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To determine the effect of 3 distinct comparison groups on associations between placental abnormalities and neonatal hypoxic-ischemic encephalopathy (HIE).This single-center, prospective case-control study of singletons of gestational age ≥36 weeks with predefined criteria for HIE (n = 30) and 3 control groups was conducted from June 2015 to January 2018. The control groups were infants born by repeat cesarean delivery (n = 60), infants born small for gestational age (SGA; n = 80), and infants receiving positive-pressure ventilation (PPV) at birth (n = 70). One pathologist blinded to infant category reviewed placental sections using the Amsterdam Placental Workshop criteria. Logistic regression with group contrasts relative to HIE was used to analyze primary placental pathologies, and ORs with 95% CIs provided effect sizes.The odds of maternal vascular malperfusion were increased among HIE group placentas compared with placentas of the repeat cesarean delivery (OR, 4.50; 95% CI, 1.45-14.00) and PPV (3.88; 1.35-11.16) groups, but not those of the SGA group. The odds of fetal vascular malperfusion were increased in the HIE group compared with the SGA group (OR, 9.75; 95% CI, 1.85-51.51). The odds of acute chorioamnionitis were higher in the HIE group compared only with the repeat cesarean delivery group, reflecting a similar incidence of chorioamnionitis in SGA group and PPV group placentas. The absence of placental findings was lowest in the HIE group (6.7%), followed by the SGA (18.8%), PPV (31.4%), and repeat cesarean delivery (75%) groups.Associations with placental abnormalities among infants with HIE varied based on the specific placental abnormality and the control group. Potentially important associations between placental pathology and HIE may be obscured if control groups are not well designed.

The world is witnessing a rising number of preterm infants who are at significant risk of medical conditions. These infants require continuous care in Neonatal Intensive Care Units (NICU). Medical parameters are continuously monitored in premature infants in the NICU using a set of wired, sticky electrodes attached to the body. Medical adhesives used on the electrodes can be harmful to the baby, causing skin injuries, discomfort, and irritation. In addition, respiration rate (RR) monitoring in the NICU faces challenges of accuracy and clinical quality because RR is extracted from electrocardiogram (ECG). This research paper presents a design and validation of a smart textile pressure sensor system that addresses the existing challenges of medical monitoring in NICU. We designed two e-textile, piezoresistive pressure sensors made of Velostat for noninvasive RR monitoring; one was hand-stitched on a mattress topper material, and the other was embroidered on a denim fabric using an industrial embroidery machine. We developed a data acquisition system for validation experiments conducted on a high-fidelity, programmable NICU baby mannequin. We designed a signal processing pipeline to convert raw time-series signals into parameters including RR, rise and fall time, and comparison metrics. The results of the experiments showed that the relative accuracies of hand-stitched sensors were 98.68 (top sensor) and 98.07 (bottom sensor), while the accuracies of embroidered sensors were 99.37 (left sensor) and 99.39 (right sensor) for the 60 BrPM test case. The presented prototype system shows promising results and demands more research on textile design, human factors, and human experimentation.

Objective: To determine the association of persistent pulmonary hypertension of the newborn (PPHN) with death or disability among infants with moderate or severe hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia. Methods: We compared infants with and without PPHN enrolled in the hypothermia arm from three randomized controlled trials (RCTs): Induced Hypothermia trial, “usual-care” arm of Optimizing Cooling trial, and Late Hypothermia trial. Primary outcome was death or disability at 18–22 months adjusted for severity of HIE, center, and RCT. Results: Among 280 infants, 67 (24%) were diagnosed with PPHN. Among infants with and without PPHN, death or disability was 47% vs. 29% (adjusted OR 1.65, 0.86–3.14) and death was 26% vs. 12% (adjusted OR 2.04, 0.92–4.53), respectively. Conclusions: PPHN in infants with moderate or severe HIE was not associated with a statistically significant increase in primary outcome. These results should be interpreted with caution given the limited sample size.

Limited data suggest that higher hemoglobin thresholds for red-cell transfusions may reduce the risk of cognitive delay among extremely-low-birth-weight infants with anemia.We performed an open, multicenter trial in which infants with a birth weight of 1000 g or less and a gestational age between 22 weeks 0 days and 28 weeks 6 days were randomly assigned within 48 hours after delivery to receive red-cell transfusions at higher or lower hemoglobin thresholds until 36 weeks of postmenstrual age or discharge, whichever occurred first. The primary outcome was a composite of death or neurodevelopmental impairment (cognitive delay, cerebral palsy, or hearing or vision loss) at 22 to 26 months of age, corrected for prematurity.A total of 1824 infants (mean birth weight, 756 g; mean gestational age, 25.9 weeks) underwent randomization. There was a between-group difference of 1.9 g per deciliter (19 g per liter) in the pretransfusion mean hemoglobin levels throughout the treatment period. Primary outcome data were available for 1692 infants (92.8%). Of 845 infants in the higher-threshold group, 423 (50.1%) died or survived with neurodevelopmental impairment, as compared with 422 of 847 infants (49.8%) in the lower-threshold group (relative risk adjusted for birth-weight stratum and center, 1.00; 95% confidence interval [CI], 0.92 to 1.10; P = 0.93). At 2 years, the higher- and lower-threshold groups had similar incidences of death (16.2% and 15.0%, respectively) and neurodevelopmental impairment (39.6% and 40.3%, respectively). At discharge from the hospital, the incidences of survival without severe complications were 28.5% and 30.9%, respectively. Serious adverse events occurred in 22.7% and 21.7%, respectively.In extremely-low-birth-weight infants, a higher hemoglobin threshold for red-cell transfusion did not improve survival without neurodevelopmental impairment at 22 to 26 months of age, corrected for prematurity. (Funded by the National Heart, Lung, and Blood Institute and others; TOP ClinicalTrials.gov number, NCT01702805.).

OBJECTIVE The objective of this paper is to compare in-hospital survival and survival without major morbidities in extremely preterm infants in relation to maternal body mass index (BMI). METHODS This retrospective cohort study included extremely preterm infants (gestational age 220/7-286/7 weeks). This study was conducted at National Institute of Child Health and Human Development Neonatal Research Network sites. Primary outcome was survival without any major morbidity. RESULTS Maternal BMI data were available for 2415 infants. Survival without any major morbidity was not different between groups: 30.8% in the underweight/normal, 28.1% in the overweight, and 28.5% in the obese (P = 0.65). However, survival was lower in the obese group (76.5%) compared with overweight group (83.2%) (P = 0.02). Each unit increase in maternal BMI was associated with decreased odds of infant survival (P

OBJECTIVE To test the hypothesis that an Apgar score at 10 minutes is independently predictive for death or moderate or severe disability. METHODS A secondary analysis of the Optimizing Cooling Trial (NCT01192776) including 347 infants with ≥36 weeks’ gestational age at birth and hypoxic-ischemic encephalopathy and 18- to 22-month outcomes from 18 US centers in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome was the composite of death or moderate/severe disability at 18 to 22 months of age. Generalized estimating equation models were used to examine the relationship between Apgar scores and outcomes, controlling for center, hypothermia treatment, and severity of hypoxic-ischemic encephalopathy (HIE). Classification and regression tree analyses were conducted to identify combinations of variables available during resuscitation that were most predictive for the composite outcome and death. RESULTS The study revealed that 50% (13 of 26) of infants with a 10-minute Apgar score of 0 survived; 46% (6 of 13) had no disability, 16% (2 of 13) had mild disability, and 38% (5 of 13) had moderate or severe disability. The 10-minute Apgar score of 0 was independently associated with death or moderate or severe disability (adjusted relative risk = 1.72, 95% confidence interval 1.11–2.68, P value = .016), but the area under the curve analysis (AUC) was low (AUC = 0.56). The predictive accuracy improved when the 10-minute Apgar score was combined with other risk variables available during resuscitation by using a classification and regression tree analysis (AUC = 0.66). CONCLUSIONS A 10-minute Apgar score of 0 alone does not predict the risk of death or moderate or severe disability well. The current study provides evidence in support of the 2020 American Heart Association/International Liaison Committee on Resuscitation recommendation for continuing resuscitative efforts for infants who need cardiopulmonary resuscitation at 10 minutes after birth.

Therapeutic hypothermia (TH) is now well established as the standard of care treatment for moderate to severe neonatal encephalopathy secondary to perinatal hypoxic ischemic encephalopathy (HIE) in infants ≥36 weeks gestation in high income countries. The Neonatal Research Network (NRN) contributed greatly to the study of TH as a neuroprotectant with three trials now completed in infants ≥36 weeks gestation and the only large randomized-controlled trial of TH in preterm infants now in the follow-up phase. Data from the first NRN TH trial combined with data from other large trials of TH affirm the safety and neuroprotective qualities of TH and highlight the importance of providing TH to all infants who qualify. In this review we will highlight the findings of the three NRN trials of TH in the term infant population and the secondary analyses that continue to inform the care of patients with HIE.

Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined.A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables.In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p 0.001).Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population.Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.

A rising number of preterm babies demands innovative solutions to monitor them in the Neonatal Intensive Care Unit (NICU) continuously. NICU monitors various kinds of vital signs. Among them, there is a strong demand for an accurate and sophisticated technology to monitor respiration rate (RR) and detect critical events such as apnea. Existing solutions for RR monitoring either rely on the indirect measurements from thoracic impedance or other invasive techniques posing discomfort and risk of infections to babies. Also, multiple wire loops lying around babies hinder the delivery of parental and clinical care. Motivated by this need, we have designed an Internet-of-Things (IoT) based smart textile chest belt called "Baby-Guard" to monitor RR and detect apnea. The Baby-Guard is a neonatal wearable system consisting of a sensor belt, a wearable embedded system, and an edge computing device. The sensor belt consists of textile-based pressure sensors and an Inertial Measurement Unit (IMU). The wearable system consists of a microcontroller equipped with wireless connectivity and power management. The edge computing device (ECD) connects with the wearable system through an MQTT networking architecture. ECD hosts signal processing and computing services to extract RR and detect apnea. We conducted simulation experiments using a high-fidelity, programmable NICU baby mannequin. We found an average error of 0.89 BrPM in breathing rate and ~97 percent accuracy in apnea detection. Computation and communication latencies were found to be ~66 and 22 ms, respectively. The Baby-Guard showed potential to be a wireless infant monitoring system in the NICU settings.

To develop a model for prediction of severe intracranial hemorrhage (ICH) or death based on variables from the first 12 h of age and to compare mortality and morbidities with and without exposure to early indomethacin.This retrospective cohort study included extreme preterm (22Of 4624 infants, 1827 received early indomethacin. Lower gestation, lack of antenatal steroids exposure, lower 1-min Apgar, male sex, and receipt of epinephrine were associated with severe ICH or death. Early indomethacin was associated with a lower risk of patent ductus arteriosus, bronchopulmonary dysplasia, and higher risk of spontaneous intestinal perforation.A model for early prediction of severe ICH/death was developed and validated. Early indomethacin was associated with a lower risk of patent ductus arteriosus and bronchopulmonary dysplasia and a higher risk of spontaneous intestinal perforation.Not applicable.Modern data on severe ICH and neonatal morbidities in relation to prophylactic indomethacin are scarce in the published literature. Prophylactic indomethacin was associated with a lower risk of patent ductus arteriosus and bronchopulmonary dysplasia and a higher risk of intestinal perforation. A risk estimator for severe intracranial hemorrhage/death was developed in a large cohort of extremely preterm infants. The risk estimator developed based on a large cohort of patients provides an estimate of severe intracranial bleeding for an individual infant.

Tagin and Gunn suggest that the current criteria from randomised controlled trials of hypothermia for moderate or severe encephalopathy are limiting the application to infants with perinatal hypoxia-ischaemia.1 They propose that current criteria be expanded and simplified based on clinical judgement to maximise potential benefit. Extending hypothermia therapy based on clinical context alone will be difficult to implement without many potential downsides (cooling for the wrong diagnosis, overtreatment, iatrogenic problems from a therapy not needed and so on). The criteria of the trials of hypothermia for moderate or severe encephalopathy used parameters which indicated that an impairment of gas exchange had occurred close to the time of birth and detailed the response to the impaired gas exchange [encephalopathy, abnormal amplitude integrated electroencephalogram (aEEG)].2 Acid base disturbances and elevations of lactate at birth or in the first postnatal hour provide objective measures to support critical events close to birth. The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN) screening criteria for hypoxia-ischaemia included approaches when no blood gases were available or when there was less fetal acidemia; infants then had to have evidence of an acute perinatal sentinel event and either a 10 min Apgar score

OBJECTIVE: To determine which initial surgical treatment results in the lowest rate of death or neurodevelopmental impairment (NDI) in premature infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP). SUMMARY BACKGROUND DATA: The impact of initial laparotomy versus peritoneal drainage for NEC or IP on the rate of death or NDI in extremely low birth weight infants is unknown. METHODS: We conducted the largest feasible randomized trial in 20 US centers, comparing initial laparotomy versus peritoneal drainage. The primary outcome was a composite of death or NDI at 18–22 months corrected age, analyzed using prespecified frequentist and Bayesian approaches. RESULTS: Of 992 eligible infants, 310 were randomized and 96% had primary outcome assessed. Death or NDI occurred in 69% of infants in the laparotomy group versus 70% with drainage (adjusted relative risk [aRR] = 1.0; 95% confidence interval [CI]: 0.87–1.14). A preplanned analysis identified an interaction between preoperative diagnosis and treatment group (p = 0.03). With a preoperative diagnosis of NEC, death or NDI occurred in 69% after laparotomy versus 85% with drainage (aRR=0.81; 95% CI: 0.64 to 1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference

To evaluate the effect of a nutrition care bundle in improving growth in premature infants during neonatal hospitalization.This study was a retrospective analysis of prospectively collected data for 584 surviving infants with birth weight ≤1000 g and gestational age 24-29 weeks admitted to a single-center neonatal intensive care unit between July 3, 2005, and June 6, 2016. Participants were divided into 3 discrete epochs based on evolving nutrition practices during the study period: epoch 1, baseline, open-bay setting; epoch 2, improved lactation staffing, introduction of high-protein formula, single-family room setting; epoch 3, complete nutrition care bundle. Infants in each epoch were evaluated for the primary outcome of change in weight z-score between postnatal day 7 and 36 weeks postmenstrual age (PMA) or discharge if sooner. Univariate and multivariable regression analyses were conducted to evaluate the effect of clinical variables on outcome.Significant increases in weight z-score between day of life 7 and 36 weeks PMA were observed across the 3 epochs, which accounted for 31% (P .0001) of the variance. Variables that were positive predictors of weight z-score change included birth weight z-score, cesarean delivery, and later epochs of nutritional support. Variables that were negative predictors of weight change included gestational age, postnatal steroids, and days on parenteral nutrition.Implementation of a nutrition care bundle was associated with improved weight gain in extremely low birth weight infants.

Introduction: Research capacity building is a critical component of professional development for pediatrician scientists, yet this process has been elusive in the literature. The ECHO IDeA States Pediatric Clinical Trials Network (ISPCTN) seeks to implement pediatric trials across medically underserved and rural populations. A key component of achieving this objective is building pediatric research capacity, including enhancement of infrastructure and faculty development. This article presents findings from a site assessment inventory completed during the initial year of the ISPCTN.Methods: An assessment inventory was developed for surveying ISPCTN sites. The inventory captured site-level activities designed to increase clinical trial research capacity for pediatrician scientists and team members. The inventory findings were utilized by the ISPCTN Data Coordinating and Operations Center to construct training modules covering 3 broad domains: Faculty/coordinator development; Infrastructure; Trials/Research concept development.Results: Key lessons learned reveal substantial participation in the training modules, the importance of an inventory to guide the development of trainings, and recognizing local barriers to clinical trials research.Conclusions: Research networks that seek to implement successfully completed trials need to build capacity across and within the sites engaged. Our findings indicate that building research capacity is a multi-faceted endeavor, but likely necessary for sustainability of a unique network addressing high impact pediatric health problems. The ISPCTN emphasis on building and enhancing site capacity, including pediatrician scientists and team members, is critical to successful trial implementation/completion and the production of findings that enhance the lives of children and families.

The objectives describe the frequency that inadequate oral feeding (IOF) is the reason why moderately preterm (MPT) infants remain hospitalized and its association with neonatal morbidities. Prospective study using the NICHD Neonatal Research Network MPT Registry. Multivariable logistic regression was used to describe associations between IOF and continued hospitalization at 36 weeks postmenstrual age (PMA). A total of 6017 MPT infants from 18 centers were included. Three-thousand three-seventy-six (56%) remained hospitalized at 36 weeks PMA, of whom 1262 (37%) remained hospitalized due to IOF. IOF was associated with RDS (OR 2.02, 1.66–2.46), PDA (OR 1.86, 1.37–2.52), sepsis (OR 2.36, 95% 1.48–3.78), NEC (OR 16.14, 7.27–35.90), and BPD (OR 3.65, 2.56–5.21) compared to infants discharged and was associated with medical NEC (OR 2.06, 1.19–3.56) and BPD (OR 0.46, 0.34–0.61) compared to infants remaining hospitalized for an alternative reason. IOF is the most common barrier to discharge in MPT infants, especially among those with neonatal morbidities.

The Induced Hypothermia (IH) and Optimizing Cooling (OC) trials for hypoxic–ischemic encephalopathy (HIE) had similar inclusion criteria. The rate of death/moderate–severe disability differed for the subgroups treated with therapeutic hypothermia (TH) at 33.5 °C for 72 h (44% vs. 29%, unadjusted p = 0.03). We aimed to evaluate differences in patient characteristics and care practices between the trials. We compared pre/post-randomization characteristics and care practices between IH and OC. There were 208 patients in the IH trial, 102 cooled, and 364 in the OC trial, 95 cooled to 33.5 °C for 72 h. In OC, neonates were less ill, fewer had severe HIE, and the majority were cooled prior to randomization. Differences between IH and OC were observed in the adjusted difference in the lowest PCO2 (+3.08 mmHg, p = 0.005) and highest PO2 (−82.7 mmHg, p

To determine if pre-specified placental abnormalities among newborns with hypoxic-ischemic encephalopathy (HIE) differ compared to newborns admitted to a NICU without encephalopathy.Retrospective case-control study of newborns with HIE (2006-2014) and controls matched for birth year, gestational age, weight, and gender. One pathologist reviewed archived placental sections using pre-specified criteria.Sixty-seven newborns had HIE, 46 had available placentas and were matched with 92 controls. HIE had more maternal vascular malperfusion (46% vs 25%, p = 0.02), fetal vascular malperfusion (13% vs 0%, p 0.001), and clinical abruption (22% vs 4%, p = 0.001). Controls had more normal placentas (29% vs 7%, p = 0.002), and chorioamnionitis (30% vs 9%, p = 0.005). Pre-specified placental lesions occurred in 87% of HIE and 65% of controls (p = 0.008) and identified90% of primary diagnoses.Pre-specified placental lesions identified nearly all abnormalities in HIE and represented both acute and chronic processes.

ImportanceThe 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.ObjectiveTo 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 ParticipantsThis 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.ExposureInfants were classified as having no, partial, or complete exposure to antenatal steroids.Main Outcomes and MeasuresThe 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.ResultsA 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 RelevanceIn 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.

The opioid epidemic has reached into all aspects of life in the United States. The epidemic has crossed racial, economic, social, and generational barriers. This epidemic also impacts infants. Fetal exposure to opioids can produce a withdrawal effect in newborns, referred to as Neonatal Opioid Withdrawal Syndrome (NOWS). NOWS treatment lacks a standard approach, with prominent variation across the United States. Furthermore, many treatment strategies for NOWS are not evidence-based but reflect anecdotal experience. Variable approaches to NOWS treatment contribute to more extended hospital stays and greater postnatal opioid exposure. The most prolonged period of NOWS treatment occurs during the weaning phase. This paper describes the first prospective randomized control trial to address systematized weaning of opioids for infants with NOWS.

To determine if antenatal variables affect the risk of spontaneous intestinal perforation (SIP) among preterm infants when prophylactic indomethacin is used.Retrospective case-control study of infants29 weeks of gestational age between January 2010 and June 2018 at one hospital. SIP was defined as acute abdominal distension and pneumoperitoneum without signs of necrotizing enterocolitis at14 days of life. Each case (n = 57) was matched with 2 controls (n = 114) for gestational age and birth year. Maternal and infant data were abstracted until the SIP or equivalent day for controls. Univariate analyses were followed by adjusted conditional logistic regressions and reported as OR and 95% CI.Mothers of cases were younger, more often delivering multiples (31% vs 14%, P = .007), and less abruptions (15% vs 29%, P = .045) but did not differ in intra-partum betamethasone, magnesium, or indomethacin use. Prophylactic indomethacin was given on day 1 to 99% of infants. SIP was associated with a shorter interval from last betamethasone dose to delivery (46 hours vs 96 hours, P = .01). Dopamine use (14% vs 4%, P = .02), volume expansion (23% vs 8%, P = .003), and high grade intraventricular hemorrhage (28% vs 8%, P = .0008) were related postnatal factors. The adjusted odds of SIP increased by 1% for each hour decrease between the last dose of betamethasone and delivery (OR 1.01, 95% CI 1.002-1.019) and with multiple births (OR 2.66, 95% CI 1.05-6.77).Antenatal betamethasone given shortly before delivery is associated with an increased risk of SIP. Potential interaction with medications such as postnatal indomethacin needs study.

Introduction/objectives The chorionic plate vessels of the placenta are in direct continuity with the fetal vasculature, suggesting chorionic and fetal angiogenesis may be subjected to similar regulatory mechanisms. In this study, we determined the correlation between chorionic plate vascularization and complications of prematurity, focusing on bronchopulmonary dysplasia (BPD) and other conditions with important microvascular components. Methods We performed a clinicoplacental analysis of 127 extremely preterm infants (23–28 weeks gestation). Chorionic plate vascularization was assessed by number and density of perforating chorionic vessels (PCVs). Charts were reviewed for relevant maternal and neonatal data, including respiratory, neurologic and gastrointestinal complications of prematurity. Results The placentas displayed marked variability in number (36–523/placenta) and density of PCVs (0.46–3.74 PC V/cm2). The median PCV density of infants with severe BPD was significantly higher than that of infants without BPD (1.51 PC V/cm2 versus 1.09 PC V/cm2, P Conclusion Chorionic plate vascularization correlates with frequency and severity of BPD, supporting a vascular basis that in part is antenatal in origin. Quantitative assessment of chorionic plate vascularization may allow early identification of preterm infants at high risk for BPD (proposed threshold: PCV density ≥1.50 PC V/cm2). The lack of correlation between chorionic vascularization and neurologic/gastrointestinal complications suggests these conditions may have less important antenatal and/or vascular contributions.

The objective of this paper is to compare in-hospital survival and survival without major morbidities in extremely preterm infants in relation to maternal body mass index (BMI).This retrospective cohort study included extremely preterm infants (gestational age 22Maternal BMI data were available for 2415 infants. Survival without any major morbidity was not different between groups: 30.8% in the underweight/normal, 28.1% in the overweight, and 28.5% in the obese (P = 0.65). However, survival was lower in the obese group (76.5%) compared with overweight group (83.2%) (P = 0.02). Each unit increase in maternal BMI was associated with decreased odds of infant survival (P 0.01).Survival without any major morbidity was not associated with maternal obesity. An increase in maternal prepregnancy BMI was associated with decreased odds of infant survival.

Key Points Question Are racial/ethnic disparities in care practices and major outcomes increasing or decreasing among extremely preterm infants in the US? Findings In this cohort study of 20 092 extremely preterm infants, racial/ethnic disparities in rates of antenatal corticosteroids and cesarean delivery decreased over time. Changes in rates of mortality and most major morbidities did not differ among white, black, and Hispanic infants, and while mortality decreased over time from 2002 to 2016, rates of moderate-severe neurodevelopmental impairment increased over time in all groups. Meaning Racial/ethnic disparities in rates of potentially life-saving care practices decreased over time in the US, with reductions in mortality but increases in neurodevelopmental impairment in all racial/ethnic groups., Importance Racial/ethnic disparities in quality of care among extremely preterm infants are associated with adverse outcomes. Objective To assess whether racial/ethnic disparities in major outcomes and key care practices were changing over time among extremely preterm infants. Design, Setting, and Participants This observational cohort study used prospectively collected data from 25 US academic medical centers. Participants included 20 092 infants of 22 to 27 weeks’ gestation with a birth weight of 401 to 1500 g born at centers participating in the National Institute of Child Health and Human Development Neonatal Research Network from 2002 to 2016. Of these infants, 9316 born from 2006 to 2014 were eligible for follow-up at 18 to 26 months’ postmenstrual age (excluding 5871 infants born before 2006, 2594 infants born after 2014, and 2311 ineligible infants including 64 with birth weight >1000 g and 2247 infants with gestational age >26 6/7 weeks), of whom 745 (8.0%) did not have known follow-up outcomes at 18 to 26 months. Main Outcomes and Measures Rates of mortality, major morbidities, and care practice use over time were evaluated using models adjusted for baseline characteristics, center, and birth year. Data analyses were conducted from 2018 to 2019. Results In total, 20 092 infants with a mean (SD) gestational age of 25.1 (1.5) weeks met the inclusion criteria and were available for the primary outcome: 8331 (41.5%) black infants, 3701 (18.4%) Hispanic infants, and 8060 (40.1%) white infants. Hospital mortality decreased over time in all groups. The rate of improvement in hospital mortality over time did not differ among black and Hispanic infants compared with white infants (black infants went from 35% to 24%, Hispanic infants went from 32% to 27%, and white infants went from 30% to 22%; P = .59 for race × year interaction). The rates of late-onset sepsis among black infants (went from 37% to 24%) and Hispanic infants (went from 45% to 23%) were initially higher than for white infants (went from 36% to 25%) but decreased more rapidly and converged during the most recent years (P = .02 for race × year interaction). Changes in rates of other major morbidities did not differ by race/ethnicity. Death before follow-up decreased over time (from 2006 to 2014: black infants, 14%; Hispanic infants, 39%, white infants, 15%), but moderate-severe neurodevelopmental impairment increased over time in all racial/ethnic groups (increase from 2006 to 2014: black infants, 70%; Hispanic infants, 123%; white infants, 130%). Rates of antenatal corticosteroid exposure (black infants went from 72% to 90%, Hispanic infants went from 73% to 83%, and white infants went from 86% to 90%; P = .01 for race × year interaction) and of cesarean delivery (black infants went from 45% to 59%, Hispanic infants went from 49% to 59%, and white infants went from 62% to 63%; P = .03 for race × year interaction) were initially lower among black and Hispanic infants compared with white infants, but these differences decreased over time. Conclusions and Relevance Among extremely preterm infants, improvements in adjusted rates of mortality and most major morbidities did not differ by race/ethnicity, but rates of neurodevelopmental impairment increased in all groups. There were narrowing racial/ethnic disparities in important care practices, including the use of antenatal corticosteroids and cesarean delivery., This cohort study evaluates whether racial/ethnic disparities in key care practices and major outcomes changed among extremely preterm infants from 2002 to 2016 at centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network.

Despite improvement during recent decades, extremely preterm infants continue to contribute disproportionately to neonatal mortality and childhood morbidity.To review survival, in-hospital morbidities, care practices, and neurodevelopmental and functional outcomes at 22-26 months' corrected age for extremely preterm infants.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.Extremely preterm birth.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.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.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 hypoxic-ischemic encephalopathy remains associated with considerable death and disability. In multiple randomized controlled trials, therapeutic hypothermia for neonatal moderate or severe hypoxic-ischemic encephalopathy among term infants has been shown to be safe and effective in reducing death and disability in survivors. In this article, the current status of infant and childhood outcomes following this therapy is reviewed. The clinical approaches that may help to optimize this innovative neuroprotective therapy are presented.

Objective We aimed to compare the rates of “surfactant treated respiratory disease” and other neonatal morbidities among moderately preterm (MPT) infants exposed to no, partial, or a complete course of antenatal corticosteroids (ANS). Study Design This observational cohort study evaluated MPT infants (290/7–336/7 weeks' gestational age), born between January 2012 and November 2013 and enrolled in the “MPT Registry” of the National Institute of Child Health and Human Development Neonatal Research Network. Results Data were available for 5,886 infants, including 676 with no exposure, 1225 with partial, and 3,985 with a complete course of ANS. Among no, partial, and complete ANS groups, respectively, there were significant differences in rates of delivery room resuscitation (4.1, 1.4, and 1.2%), surfactant-treated respiratory disease (26.5, 26.3, and 20%), and severe intracranial hemorrhage (3, 2, and 0.8%). Complete ANS course was associated with lower surfactant-treated respiratory disease, compared with partial ANS (odds ratio [OR] 0.62; 95% confidence interval [CI] 0.52–0.74), and no ANS groups (OR 0.52; 95% CI 0.41–0.66) on adjusted analysis. Conclusion In MPT infants, ANS exposure is associated with lower delivery room resuscitation, surfactant-treated respiratory disease, and severe intracranial hemorrhage; with the lowest frequency of morbidities associated with a complete course.

Importance Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, setting, and participants This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main outcomes and measures The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and relevance Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial registration ClinicalTrials.gov Identifier: NCT01192776.

OBJECTIVE: To evaluate the effects of early treatment with CPAP on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (24–0/7 to 27–6/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks’ postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks’ PMA and follow-up outcomes at 18–22 months’ corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: 810 of 1316 infants enrolled in SUPPORT (414 in intervention group, 396 in control group) had growth data analyzed. Median gestational age was 26 weeks and mean birthweight was 839 grams. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between groups. In a regression model, growth rates between birth and 36 weeks’ PMA as well as growth rates during multiple intervals from birth to day 7, day 7 to14, day 14 to 21, day 21 to 28, day 28 to 32 weeks’ PMA, and 32 weeks’ PMA to 36 weeks’ PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of Bayley III cognitive score

Background:Late-onset sepsis (LOS) is an important cause of death and neurodevelopmental impairment in premature infants. The purpose of this study was to assess overall incidence of LOS, distribution of LOS-causative organisms and center variation in incidence of LOS for extremely premature infants

Importance Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks’ or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks’ or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks’ gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, −1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness. Trial Registration clinicaltrials.gov Identifier:NCT00614744

OBJECTIVE: To evaluate neurodevelopmental outcomes of preterm infants with need for Child Protective Services (CPS) supervision at hospital discharge compared with those discharged without CPS supervision. STUDY DESIGN: For infants born at

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

OBJECTIVE: To compare in-hospital outcomes after umbilical cord milking versus delayed cord clamping among infants

Objective To investigate if magnetic resonance imaging (MRI) is an accurate predictor for death or moderate-severe disability at 18-22 months of age among infants with neonatal encephalopathy in a trial of cooling initiated at 6-24 hours. Study design Subgroup analysis of infants ≥36 weeks of gestation with moderate-severe neonatal encephalopathy randomized at 6-24 postnatal hours to hypothermia or usual care in a multicenter trial of late hypothermia. MRI scans were performed per each center's practice and interpreted by 2 central readers using the Eunice Kennedy Shriver National Institute of Child Health and Human Development injury score (6 levels, normal to hemispheric devastation). Neurodevelopmental outcomes were assessed at 18-22 months of age. Results Of 168 enrollees, 128 had an interpretable MRI and were seen in follow-up (n = 119) or died (n = 9). MRI findings were predominantly acute injury and did not differ by cooling treatment. At 18-22 months, death or severe disability occurred in 20.3%. No infant had moderate disability. Agreement between central readers was moderate (weighted kappa 0.56, 95% CI 0.45-0.67). The adjusted odds of death or severe disability increased 3.7-fold (95% CI 1.8-7.9) for each increment of injury score. The area under the curve for severe MRI patterns to predict death or severe disability was 0.77 and the positive and negative predictive values were 36% and 100%, respectively. Conclusions MRI injury scores were associated with neurodevelopmental outcome at 18-22 months among infants in the Late Hypothermia Trial. However, the results suggest caution when using qualitative interpretations of MRI images to provide prognostic information to families following perinatal hypoxia–ischemia. Trial registration Clinicaltrials.gov: NCT00614744 .

In this article, we summarize the NICHD Neonatal Research Network (NRN) trial of whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy in relation to other randomized controlled trials (RCTs) of hypothermia neuroprotection. We describe the NRN secondary studies that have been published in the past 10 years evaluating clinical, genetic, biochemical, and imaging biomarkers of outcome.

Acute post-asphyxial encephalopathy around the time of birth remains a major cause of death and disability. The possibility that hypothermia may be able to prevent or lessen asphyxial brain injury is a “dream revisited”. In this review, a historical perspective is provided from the first reported use of therapeutic hypothermia for brain injuries in antiquity, to the present day. The first uncontrolled trials of cooling for resuscitation were reported more than 50 years ago. The seminal insight that led to the modern revival of studies of neuroprotection was that after profound asphyxia, many brain cells show initial recovery from the insult during a short “latent” phase, typically lasting approximately 6 h, only to die hours to days later after a “secondary” deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this conceptual framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration to allow the secondary deterioration to resolve, is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild induced hypothermia significantly improves intact survival and neurodevelopmental outcomes to mid-childhood.

Birth asphyxia, also termed perinatal hypoxia-ischemia, is a modifiable condition as evidenced by improved outcomes of infants ≥36 weeks' gestation provided hypothermia treatment in randomized trials. Preterm animal models of asphyxia in utero demonstrate that hypothermia can provide short-term neuroprotection for the developing brain, supporting the interest in extending therapeutic hypothermia to preterm infants. This review focuses on the challenge of identifying preterm infants with perinatal asphyxia; the neuropathology of hypoxic-ischemic brain injury across extreme, moderate, and late preterm infants; and patterns of brain injury, use of therapeutic hypothermia, and approach to patient selection for neuroprotective treatments among preterm infants.

Objective The objective of this study was to study the temporal profile of pulmonary hypertension (PH) in preterm infants. Study Design Infants 28 weeks were screened for early PH at 10 to 14 days of life. Infants with early PH (n = 10) and gestationally matched controls (n = 18) underwent serial echocardiography every 7 to 10 days until 36 weeks postmenstrual age. Results Groups with and without early PH were comparable except for higher Fio 2 by day 10 among infants with early PH. Early PH was moderate in extent and resolved in all infants with recurrence in one infant. Among infants without early PH, five infants developed late PH. In both groups, development of late PH occurred in association with important neonatal morbidities, such as patent ductus arteriosus, bronchopulmonary dysplasia, and infection. Conclusion Early moderate PH among preterm infants resolves over a variable time period but recurrence is possible. Late PH can appear during the course of hospitalization in association with other clinical morbidities.

Objective Indomethacin prophylaxis (IP) reduces the risk of intraventricular haemorrhage (IVH) and patent ductus arteriosus (PDA) in preterm infants. However, the optimal time to administer IP has not been determined. We hypothesised that IP at ≤6 h is associated with a lower incidence of IVH or death than if administered at >6–24 h of age. Methods We performed a retrospective cohort study of extremely low birth weight infants (≤1000 g birth weight) treated in the neonatal intensive care units in the Neonatal Research Network from 2003 to 2010 and who received IP in the first 24 h of age. Infants were dichotomised based upon receipt of IP at ≤6 or >6–24 h of age. The primary outcomes were IVH alone and IVH or death. Secondary outcomes were PDA alone and PDA or death. We used multivariable analyses to determine associations between the age of IP and the study outcomes expressed as an OR and 95% CI. Results IP was given at ≤6 h to 2340 infants and at >6–24 h to 1915 infants. Infants given IP at ≤6 h had more antenatal steroid exposure, more inborn and less cardiopulmonary resuscitation (p 6–24 h (OR 0.83, 95% CI 0.71 to 0.98). Conclusions IP at ≤6 h of age is not associated with less IVH or death, but is associated with less PDA receiving treatment/ligation or death.

Objective To assess outcomes following post-hemorrhagic ventricular dilatation (PHVD) among infants born at ≤26 weeks of gestation. Study design Observational study of infants born April 1, 2011, to December 31, 2015, in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and categorized into 3 groups: PHVD, intracranial hemorrhage without ventricular dilatation, or normal head ultrasound. PHVD was treated per center practice. Neurodevelopmental impairment at 18-26 months was defined by cerebral palsy, Bayley Scales of Infant and Toddler Development, 3rd edition, cognitive or motor score Results Of 4216 infants, 815 had PHVD, 769 had hemorrhage without ventricular dilatation, and 2632 had normal head ultrasounds. Progressive dilatation occurred among 119 of 815 infants; the initial intervention in 66 infants was reservoir placement and 53 had ventriculoperitoneal shunt placement. Death or impairment occurred among 68%, 39%, and 28% of infants with PHVD, hemorrhage without dilatation, and normal head ultrasound, respectively; aOR (95% CI) were 4.6 (3.8-5.7) PHVD vs normal head ultrasound scan and 2.98 (2.3-3.8) for PHVD vs hemorrhage without dilatation. Death or impairment was more frequent with intervention for progressive dilatation vs no intervention (80% vs 65%; aOR 2.2 [1.38-3.8]). Death or impairment increased with parenchymal hemorrhage, intervention for PHVD, male sex, and surgery for retinopathy; odds decreased with each additional gestational week. Conclusions PHVD was associated with high rates of death or impairment among infants with gestational ages ≤26 weeks; risk was further increased among those with progressive ventricular dilation requiring intervention.

Importance Early-onset sepsis (EOS) remains a potentially fatal newborn condition. Ongoing surveillance is critical to optimize prevention and treatment strategies. Objective To describe the current incidence, microbiology, morbidity, and mortality of EOS among a cohort of term and preterm infants. Design, setting, and participants This prospective surveillance study included a cohort of infants born at a gestational age (GA) of at least 22 weeks and birth weight of greater than 400 g from 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from April 1, 2015, to March 31, 2017. Data were analyzed from June 14, 2019, to January 28, 2020. Main outcomes and measures Early-onset sepsis defined by isolation of pathogenic species from blood or cerebrospinal fluid culture within 72 hours of birth and antibiotic treatment for at least 5 days or until death. Results A total of 235 EOS cases (127 male [54.0%]) were identified among 217 480 newborns (1.08 [95% CI, 0.95-1.23] cases per 1000 live births). Incidence varied significantly by GA and was highest among infants with a GA of 22 to 28 weeks (18.47 [95% CI, 14.57-23.38] cases per 1000). No significant differences in EOS incidence were observed by sex, race, or ethnicity. The most frequent pathogens were Escherichia coli (86 [36.6%]) and group B streptococcus (GBS; 71 [30.2%]). E coli disease primarily occurred among preterm infants (68 of 131 [51.9%]); GBS disease primarily occurred among term infants (54 of 104 [51.9%]), with 24 of 45 GBS cases (53.3%) seen in infants born to mothers with negative GBS screening test results. Intrapartum antibiotics were administered to 162 mothers (68.9%; 110 of 131 [84.0%] preterm and 52 of 104 [50.0%] term), most commonly for suspected chorioamnionitis. Neonatal empirical antibiotic treatment most frequently included ampicillin and gentamicin. All GBS isolates were tested, but only 18 of 81 (22.2%) E coli isolates tested were susceptible to ampicillin; 6 of 77 E coli isolates (7.8%) were resistant to both ampicillin and gentamicin. Nearly all newborns with EOS (220 of 235 [93.6%]) displayed signs of illness within 72 hours of birth. Death occurred in 38 of 131 infected infants with GA of less than 37 weeks (29.0%); no term infants died. Compared with earlier surveillance (2006-2009), the rate of E coli infection increased among very low-birth-weight (401-1500 g) infants (8.68 [95% CI, 6.50-11.60] vs 5.07 [95% CI, 3.93-6.53] per 1000 live births; P = .008). Conclusions and relevance In this study, EOS incidence and associated mortality disproportionately occurred in preterm infants. Contemporary cases have demonstrated the limitations of current GBS prevention strategies. The increase in E coli infections among very low-birth-weight infants warrants continued study. Ampicillin and gentamicin remained effective antibiotics in most cases, but ongoing surveillance should monitor antibiotic susceptibilities of EOS pathogens.

ObjectiveTo assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight.Study designThis trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight

Objective To determine the characteristics of term infants with persistent pulmonary hypertension of the newborn (PPHN) associated with moderate or severe hypoxic ischemic encephalopathy (HIE). Methods We compared infants with and without PPHN enrolled in 2 randomized trials of therapeutic hypothermia: the induced hypothermia trial of cooling to 33.5°C for 72 hours vs normothermia, and the “usual-care” arm (33.5°C for 72 hours) of the optimizing cooling trial. Results Among 303 infants with HIE from these 2 studies, 67 (22%) had PPHN and 236 (78%) did not. We compared infants with PPHN with those without PPHN. The proportion of patients treated with therapeutic hypothermia was similar in PPHN and no-PPHN groups (66% vs 65%). Medication use during resuscitation (58% vs 44%), acidosis after birth (pH: 7.0 ± 0.2 vs 7.1 ± 0.2), severe HIE (43% vs 28%), meconium aspiration syndrome (39% vs 7%), pulmonary hemorrhage (12% vs 3%), culture-positive sepsis (12% vs 3%), systemic hypotension (65% vs 28%), inhaled nitric oxide therapy (64% vs 3%), and extracorporeal membrane oxygenation (12% vs 0%) were more common in the PPHN group. Length of stay (26 ± 21 vs 16 ± 14 days) and mortality (27% vs 16%) were higher in the PPHN group. Conclusions PPHN is common among infants with moderate/severe HIE and is associated with severe encephalopathy, lung disease, sepsis, systemic hypotension, and increased mortality. The prevalence of PPHN was not different between those infants receiving therapeutic hypothermia at 33.5°C in these 2 trials (44/197 = 22%) compared with infants receiving normothermia in the induced hypothermia trial (23/106 = 22%).

Objective To investigate associations in toddlers born extremely preterm ( Study design Cohort analysis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial Neuroimaging and Neurodevelopmental Outcomes Study of infants born extremely preterm. Subjects underwent cranial ultrasonography and near-term magnetic resonance imaging (MRI). At 18-22 months of corrected age, the assessment included the Brief Infant Toddler Social Emotional Assessment (BITSEA) Problem and Competence Scale scores and the Bayley Scales of Infant Development, Third Edition (Bayley-III). The BITSEA Problem Scale assesses dysregulation; the Competence Scale assesses social-emotional competence. We examined associations of Problem and Competence scores and positive screen rates with cranial ultrasonography and near-term MRI. Mean BITSEA and Bayley-III scores were compared using ANOVA and positive screen rates with the χ2 test. We computed correlations between BITSEA and Bayley-III scores. Results Of the 397 children, positive BITSEA screens were found in 34% for the Problem score and 26% for the Competence score. Presence of lesions on near-term MRI that included cerebellar lesions were significantly associated with lower BITSEA Competence but not with Problem scores; Competence scores were inversely related to the presence/significance of lesions. Positive screens on Competence scores and on both Competence and Problem scores were significantly associated with Bayley-III cognitive and language scores Conclusions Social–emotional competence contributes to deficits in cognitive and language development. Presence of injury on near-term MRI that includes cerebellar lesions is associated with later social–emotional competence and may be a useful predictor to guide early assessment and intervention. Trial registration ClinicalTrials.gov : NCT00063063 and NCT00233324 .

Background We previously reported on the overall incidence, management, and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short-term outcomes in term and late preterm newborn infants. Objective This study aims to evaluate how four definitions of CVI relate to short-term outcomes and death. Study Design The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short-term outcomes at discharge and four different definitions of CVI were further analyzed. Results All the four definitions were associated with greater number of days on MV and days on O 2 . The definition using a threshold blood pressure (BP) measurement alone was not associated with days of full feeding, days in the NICU or death. The definition based on the treatment of CVI was associated with all the outcomes including death. Conclusions The definition using a threshold BP alone was not consistently associated with adverse short-term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.

Screening neuroimaging helps in detecting clinically silent brain injury in extremely low birth weight (ELBW) preterm infants.1 Cranial ultrasound (CUS) is commonly used in ELBW newborns for routine screening; early CUS examination mostly detects hemorrhagic lesions, whereas a later CUS usually allows diagnosis of white matter abnormalities, including cystic periventricular leukomalacia (cPVL).2 Among all the white matter abnormalities, detection of cPVL on the late CUS examination has the highest correlation with neuropathologic findings3,4 and subsequent neurodevelopmental outcome.5–9 The late timing of the screening neuroimaging for detection of cPVL is intended to maximize cost-effectiveness, by focusing on time points when almost all cases of cPVL are expected to become evident on neuroimaging.10 The timing of “late” ultrasound examination varies with different guidelines for screening; the Canadian Pediatric Society recommends later CUS examination in the6thweekof life,2 and the American Academy of Neurology and the Child Neurology Society recommend it to be done between 36 and 40weeks’ postmenstrual age (PMA).1,11 However, studies in ELBW infants using serial CUS have shown that in some instances cPVL may be apparent for only 1 to 2 weeks before the cysts coalesce, collapse, and then disappear.12,13 If the later cranial screening imaging is deferred until 36 to 40 weeks’ PMA some cases of cPVL, especially in more premature ELBW infants, may be missed because the screening cranial imaging might be performed after the cysts collapsed and disappeared. For example, using the criterion of 36 to 40 weeks, PMA for an infant born at 23 weeks’ gestational age (GA), the later screening imaging would be performed at 13 to 17 weeks’ chronological age (CA). This same infant would be screened earlier, at 29 weeks’ PMA, using the Canadian Pediatric Society CA criterion of 6 weeks. This 7- to 11-week difference in obtaining routine cranial screening imaging may be crucial, if it results in underestimation of cPVL. We hypothesize that “late” screening cranial imaging only at 36 to 40 weeks PMA as recommended by the American Academy of Neurology and the Child Neurology Society will underestimate the incidence of cPVL in ELBW infants. We also hypothesize that cPVL underdetection at 36 to 40 weeks PMA will increase as GA at birth decreases because of longer delay in obtaining cranial screening imaging in infants who are more preterm. To explore this hypothesis, we assessed the detection of cPVL on screening cranial imaging performed closest to 36 weeks’ PMA (PMA criterion) compared with an earlier time point (CUS performed within 28 days CA) to determine if some cPVL had resolved by the time of later screening cranial imaging. We also compared the cPVL detection rate between ELBW infants born at < 26 weeks’ GA and those born at 26 to 28 weeks’ GA using PMA and CA criteria to determine if the incidence of potentially missed cases of cPVL differs between the two groups. This information might assist clinicians to provide better prognostic information to guide long-term care strategies in high-risk preterm neonates.