.22, 95% CL 2.54, 10.73) for infants with 3 risk-associated SDOH compared with those with none. CONCLUSIONS: Children born to mothers with public/no insurance were older at discharge and more likely to be readmitted than those born to privately insured mothers. NDI and death postdischarge were more common among children exposed to multiple risk-associated SDOH at birth compared with those not exposed. Addressing disparities due to maternal education, insurance coverage, and systemic racism are potential intervention targets to improve outcomes for children born preterm.

Trends in fetal and neonatal outcomes during the COVID-19 pandemic in Alabama.

BACKGROUND: The current study evaluated the hypothesis that the COVID-19 pandemic is associated with higher stillbirth but lower neonatal mortality rates. METHODS: We compared three epochs: baseline (2016-2019, January-December, weeks 1-52, and 2020, January-February, weeks 1-8), initial pandemic (2020, March-December, weeks 9-52, and 2021, January-June, weeks 1-26), and delta pandemic (2021, July-September, weeks 27-39) periods, using Alabama Department of Public Health database including deliveries with stillbirths ≥20 weeks or live births ≥22 weeks gestation. The primary outcomes were stillbirth and neonatal mortality rates. RESULTS: A total of 325,036 deliveries were included (236,481 from baseline, 74,076 from initial pandemic, and 14,479 from delta pandemic period). The neonatal mortality rate was lower in the pandemic periods (4.4 to 3.5 and 3.6/1000 live births, in the baseline, initial, and delta pandemic periods, respectively, p < 0.01), but the stillbirth rate did not differ (9 to 8.5 and 8.6/1000 births, p = 0.41). On interrupted time-series analyses, there were no significant changes in either stillbirth (p = 0.11 for baseline vs. initial pandemic period, and p = 0.67 for baseline vs. delta pandemic period) or neonatal mortality rates (p = 0.28 and 0.89, respectively). CONCLUSIONS: The COVID-19 pandemic periods were not associated with a significant change in stillbirth and neonatal mortality rates compared to the baseline period. IMPACT: The COVID-19 pandemic could have resulted in changes in fetal and neonatal outcomes. However, only a few population-based studies have compared the risk of fetal and neonatal mortality in the pandemic period to the baseline period. This population-based study identifies the changes in fetal and neonatal outcomes during the initial and delta COVID-19 pandemic period as compared to the baseline period. The current study shows that stillbirth and neonatal mortality rates were not significantly different in the initial and delta COVID-19 pandemic periods as compared to the baseline period.

Insulin, Testosterone, and Albumin in Term and Preterm Breast Milk, Donor Milk, and Infant Formula.

BACKGROUND: Infants have three options for feeding: their own mother's breast milk, donor milk, or infant formula. Insulin, testosterone, total protein, and albumin levels were measured in breast milk samples from the first 6 months of lactation, in donor milk samples, and in different infant formulas. METHODS: Mothers who gave birth to term (n = 19) or preterm (n = 19) infants were recruited to collect breast milk samples during the first 6 months of lactation. The Breast Milk Collection Center (Unified Health Institution, Pécs, Hungary) provided 96 donor milk (DM) samples for analysis in our study. Insulin, testosterone, total protein, and albumin levels were measured in breast milk, donor milk, and infant formulas. RESULTS: During the first 2 months of lactation, the concentration of insulin was lower (-27.4%) while the testosterone concentration was higher (+20.8%) compared to the period between the 3rd and 6th months only in the preterm breast milk samples. The infant formulas examined did not contain insulin or testosterone. Holder pasteurization (HoP) did not influence the level of testosterone in human milk, although HoP decreased the insulin (-53.6%) and albumin (-38.6%) concentrations. CONCLUSIONS: Diet impacts the hormone intake of infants, underlining the importance of breastfeeding and the possible supplementation of formula-fed infants.

Relationships between retinopathy of prematurity without ophthalmologic intervention and neurodevelopment and vision at 2 years.

BACKGROUND: Severe retinopathy of prematurity (ROP) is associated with adverse outcomes. Relationships between milder ROP and outcomes have not been defined. We hypothesized that children with ROP stage ≤3 who did not receive ophthalmologic intervention would have worse motor, cognitive, and language skills and more vision abnormalities than children without ROP. METHODS: This was a secondary analysis of a randomized trial evaluating the effects of myo-inositol on ROP in the NICHD Neonatal Research Network. Primary outcomes were Bayley Scales of Infant Development composite scores; secondary outcomes included behavioral difficulties and ophthalmologic measures. Outcomes were compared using adjusted linear or modified Poisson models. RESULTS: Of 506 children, 173 (34%) had no ROP, 262 (52%) had ROP stage ≤3 without intervention, and 71 (14%) had ROP with intervention. There was no difference in motor, cognitive, or language scores between children with ROP stage ≤3 without intervention and children without ROP. Children with ROP stage ≤3 without intervention had a higher rate of strabismus compared to children without ROP (p = 0.040). CONCLUSION: Children with ROP stage ≤3 without intervention did not have adverse neurodevelopmental outcomes at 2 years' corrected age compared to children without ROP but did have an increased incidence of strabismus. IMPACT: This study addresses a gap in the literature regarding the relationship between milder forms of retinopathy of prematurity (ROP) that regress without intervention and neurodevelopment and vision outcomes. Children with a history of ROP stage ≤3 without intervention have similar neurodevelopmental outcomes at 2 years' corrected age as children born extremely preterm without a history of ROP and better outcomes than children with a history of ROP with ophthalmologic intervention. Counseling about likely neurodevelopment and vision outcomes for children born extremely preterm with a history of ROP may be tailored based on the severity of ROP. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID: Inositol to Reduce Retinopathy of Prematurity Trial: NCT01954082.

Incidence of and Neurodevelopmental Outcomes After Late-Onset Meningitis Among Children Born Extremely Preterm.

Importance: Late-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm. Objective: To report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months' corrected age. Design, Setting, and Participants: This cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks' gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers. Exposures: Culture-confirmed LOM. Main Outcomes and Measures: Incidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021). Results: Among 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection. Conclusions and Relevance: In this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Association of Antenatal Steroid Exposure at 21 to 22 Weeks of Gestation With Neonatal Survival and Survival Without Morbidities.

Importance: The provision of antenatal corticosteroids to pregnant patients at gestational age (GA) 22 6/7 weeks or less remains controversial and lacks support from randomized clinical trials. Objective: To compare rates of survival and survival without major morbidities among infants born at GA 22 0/7 to 23 6/7 weeks after exposure to antenatal steroids at 22 6/7 weeks' gestation or less vs no exposure to antenatal steroids. Design, Setting, and Participants: This cohort study enrolled infants born at GA 22 0/7 to 23 6/7 weeks between January 1, 2016, and December 31, 2019, at centers in the National Institute of Child Health and Human Development Neonatal Research Network. Infants who did not receive intensive care and infants with antenatal steroid exposure after GA 22 6/7 weeks were excluded. Exposure: Infants were classified as having no, partial, or complete exposure to antenatal steroids. Main Outcomes and Measures: The primary outcome was survival to discharge. The main secondary outcome was survival without major neonatal morbidity. The associations of differential exposures to antenatal steroids with outcomes were evaluated using logistic regression, adjusting for GA, sex, race, maternal education, small for GA status, mode of delivery, multiple birth, prolonged rupture of membranes, year of birth, and Neonatal Research Network center. Results: A total of 431 infants (mean [SD] GA, 22.6 [0.5] weeks; 232 [53.8%] boys) were included, with 110 infants (25.5%) receiving no antenatal steroids, 80 infants (18.6%) receiving partial antenatal steroids, and 241 infants (55.9%) receiving complete antenatal steroids. Seventeen infants were exposed to antenatal steroids at GA 21 weeks. Among infants exposed to complete antenatal steroids, 130 (53.9%) survived to discharge, compared with 30 infants (37.5%) with partial antenatal steroid exposure and 239 infants (35.5%) with no antenatal steroids. Infants born after complete antenatal steroid exposure, compared with those without antenatal steroid exposure, were more likely to survive to discharge (adjusted odds ratio [aOR], 1.95 [95% CI, 1.07-3.56]) and to survive without major morbidity (aOR, 2.74 [95% CI, 1.19-6.30]). Conclusions and Relevance: In this retrospective cohort study, among infants born between GA 22 0/7 and 23 6/7 weeks who received intensive care, exposure to a complete course of antenatal steroids at GA 22 6/7 weeks or less was independently associated with greater odds of survival and survival without major morbidity. These data suggest that the use of antenatal steroids in patients at GA 22 6/7 weeks or less could be beneficial when active treatment is considered.

Duration of skin-to-skin care and rectal temperatures in late preterm and term infants.

BACKGROUND: Hypothermia during the newborn period is widely regarded as a major contributory cause of significant morbidity and mortality of newborn infants. Thermoprotective behaviours such as skin-to-skin care (SSC) or the use of appropriate devices have been recommended as simple tools for the avoidance of neonatal hypothermia. We examined the relation between the duration of skin-to-skin care and infant temperature change after birth in suboptimal delivery room temperatures. METHODS: We reviewed the medical charts of all vaginally born infants of gestational age ≥ 35 weeks born January-July 2018 and admitted to the well-baby nursery. After SSC was discontinued, the infant's rectal temperature was measured to determine the frequency and severity of hypothermia. RESULTS: The charts of 688 vaginally born infants were examined. Our mean delivery room temperature was 21.7 (SD 2.2) °C, well below the WHO recommendation of 25 °C. After SSC 347 (50.4%) infants were normothermic (temperature 36.5-37.5 °C), 262 (38.0%) were mildly hypothermic (36.0-36.4 °C), and 79 (11.4%) were moderately hypothermic (32.0-35.9 °C). The mean skin-to-skin time in infants was 63.9 (SD 20.9) minutes. SSC duration was associated with increase in rectal temperature for patients of gestational ages ≥ 38 weeks and with decrease in rectal temperature in patients of gestational age < 38 weeks. CONCLUSION: SSC is effective, even at suboptimal delivery room temperatures, for promoting normothermia in infants of ≥ 38 weeks' gestation but may not provide adequate warmth for infants of < 38 weeks.

Outcome prediction in newborn infants: Past, present, and future.

The perinatal and neonatal periods are the periods of considerable organ development and maturation. Perinatal and neonatal illnesses can result in mortality and morbidities that burden families and the healthcare system. Outcome prediction is essential for informing perinatal and intensive care management, prognosis, and post-discharge interventions. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) research databases include hospital and neurodevelopment follow-up outcomes of infants with various underlying diseases and conditions receiving intensive care, providing a unique opportunity to assess outcome risk prediction. The NRN has developed outcome risk prediction tools for use in infants with various diseases and conditions that allow data-driven, transparent discussions to inform family-focused communications and clinical management. This review presents the published neonatal outcome risk prediction research from the NRN, their present clinical utility, and possible future directions for advanced individualized risk prediction.

Contributions of the NICHD neonatal research network's generic database to documenting and advancing the outcomes of extremely preterm infants.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) maintains a database of extremely preterm infants known as the Generic Database (GDB). Begun in 1987, this database now includes more than 91,000 infants, most of whom are extremely preterm (<29 weeks gestation). The GDB has been the backbone of the NRN, providing high quality, prospectively collected data to study the changing epidemiology of extreme prematurity and its outcomes over time. In addition, GDB data have been used to generate hypotheses for prospective studies and to develop new clinical trials by providing information about the numbers and characteristics of available subjects and the expected event rates for conditions and complications to be studied. Since its inception, the GDB has been the basis of more than 200 publications in peer-reviewed journals, many of which have had a significant impact on the field of neonatology.

Potential missed opportunities for antenatal corticosteroid exposure and outcomes among periviable births: observational cohort study.

OBJECTIVE: Test the hypothesis potential missed opportunities for antenatal corticosteroids increase as gestational age decreases and are associated with adverse outcomes. DESIGN: Observational cohort study. SETTING: 24 US centers in the Neonatal Research Network. POPULATION: Actively treated infants 22-25 weeks' gestation and birth weight 401-1000 grams, without major birth defects, born 2006-2018. METHODS: Potential missed opportunity was defined as no antenatal corticosteroids but did have prenatal antibiotics, and/or magnesium sulfate, and/or prolonged rupture of membranes. Poisson regression models adjusted for baseline characteristics. MAIN OUTCOME MEASURES: Antenatal corticosteroid exposure, mortality, and severe intracranial hemorrhage or periventricular leukomalacia. RESULTS: 6966 (87.5%) were exposed to antenatal corticosteroids, 454 (5.7%) had no exposure but potential missed opportunities for antenatal corticosteroid exposure, and 537 (6.7%) had no exposure and no evidence of potential missed opportunities. Compared with infants born at 25 weeks, potential missed opportunities for antenatal corticosteroid exposure were more likely at 22 weeks (adjusted relative risk (aRR) [95% CI] 11.06 [7.52-16.27]) and 23 weeks (3.24 [2.44-4.29]) but did not differ at 24 weeks (1.08 [0.82-1.42]). Potential missed opportunities for antenatal corticosteroids decreased over time at 22-23 weeks' gestation. Antenatal corticosteroid exposed infants had lower risk of death (31.0% vs 54.8%; 0.77 [0.70-0.84]) and survivors had lower risk of severe brain injury (25.0% v 44.5%; 0.64 [0.55-0.73]) compared with infants with potential missed opportunities. CONCLUSION: Potential missed opportunities for antenatal corticosteroid exposure increased with decreasing gestational age and were associated with higher rates of death and severe brain injury among actively treated periviable births.