Search

Background: Extremely low birth weight (ELBW) infants frequently develop chronic lung disease (CLD). Meta-analyses suggest that early postnatal steroid administration may reduce this risk. Association of early cortisol insufficiency with subsequent CLD supports use of a lower stress steroid dose that may reduce complications associated with higher doses. We initiated a randomized, multicenter, controlled trial to determine whether a tapering course of stress dose steroid started on the first day would reduce the risk of CLD or death in ELBW infants. Methods: Infants with birth weight 501-1000 gm mechanically ventilated before 12 hours were eligible for the study. Infants with birth weight [is greater than] 750 gm also needed to receive Fi[O.sub.2] [is greater than or equal to] 0.30 and surfactant. Infants were randomized to receive dexamethasone (initial dose 0.15 mg/kg/d for 3 days, then tapered over 7 days) or placebo. In a factorial design, infants were also randomized to routine ventilator management or a strategy of minimal ventilator support to reduce mechanical lung injury. Results: After enrolling 220 patients (sample size estimate was 1200), the trial was halted for unanticipated adverse events. Steroid (n = 111) and placebo (n = 109) infants had similar clinical characteristics at randomization. Study Death or [O.sub.2] at PIE Steroid Drug CLD % 28 d % Rx % RX % Steroid 63 78 9 34 Placebo 69 94(*) 23(*) 51(*) Study Systolic Insulin GI Drug BP [is greater than] 80 RX % Perf % mmHg % Steroid 27 23 13 Placebo 4(*) 12(*) 3(*) (*) p = 0.05. The relative risk for the primary outcome, death or CLD at 36 postmenstrual weeks, was 0.92 (95% CI = 0.76-1.11). Fewer infants in the steroid group had pulmonary interstitial emphysema (PIE), required oxygen at 28 days, or had subsequent steroid treatment. Rates of severe intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, and nosocomial infection were similar. Hypertension and hyperglycemia (insulin Rx) were more frequent in the steroid group. During the first 14 days, 14 (13%) infants in the steroid group and 3 (3%) infants in the placebo group had spontaneous gastrointestinal perforation without necrotizing enterocolitis. Perforation was associated with indomethacin exposure (p = 0.005) and there was an interaction between indomethacin and steroid (p = 0.04). No interaction was observed with ventilator strategy. Conclusion: The increased risk of gastrointestinal perforation, as well as other previously identified complications, should be considered in decisions regarding steroid treatment in ELBW infants. A R Stark, MD, FAAP, W Carlo, MD, FAAP, C Bauer, MD, FAAP E Donovan, MD, FAAP, W Oh, MD AAP, L Papile, MD, FAAP, S Shankaran, MD, FAAP, JE Tyson, MD, LL Wright, MD, FAAP, M Temprosa, K Poole, Ph, D.; for the NICHD Neonatal Research Network.3, A R Stark, MD, FAAP, W Carlo, MD, FAAP, C Bauer, MD, FAAP E Donovan, MD, FAAP, W Oh, MD AAP, L Papile, MD, FAAP, S Shankaran, MD, FAAP, JE [...]

OBJECTIVE: To relate volumetric magnetic resonance imaging (MRI) findings to hypothermia therapy and neurosensory impairments. STUDY DESIGN: Newborns > or =36 weeks' gestation with hypoxic-ischemic encephalopathy who participated in the National Institute of Child Health and Human Development hypothermia randomized trial at our center were eligible. We determined the relationship between hypothermia treatment and usual care (control) to absolute and relative cerebral tissue volumes. Furthermore, we correlated brain volumes with death or neurosensory impairments at 18 to 22 months. RESULT: Both treatment groups were comparable before randomization. Total brain tissue volumes did not differ in relation to treatment assignment. However, relative volumes of subcortical white matter were significantly larger in hypothermia-treated than control infants. Furthermore, relative total brain volumes correlated significantly with death or neurosensory impairments. Relative volumes of the cortical gray and subcortical white matter also correlated significantly with Bayley Scales psychomotor development index. CONCLUSION: Selected volumetric MRI findings correlated with hypothermia therapy and neurosensory impairments. Larger studies using MRI brain volumes as a secondary outcome measure are needed. [ABSTRACT FROM AUTHOR]

Background: Decisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients.Methods: We prospectively studied a cohort of 4446 infants born at 22 to 25 weeks' gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months.Results: Among study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone.Conclusions: The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. (ClinicalTrials.gov numbers, NCT00063063 [ClinicalTrials.gov] and NCT00009633 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the association between peak total serum bilirubin (PSB) levels during the first 2 weeks of life and neurodevelopmental outcomes of extremely low birth weight (ELBW) infants at 18 to 22 months' postmenstrual age. METHODS: A retrospective analysis was conducted of a cohort of ELBW infants (401-1000 g) who survived to 14 days of age in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1, 1994, and December 31, 1997. Demographic and clinical risk factors and PSB levels during the first 14 days were analyzed with reference to death or adverse neurodevelopmental outcomes at 18 to 22 months' postmenstrual age. The neurodevelopmental variables considered were Psychomotor Developmental Index (PDI) <70, Mental Developmental Index (MDI) <70, moderate or severe cerebral palsy (CP), hearing impairment (needs hearing aids), and a composite category designated as neurodevelopmental impairment (NDI). The NDI is defined as infants with any 1 or more of the following: PDI <70, MDI <70, moderate to severe CP, bilateral blindness, or bilateral hearing impairment requiring amplification. RESULTS: The subjects of this cohort analysis are infants who were admitted to the Network centers during calendar years 1994-1997 and survived beyond 14 days and had PSB recorded during the 14-day period. From this cohort, 3246 infants survived at discharge, 79 died after discharge, and 592 were lost to follow-up. Thus, 2575 of 3167 infants were seen in the follow-up clinics with a compliance rate of 81%. Logistic regression analysis showed that various demographic and clinical variables are associated with poor neurodevelopmental outcomes. After adjustment for these risk factor, significant association were found between PSB (mg/dL) and death or NDI (odds ratio: 1.068; 95% confidence interval [CI]: 1.03-1.11); PDI <70 (R = 1.057; 95% CI: 1.00-1.12), and hearing impairment requiring hearing aids (odds ratio: 1138; 95% CI: 1.00-1.30). There was no significant association between PSB (mg/dL) and CP, MDI <70, and NDI. CONCLUSIONS: PSB concentrations during the first 2 weeks of life are directly correlated with death or NDI, hearing impairment, and PDI <70 in ELBW infants. The statistical association based on retrospective analysis of observational data and relatively small effect size should be interpreted with caution. Furthermore, because of the possibility of compounding effects of variables on outcome, the potential benefits of moderate hyperbilirubinemia and the potential adverse effects of phototherapy, a randomized, controlled trial of aggressive and conservative phototherapy is needed to address this controversial issue. [ABSTRACT FROM AUTHOR]

BACKGROUND: Glutamine is one of the most abundant amino acids in both plasma and human milk and may be conditionally essential in premature infants. However, glutamine is not provided by standard intravenous amino acid solutions. OBJECTIVE: We assessed the effect of parenteral glutamine supplementation on plasma amino acid concentrations in extremely low-birth-weight infants receiving parenteral nutrition (PN). DESIGN: A total of 141 infants with birth weights of 401-1000 g were randomly assigned to receive a standard intravenous amino acid solution that did not contain glutamine or an isonitrogenous amino acid solution with 20% of the total amino acids as glutamine. Blood samples were obtained just before initiation of study PN and again after the infants had received study PN (mean intake: 2.3 +/- 1.0 g amino acids x kg(-1) x d(-1)) for approximately 10 d. RESULTS: Infants randomly assigned to receive glutamine had mean plasma glutamine concentrations that increased significantly and were approximately 30% higher than those in the control group in response to PN (425 +/- 182 and 332 +/- 148 micromol/L for the glutamine and control groups, respectively). There was no significant difference between the 2 groups in the relative change in plasma glutamate concentration between the baseline and PN samples. In both groups, there were significant decreases in plasma phenylalanine and tyrosine between the baseline and PN samples; the decrease in tyrosine was greater in the group that received glutamine. CONCLUSIONS: In extremely low-birth-weight infants, parenteral glutamine supplementation can increase plasma glutamine concentrations without apparent biochemical risk. Currently available amino acid solutions are likely to be suboptimal in their supply of phenylalanine, tyrosine, or both for these infants. Copyright © 2003 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Context: Inner-city high-risk infants often receive limited and fragmented care, a problem that may increase serious illness.Objective: To assess whether access to comprehensive care in a follow-up clinic is cost-effective in reducing life-threatening illnesses among high-risk, inner-city infants.Design: Randomized controlled trial.Setting and Participants: A total of 887 very-low-birth-weight infants born in a Texas county hospital between January 1988 and March 1996 and followed up in a children's hospital clinic. One hundred four infants who became ineligible or died after randomization but before nursery discharge were excluded from the analysis.Interventions: Infants were randomly assigned to receive routine follow-up care (well-baby care and care for chronic illnesses; n = 441) or comprehensive care (which included the components of routine care plus care for acute illnesses, with 24-hour access to a primary caregiver; n = 446).Main Outcome Measures: Life-threatening illnesses (ie, causing death or hospital admission for pediatric intensive care) occurring between nursery discharge and age 1 year, assessed by blinded evaluators from inpatient charts and state Medicaid and vital statistics records; and hospital costs (estimated from department-specific cost-to-charge ratios).Results: Comprehensive care resulted in a mean of 3.1 more clinic visits and 6.7 more telephone conversations with clinic staff (P<.001 for both). One-year outcomes were unknown for fewer comprehensive-care infants than routine-care infants (9 vs 28; P =.001). Identified deaths were similar (11 in comprehensive care vs 13 in routine care; P =.68). The comprehensive-care group had 48% fewer life-threatening illnesses (33 vs 63; P<.001), 57% fewer intensive care admissions (23 vs 53; P =.003), and 42% fewer intensive care days (254 vs 440; P =.003). Comprehensive care did not increase the mean estimated cost per infant for all care ($6265 with comprehensive care and $9913 with routine care).Conclusion: Comprehensive follow-up care by experienced caregivers can be highly effective in reducing life-threatening illness without increasing costs among high-risk inner-city infants. JAMA. 2000;284:2070-2076. [ABSTRACT FROM AUTHOR]

OBJECTIVES: In the era before widespread use of inhaled nitric oxide, to determine the prevalence of persistent pulmonary hypertension (PPHN) in a multicenter cohort, demographic descriptors of the population, treatments used, the outcomes of those treatments, and variation in practice among centers. STUDY DESIGN: A total of 385 neonates who received >/=50% inspired oxygen and/or mechanical ventilation and had documented evidence of PPHN (2D echocardiogram or preductal or postductal oxygen difference) were tracked from admission at 12 Level III neonatal intensive care units. Demographics, treatments, and outcomes were documented. RESULTS: The prevalence of PPHN was 1.9 per 1000 live births (based on 71 558 inborns) with a wide variation observed among centers (.43-6.82 per 1000 live births). Neonates with PPHN were admitted to the Level III neonatal intensive care units at a mean of 12 hours of age (standard deviation: 19 hours). Wide variations in the use of all treatments studied were found at the centers. Hyperventilation was used in 65% overall but centers ranged from 33% to 92%, and continuous infusion of alkali was used in 75% overall, with a range of 27% to 93% of neonates. Other frequently used treatments included sedation (94%; range: 77%-100%), paralysis (73%; range: 33%-98%), and inotrope administration (84%; range: 46%-100%). Vasodilator drugs, primarily tolazoline, were used in 39% (range: 13%-81%) of neonates. Despite the wide variation in practice, there was no significant difference in mortality among centers. Mortality was 11% (range: 4%-33%). No specific therapy was clearly associated with a reduction in mortality. To determine whether the therapies were equivalent, neonates treated with hyperventilation were compared with those treated with alkali infusion. Hyperventilation reduced the risk of extracorporeal membrane oxygenation without increasing the use of oxygen at 28 days of age. In contrast, the use of alkali infusion was associated with increased use of extracorporeal membrane oxygenation (odds ratio: 5.03, compared with those treated with hyperventilation) and an increased use of oxygen at 28 days of age. CONCLUSIONS: Hyperventilation and alkali infusion are not equivalent in their outcomes in neonates with PPHN. Randomized trials are needed to evaluate the role of these common therapies. [ABSTRACT FROM AUTHOR]

Objectives: To assess risk factors affecting viability and analyze the effects of mechanical ventilation (MV) on neonatal outcome and resource use among extremely premature infants.Design: Inception cohort study.Setting: Neonatal intensive care units of the 12-center National Institute of Child Health and Human Development Neonatal Research Network.Participants: A total of 1126 infants with a birth weight of 501 to 800 g born in network centers between January 1, 1994, and December 31, 1995.Main Outcome Measures: Observed survival; maximum estimated survival (assuming the same survival among infants who died without MV as among infants in the same risk category who received MV); observed and maximum estimated survival without severe brain injury (either interventricular echodensity with ventricular dilation or parenchymal echodensity); hospital stay; resource investment.Results: Overall mortality was 43%; mortality in infants without MV was 93%. A total of 15% of all the infants died without MV. Females, small-for-gestational-age infants, and infants whose mothers received antenatal steroids had an advantage in survival with MV equivalent to an increase in birth weight of 90 g, 57 g, and 67 g, respectively. The corresponding advantage of these infants in survival without severe brain injury was 107 g, 97 g, and 64 g, respectively. Females in the lowest birth-weight group were more likely to die without MV than were larger males with a similar estimated likelihood of survival with MV. Mean hospital stay was 115 days for the survivors, values much greater than the 17.9-day standard for 501- to 800-g survivors under the diagnosis related group system. Resource investment was considerable (127 hospital days per survivor and 148 days per survivor without severe brain injury), but, like outcome, varied markedly between risk categories. Had MV been used for all infants who died, we estimate a substantial increase in resource use and a maximum of 8 additional survivors (no more than 6 without severe brain injury per 100 infants with a birth weight of 501 to 800 g.Conclusions: Although recommendations to initiate or forgo MV for extremely premature infants have often focused on 1 factor (birth weight or gestational age), multiple factors should be considered. Other factors being equal, our analyses support use of MV for females at a minimum birth weight approximately 100 g lower than that for males. The current diagnosis related group reimbursement system can be expected to compromise resources for 501- to 800-g infants who would benefit from MV. Such care entails considerable resource use, although the cost per life-year gained is likely to be considerably less than that for many adults given intensive care. Our findings can be used to facilitate more appropriate treatment decisions, determine adequate resources, and better inform the debate about the benefits and burdens of intensive care for extremely premature newborns. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Extremely low birth weight (ELBW; < or =1000 g) infants with necrotizing enterocolitis (NEC) or isolated intestinal perforation (IP) are treated surgically with either initial laparotomy or peritoneal drain placement. The only published data comparing these therapies are from small, retrospective, single-center studies that do not address outcomes beyond nursery discharge. The objective of this study was to conduct a prospective, multicenter, observational study to (1) develop a hypothesis about the relative effect of these 2 therapies on risk-adjusted outcomes through 18 to 22 months in ELBW infants and (2) to obtain data that would be useful in designing and conducting a successful trial of this hypothesis. METHODS: A prospective, cohort study was conducted at 16 clinical centers within the National Institute of Child Health and Human Development Neonatal Research Network. To assist in risk adjustment, the attending pediatric surgeon recorded the preoperative diagnosis and intraoperative diagnosis and identified infants who were considered to be too ill for laparotomy. Predefined measures of short- and longer-term outcome included (1) either predischarge death or prolonged parenteral nutrition (>85 days) after enrollment and (2) either death or neurodevelopmental impairment on a standardized examination at 18 to 22 months' adjusted age. RESULTS: Severe NEC or IP occurred in 156 (5.2%) of 2987 ELBW infants; 80 were treated with initial drainage, and 76 were treated with initial laparotomy. By 18 to 22 months, 78 (50%) had died; 112 (72%) had died or were shown to be impaired. Outcome was worse in the subgroup with NEC. Laparotomy was never performed in 76% (28 of 36) of drain-treated survivors. CONCLUSIONS: Drainage was commonly used, and outcome was poor. Our findings, particularly the risk-adjusted odds ratio favoring laparotomy for death or impairment, indicate the need for a large, multicenter clinical trial to assess the effect of the initial surgical therapy on outcome at > or =18 months. [ABSTRACT FROM AUTHOR]

Background. A National Institute of Child Health and Human Development Neonatal Research Network randomized trial showed that vitamin A supplementation reduced bronchopulmonary dysplasia (O[2] at 36 weeks' postmenstrual age) or death in extremely low birth weight (ELBW) neonates (relative risk [RR]: 0.89). As with postnatal steroids or other interventions, it is important to ensure that there are no longer-term adverse effects that outweigh neonatal benefits.Primary Objective. To determine if vitamin A supplementation in ELBW infants during the first month after birth affects survival without neurodevelopmental impairment at a corrected age of 18 to 22 months.Design/Methods. Infants enrolled in the National Institute of Child Health and Human Development vitamin A trial were evaluated at 18 to 22 months by carefully standardized assessments: Bayley Mental Index (MDI) and Psychomotor Index (PDI), visual and hearing screens, and physical examination for cerebral palsy (CP). The medical history was also obtained. Neurodevelopmental impairment (NDI) was predefined as 1 of MDI <70, PDI <70, CP, blind in both eyes, or hearing aids in both ears.Results. Of 807 enrolled infants, 133 died before and 16 died after discharge. Five hundred seventy-nine (88%) of the 658 remaining infants were followed up. The primary outcome of NDI or death could be determined for 687 of 807 randomized infants (85%). Baseline characteristics and predischarge and postdischarge mortality were comparable in both study groups. NDI or death by 18 to 22 months occurred in 190 of 345 (55%) infants in the vitamin A group and in 204 of 342 (60%) of the control group (RR: 0.94; 95% confidence interval: 0.80-1.07). RRs for low MDI, low PDI, and CP were also <1.0. We found no evidence that neonatal vitamin A supplementation reduces hospitalizations or pulmonary problems after discharge.Conclusion. Vitamin A supplementation for ELBW infants reduces bronchopulmonary dysplasia without increasing mortality or neurodevelopmental impairment at 18 to 22 months. However, this study was not powered to evaluate small magnitudes of change in long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims: To examine the effects of light on retinal development and function in preterm infants as measured by the electroretinogram (ERG). Secondary outcomes included visual acuity testing, the incidence of retinopathy of prematurity, and general wellbeing, reflected in feeding tolerance, rate of weight gain, and length of hospital stay.Methods: Eligibility criteria for enrollment were birthweight < or = 1250 g and gestational age < or = 31 weeks. Sixty one infants were randomly allocated by 6 hours after birth to a control or treatment group which wore 97% light filtering goggles for a minimum of four weeks or until the infant reached 31 weeks postmenstrual age.Results: There were no significant differences between the two groups in the numbers of electroretinograms performed at 36 weeks of postmenstrual age. Although the sample size was not large enough to exclude clinically important differences in secondary outcomes, no significant differences were observed between the groups in visual acuity testing at 4-6 months corrected age, incidence of retinopathy of prematurity, weight gain, or length of stay.Conclusion: These data support the safety and feasibility of this intervention. A much larger study will be needed to determine whether light reduction to the eyes of very low birthweight infants will reduce the incidence of retinopathy of prematurity or enhance general well-being. [ABSTRACT FROM AUTHOR]

Background: Early administration of high doses of dexamethasone may reduce the risk of chronic lung disease in premature infants but can cause complications. Whether moderate doses would be as effective but safer is not known.Methods: We randomly assigned 220 infants with a birth weight of 501 to 1000 g who were treated with mechanical ventilation within 12 hours after birth to receive dexamethasone or placebo with either routine ventilatory support or permissive hypercapnia. The dexamethasone was administered within 24 hours after birth at a dose of 0.15 mg per kilogram of body weight per day for three days, followed by a tapering of the dose over a period of seven days. The primary outcome was death or chronic lung disease at 36 weeks' postmenstrual age.Results: The relative risk of death or chronic lung disease in the dexamethasone-treated infants, as compared with those who received placebo, was 0.9 (95 percent confidence interval, 0.8 to 1.1). Since the effect of dexamethasone treatment did not vary according to the ventilatory approach, the two dexamethasone groups and the two placebo groups were combined. The infants in the dexamethasone group were less likely than those in the placebo group to be receiving oxygen supplementation 28 days after birth (P=0.004) or open-label dexamethasone (P=0.01), were more likely to have hypertension (P<0.001), and were more likely to be receiving insulin treatment for hyperglycemia (P=0.02). During the first 14 days, spontaneous gastrointestinal perforation occurred in a larger proportion of infants in the dexamethasone group (13 percent, vs. 4 percent in the placebo group; P=0.02). The dexamethasone-treated infants had a lower weight (P=0.02) and a smaller head circumference (P=0.04) at 36 weeks' postmenstrual age.Conclusions: In preterm infants, early administration of dexamethasone at a moderate dose has no effect on death or chronic lung disease and is associated with gastrointestinal perforation and decreased growth. [ABSTRACT FROM AUTHOR]

Background: Hypothermia is protective against brain injury after asphyxiation in animal models. However, the safety and effectiveness of hypothermia in term infants with encephalopathy is uncertain.Methods: We conducted a randomized trial of hypothermia in infants with a gestational age of at least 36 weeks who were admitted to the hospital at or before six hours of age with either severe acidosis or perinatal complications and resuscitation at birth and who had moderate or severe encephalopathy. Infants were randomly assigned to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 degrees C for 72 hours, followed by slow rewarming (hypothermia group). Neurodevelopmental outcome was assessed at 18 to 22 months of age. The primary outcome was a combined end point of death or moderate or severe disability.Results: Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Adverse events were similar in the two groups during the 72 hours of cooling. Primary outcome data were available for 205 infants. Death or moderate or severe disability occurred in 45 of 102 infants (44 percent) in the hypothermia group and 64 of 103 infants (62 percent) in the control group (risk ratio, 0.72; 95 percent confidence interval, 0.54 to 0.95; P=0.01). Twenty-four infants (24 percent) in the hypothermia group and 38 (37 percent) in the control group died (risk ratio, 0.68; 95 percent confidence interval, 0.44 to 1.05; P=0.08). There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19 percent) in the hypothermia group as compared with 19 of 64 (30 percent) in the control group (risk ratio, 0.68; 95 percent confidence interval, 0.38 to 1.22; P=0.20).Conclusions: Whole-body hypothermia reduces the risk of death or disability in infants with moderate or severe hypoxic-ischemic encephalopathy. [ABSTRACT FROM AUTHOR]

Objective: This study investigates whether and to what extent cerebral injury is associated with bilateral blindness in extremely preterm infants, which has been attributed mainly to retinopathy of prematurity (ROP)., Design: Multicentre analysis of children born from 1994 to 2021 at gestational age 22 0/7 to 28 6/7 weeks with follow-up at 18-26 months. Logistic regression examined the adjusted association of bilateral blindness with severe ROP and/or cerebral injury among extremely preterm infants., Exposures: Severe ROP and cerebral injury, the latter defined as any of the following on cranial imaging: ventriculomegaly; blood/increased echogenicity in the parenchyma; cystic periventricular leukomalacia., Main Outcome Measures: Bilateral blindness, defined as a follow-up examination meeting criteria of 'blind-some functional vision' or 'blind-no useful vision' in both eyes., Results: The 19 863 children included had a mean gestational age of 25.6±1.7 weeks, mean birth weight of 782±158 g and 213 (1%) had bilateral blindness. Multiplicative interaction between ROP and cerebral injury was statistically significant. For infants with only severe ROP (n=3130), odds of blindness were 8.14 times higher (95% CI 4.52 to 14.65), and for those with only cerebral injury (n=2836), odds were 8.38 times higher (95% CI 5.28 to 13.28), compared with the reference group without either condition. Risks were not synergistic for infants with both severe ROP and cerebral injury (n=1438, adjusted OR=28.7, 95% CI 16.0 to 51.7, p<0.0001)., Conclusions: In a group of extremely preterm infants, severe ROP and cerebral injury were equally important risk factors for blindness. Besides ROP, clinicians should consider cerebral injury as a cause of blindness in children born extremely preterm., Trial Registration Number: NCT00063063., Competing Interests: Competing interests: NA is an advisor to ResBiotic and Alveolus Bio and serves on the Data and Safety Monitoring Board for Shire/Oak Hill Bio. CMC has a consulting agreement with ReAlta Life Sciences (for a new drug in clinical trials for hypoxic ischaemic encephalopathy), and IP in a company, CryoCell (for a cell therapy for HIE). AD has a grant from the Neonatal Research Network (NRN). CPT is supported by grants from the National Institutes of Health (K23HL157618). CPT is supported by a grant from Owlet Baby Care for an investigator-initiated study (ClinicalTrials.gov identifier: NCT05774470) and also has a patent application pending for a bradycardia predictor and interrupter. VVS is supported by a grant from the American Heart Association (23CDA1048106)., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine whether changes in survival without moderate or severe neurodevelopmental impairment (NDI) at 18-26 months' corrected age from 1999 to 2018 differed between male and female infants., Design: This retrospective cohort study used data from the NICHD Neonatal Research Network hospitals. Robust Poisson regression models were used to estimate adjusted relative risks (aRRs) and 95% CIs for survival without moderate or severe NDI between males and females. Interactions between sex and time were assessed to evaluate temporal differences in the outcome by sex. Variables adjusted for included centre, maternal age, ethnicity/race, gestational age and small for gestational age., Patients: Inborn infants with gestational age of 22-26 weeks at NICHD Neonatal Research Network hospitals from 1999 to 2018., Main Outcome Measure: Change over time in survival without moderate or severe NDI at 18-26 months' corrected age between male and female infants., Results: Of 26 307 infants, 13 045 (49.6%) were male. Survival without moderate or severe NDI declined for both sexes over time, from 32.9% to 30.6% for males and from 47.4% to 40.0% for females, between 1999-2003 and 2014-2018. Males were less likely than females to survive without moderate or severe NDI (aRR=0.80; 95% CI 0.78 to 0.83). Changes in survival without moderate or severe NDI did not differ between males and females., Conclusion: There were no differential changes in survival without moderate or severe NDI between male and female infants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We aimed to determine the incidence of growth failure in infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) and whether initial laparotomy versus peritoneal drainage (PD) impacted the likelihood of growth failure., Summary Background Data: Infants with surgical NEC and SIP have high mortality, and most have neurodevelopmental impairment and poor growth. Existing literature on growth outcomes for these infants is limited., Methods: This is a preplanned secondary study of the Necrotizing Enterocolitis Surgery Trial dataset. The primary outcome was growth failure (Z-score for weight <-2.0) at 18 to 22 months. We used logistic regression, including diagnosis and treatment, as covariates. Secondary outcomes were analyzed using the Fisher exact or Pearson χ2 test for categorical variables and the Wilcoxon rank sum test or one-way ANOVA for continuous variables., Results: Among 217 survivors, 207 infants (95%) had primary outcome data. Growth failure at 18 to 22 months occurred in 24/50 (48%) of NEC infants versus 65/157 (42%) SIP (P=0.4). The mean weight-for-age Z-score at 18 to 22 months in NEC infants was -2.05±0.99 versus -1.84±1.09 SIP (P=0.2), and the predicted mean weight-for-age Z-score SIP (Beta -0.27; 95% CI: -0.53, -0.01; P=0.041). Median declines in weight-for-age Z-score between birth and 18 to 22 months were significant in all infants but most severe (>2) in NEC infants (P=0.2)., Conclusions: This first ever prospective study of growth outcomes in infants with surgical NEC or SIP demonstrates that growth failure is very common, especially in infants with NEC, and persists at 18-22 months., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Most extremely preterm (EP) infants are vitamin D deficient (serum 25-hydroxyvitamin D levels below 20 ng/mL), and optimal supplementation practices for EP infants remain unknown. Our objective is to assess current vitamin D supplementation practices in U.S. neonatal intensive care units (NICU) for EP infants to provide baseline information for the design of future clinical trials., Methods: We conducted an online survey to study vitamin D intake and supplementation practices in U.S. NICUs caring for EP infants. Descriptive statistics compared responses by affiliation and level of care., Results: We analyzed responses from 253 NICUs, representing the majority of academic and level IV centers. Nearly all centers (97%) provided enteral vitamin D supplementation during the NICU stay, with 400 IU/day as the most common dosage (77%). Over half (56%) used feeding volume to initiate supplementation, with 71% of centers starting after achieving at least 120 ml/kg/day. Additionally, 94% of NICUs reported prescribing a vitamin D supplementation at discharge., Conclusions: Most NICUs in the U.S. supplement EP infants with 400 IU/day of enteral vitamin D. Clinical trials of vitamin D supplementation comparing the most common regimen to earlier and higher doses are needed to identify adequate regimens for EP infants., Impact: Despite the prevalence of vitamin D deficiency in extremely preterm (EP) infants at birth, optimal levels and supplementation strategies remain debated. Recent studies have suggested benefits of early high-dose vitamin D supplementation (800 IU/day) for reducing complications like bronchopulmonary dysplasia, infections, and disability. There is US center variation in timing and dose of vitamin D supplementation, being the most common regimen 400 IU/d started after established feedings (≥120 ml/kg/day). These findings inform and highlight the need for clinical trials of usual vs. early, higher-dose vitamin D supplementation to advance clinical outcomes and define desirable blood levels of EP infants., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Vitamin D is necessary to develop healthy lungs and other organs early in life. Most infants born before 28 weeks' gestation have low vitamin D levels at birth and a limited intake during the first month. Enteral vitamin D supplementation is inexpensive and widely used. The appropriate supplementation regimen for extremely preterm infants is controversial, and the effect of different regimens on their blood levels and outcomes is unclear., Methods: Randomized, blinded comparative effectiveness trial to compare two vitamin D supplementation regimens for inborn infants <28 weeks gestation or <1000 g birth weight at a large academic center in the United States. Infants are stratified by birth weight and randomized within 96 h after birth to either routine supplementation (400 IU/day with established feedings) or increased supplementation (800 IU/day with any feedings) during the first 28 days after birth. We hypothesize that the higher and early vitamin D dose (800 IU/day with early feeding) compared to placebo plus routine dose (400 IU/day with established feeding) will substantially increase total 25-hydroxyvitamin D3 levels measured as state-of-art at 1 month, reduce respiratory support at 36 weeks' postmenstrual age (on an ordinal scale predictive of later adverse outcomes), and improve or at least not worsen other important secondary outcomes. The infants in the study will follow up at 22-26 months' corrected age (~2 years) with blinded certified examiners to evaluate neurodevelopmental outcomes. The sample size of a minimum of 180 infants provides >90% power to detect a >95% posterior probability of a 33% increase in serum 25-hydroxy vitamin D3 and >80% power to detect a >80% posterior probability of a relative risk decrease of 20% of reducing respiratory support by intention-to-treat Bayesian analyses using a neutral prior probability., Discussion: Our study will help clarify the uncertain relationship of vitamin D supplementation and its associated serum metabolites to clinical outcomes of extremely preterm infants. Confirmation of our hypotheses would prompt reconsideration of the supplementation regimens used in extremely preterm infants and justify a large multicenter study to verify the generalizability of the results., Trial Registration: ClinicalTrials.gov NCT05459298. Registered on July 14, 2022., (© 2024. The Author(s).)

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial., Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia., Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023., Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age., Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period., Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup)., Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit., Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Importance: Risk-adjusted neonatal intensive care unit (NICU) utilization and outcomes vary markedly across regions and hospitals. The causes of this variation are poorly understood., Objective: To assess the association of hospital-level NICU bed capacity with utilization and outcomes in newborn cohorts with differing levels of health risk., Design, Setting, and Participants: This population-based retrospective cohort study included all Medicaid-insured live births in Texas from 2010 to 2014 using linked vital records and maternal and newborn claims data. Participants were Medicaid-insured singleton live births (LBs) with birth weights of at least 400 g and gestational ages between 22 and 44 weeks. Newborns were grouped into 3 cohorts: very low birth weight (VLBW; <1500 g), late preterm (LPT; 34-36 weeks' gestation), and nonpreterm newborns (NPT; ≥37 weeks' gestation). Data analysis was conducted from January 2022 to October 2023., Exposure: Hospital NICU capacity measured as reported NICU beds/100 LBs, adjusted (ie, allocated) for transfers., Main Outcomes and Measures: NICU admissions and special care days; inpatient mortality and 30-day postdischarge adverse events (ie, mortality, emergency department visit, admission, observation stay)., Results: The overall cohort of 874 280 single LBs included 9938 VLBW (5054 [50.9%] female; mean [SD] birth weight, 1028.9 [289.6] g; mean [SD] gestational age, 27.6 [2.6] wk), 63 160 LPT (33 684 [53.3%] female; mean [SD] birth weight, 2664.0 [409.4] g; mean [SD] gestational age, 35.4 [0.8] wk), and 801 182 NPT (407 977 [50.9%] female; mean [SD] birth weight, 3318.7 [383.4] g; mean [SD] gestational age, 38.9 [1.0] wk) LBs. Median (IQR) NICU capacity was 0.84 (0.57-1.30) allocated beds/100 LB/year. For VLBW newborns, NICU capacity was not associated with the risk of NICU admission or number of special care days. For LPT newborns, birth in hospitals with the highest compared with the lowest category of capacity was associated with a 17% higher risk of NICU admission (adjusted risk ratio [aRR], 1.17; 95% CI, 1.01-1.33). For NPT newborns, risk of NICU admission was 55% higher (aRR, 1.55; 95% CI, 1.22-1.97) in the highest- vs the lowest-capacity hospitals. The number of special care days for LPT and NPT newborns was 21% (aRR, 1.21; 95% CI,1.08-1.36) and 37% (aRR, 1.37; 95% CI, 1.08-1.74) higher in the highest vs lowest capacity hospitals, respectively. Among LPT and NPT newborns, NICU capacity was associated with higher inpatient mortality and 30-day postdischarge adverse events., Conclusions and Relevance: In this cohort study of Medicaid-insured newborns in Texas, greater hospital NICU bed supply was associated with increased NICU utilization in newborns born LPT and NPT. Higher capacity was not associated with lower risk of adverse events. These findings raise important questions about how the NICU is used for newborns with lower risk.

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., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Importance: The benefit of endovascular stroke therapy (EVT) in large vessel occlusion (LVO) ischemic stroke is highly time dependent. Process improvements to accelerate in-hospital workflows are critical., Objective: To determine whether automated computed tomography (CT) angiogram interpretation coupled with secure group messaging can improve in-hospital EVT workflows., Design, Setting, and Participants: This cluster randomized stepped-wedge clinical trial took place from January 1, 2021, through February 27, 2022, at 4 comprehensive stroke centers (CSCs) in the greater Houston, Texas, area. All 443 participants with LVO stroke who presented through the emergency department were treated with EVT at the 4 CSCs. Exclusion criteria included patients presenting as transfers from an outside hospital (n = 158), in-hospital stroke (n = 39), and patients treated with EVT through randomization in a large core clinical trial (n = 3)., Intervention: Artificial intelligence (AI)-enabled automated LVO detection from CT angiogram coupled with secure messaging was activated at the 4 CSCs in a random-stepped fashion. Once activated, clinicians and radiologists received real-time alerts to their mobile phones notifying them of possible LVO within minutes of CT imaging completion., Main Outcomes and Measures: Primary outcome was the effect of AI-enabled LVO detection on door-to-groin (DTG) time and was measured using a mixed-effects linear regression model, which included a random effect for cluster (CSC) and a fixed effect for exposure status (pre-AI vs post-AI). Secondary outcomes included time from hospital arrival to intravenous tissue plasminogen activator (IV tPA) bolus in eligible patients, time from initiation of CT scan to start of EVT, and hospital length of stay. In exploratory analysis, the study team evaluated the impact of AI implementation on 90-day modified Rankin Scale disability outcomes., Results: Among 243 patients who met inclusion criteria, 140 were treated during the unexposed period and 103 during the exposed period. Median age for the complete cohort was 70 (IQR, 58-79) years and 122 were female (50%). Median National Institutes of Health Stroke Scale score at presentation was 17 (IQR, 11-22) and the median DTG preexposure was 100 (IQR, 81-116) minutes. In mixed-effects linear regression, implementation of the AI algorithm was associated with a reduction in DTG time by 11.2 minutes (95% CI, -18.22 to -4.2). Time from CT scan initiation to EVT start fell by 9.8 minutes (95% CI, -16.9 to -2.6). There were no differences in IV tPA treatment times nor hospital length of stay. In multivariable logistic regression adjusted for age, National Institutes of Health Stroke scale score, and the Alberta Stroke Program Early CT Score, there was no difference in likelihood of functional independence (modified Rankin Scale score, 0-2; odds ratio, 1.3; 95% CI, 0.42-4.0)., Conclusions and Relevance: Automated LVO detection coupled with secure mobile phone application-based communication improved in-hospital acute ischemic stroke workflows. Software implementation was associated with clinically meaningful reductions in EVT treatment times., Trial Registration: ClinicalTrials.gov Identifier: NCT05838456.

Objective: The objective of this study was to evaluate whether infants randomized in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Necrotizing Enterocolitis Surgery Trial differed from eligible infants and whether differences affected the generalizability of trial results., Study Design: Secondary analysis of infants enrolled in Necrotizing Enterocolitis Surgery Trial (born 2010-2017, with follow-up through 2019) at 20 US academic medical centers and an observational data set of eligible infants through 2013. Infants born ≤1000 g and diagnosed with necrotizing enterocolitis or spontaneous intestinal perforation requiring surgical intervention at ≤8 weeks were eligible. The target population included trial-eligible infants (randomized and nonrandomized) born during the first half of the study with available detailed preoperative data. Using model-based weighting methods, we estimated the effect of initial laparotomy vs peritoneal drain had the target population been randomized., Results: The trial included 308 randomized infants. The target population included 382 (156 randomized and 226 eligible, non-randomized) infants. Compared with the target population, fewer randomized infants had necrotizing enterocolitis (31% vs 47%) or died before discharge (27% vs 41%). However, incidence of the primary composite outcome, death or neurodevelopmental impairment, was similar (69% vs 72%). Effect estimates for initial laparotomy vs drain weighted to the target population were largely unchanged from the original trial after accounting for preoperative diagnosis of necrotizing enterocolitis (adjusted relative risk [95% CI]: 0.85 [0.71-1.03] in target population vs 0.81 [0.64-1.04] in trial) or spontaneous intestinal perforation (1.02 [0.79-1.30] vs 1.11 [0.95-1.31])., Conclusion: Despite differences between randomized and eligible infants, estimated treatment effects in the trial and target population were similar, supporting the generalizability of trial results., Trial Registration: ClinicalTrials.gov ID: NCT01029353., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Two characteristics of commonly used outcomes in medical research are zero inflation and non-negative integers; examples include the number of hospital admissions or emergency department visits, where the majority of patients will have zero counts. Zero-inflated regression models were devised to analyze this type of data. However, the performance of zero-inflated regression models or the properties of data best suited for these analyses have not been thoroughly investigated., Methods: We conducted a simulation study to evaluate the performance of two generalized linear models, negative binomial and zero-inflated negative binomial, for analyzing zero-inflated count data. Simulation scenarios assumed a randomized controlled trial design and varied the true underlying distribution, sample size, and rate of zero inflation. We compared the models in terms of bias, mean squared error, and coverage. Additionally, we used logistic regression to determine which data properties are most important for predicting the best-fitting model., Results: We first found that, regardless of the rate of zero inflation, there was little difference between the conventional negative binomial and its zero-inflated counterpart in terms of bias of the marginal treatment group coefficient. Second, even when the outcome was simulated from a zero-inflated distribution, a negative binomial model was favored above its ZI counterpart in terms of the Akaike Information Criterion. Third, the mean and skewness of the non-zero part of the data were stronger predictors of model preference than the percentage of zero counts. These results were not affected by the sample size, which ranged from 60 to 800., Conclusions: We recommend that the rate of zero inflation and overdispersion in the outcome should not be the sole and main justification for choosing zero-inflated regression models. Investigators should also consider other data characteristics when choosing a model for count data. In addition, if the performance of the NB and ZINB regression models is reasonably comparable even with ZI outcomes, we advocate the use of the NB regression model due to its clear and straightforward interpretation of the results., (© 2023. The Author(s).)

Background: Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels., Objective: To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34-36 weeks gestational age in infants born ≤ 750 g or < 27 weeks' gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered., Methods: Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks' gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34-36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22-26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis., Discussion: Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing., Trial Registration: Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983 Protocol version: Version 3.2 (10/5/2022)., (© 2023. The Author(s).)

Observational studies are notoriously susceptible to bias, and parallel-group randomized trials are important to identify the best overall treatment for eligible patients. Yet, such trials can be expected to be a misleading indicator of the best treatment for some subgroups or individual patients. In selected circumstances, patients can be treated in n-of-1 trials to address the inherent heterogeneity of treatment response in clinical populations. Such trials help to accomplish the ultimate goal of all biomedical research, to optimize the care of individual patients., Competing Interests: The authors have no conflicts of interest to declare., (© The Author(s) 2023.)

Background: Blood pressure (BP) is often inadequately controlled in children treated for hypertension, and personalized (n-of-1) trials show promise for tailoring treatment choices. We assessed whether patients whose treatment choices are informed by an n-of-1 trial have improved BP control compared to usual care., Methods: A randomized clinical trial was conducted in a pediatric hypertension clinic in Houston from April 2018 to September 2020. Hypertensive adolescents and young adults 10-22 years old were randomized 1:1 to a strategy of n-of-1 trial using ambulatory BP monitoring to inform treatment choice or usual care, with treatment selected by physician preference. The primary outcome was the proportion of patients with ambulatory BP control at 6 months in a Bayesian analysis., Results: Among 49 participants (23 randomized to n-of-1 trials and 26 to usual care), mean age was 15.6 years. Using skeptical priors, we found a 69% probability that n-of-1 trials increased BP control at 6 months (Bayesian odds ratio (OR) 1.24 (95% credible interval (CrI) 0.51, 2.97), and 74% probability using neutral informed priors (OR 1.45 (95% CrI 0.48, 4.53)). Systolic BP was reduced in both groups, with a 93% probability of greater reduction in the n-of-1 trial group (mean difference between groups = -3.6 mm Hg (95% CrI -8.3, 1.28). There was no significant difference in side effect experience or caregiver satisfaction., Conclusions: Among hypertensive adolescents and young adults, n-of-1 trials with ambulatory BP monitoring likely increased the probability of BP control. A large trial is needed to assess their use in clinical practice., Clinicaltrials.gov: NCT03461003., Clinical Trial Registry: ClinicalTrials.gov; NCT03461003., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Randomized controlled trials (RCTs) are challenging, but are the studies most likely to change practice and benefit patients. RCTs investigating neonatal surgical therapies are rare. The Necrotizing Enterocolitis Surgery Trial (NEST) was the first surgical RCT conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN), and multiple lessons were learned. NEST was conducted over a 7.25-year enrollment period and the primary outcome was death or neurodevelopmental impairment (NDI) at 18-22 months corrected age. Surgical investigators designing clinical trials involving neonatal surgical treatments have many considerations to include, including how to study eligible but non-randomized patients, heterogeneity of treatment effect, use of frequentist and Bayesian analyses, assessment of generalizability, and anticipating criticisms during peer review. Surgeons are encouraged to embrace these challenges and seek innovative methods to acquire evidence that will be used to improve patient outcomes., Competing Interests: Disclosures The authors have no conflicts to disclose. While NICHD staff had input into the study design, conduct, analysis, and manuscript drafting, the comments and views of the authors do not necessarily represent the views of NICHD, the National Institutes of Health, the Department of Health and Human Services, or the U.S. Government., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Waldemar A. Carlo, MD is on the board of directors of MEDNAX Services, Inc. All other authors have indicated that they have no conflicts of interest relevant to this article to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The use of a placebo has been considered the best method for controlling bias in a prospective randomized clinical trial and provides the most rigorous test of treatment efficacy for evaluating a medical therapy. Placebos commonly produce clinically important effects particularly in studies where the primary outcomes are subjective. Yet the potential beneficial or harmful effects of placebos are often not addressed in designing a clinical trial, calculating the sample size, seeking consent, or interpreting clinical trial results. In this manuscript, we use an actual study to indicate three approaches that might be considered in seeking informed consent for placebo-controlled trials, and we explore the fundamental ethical and scientific complexities involved with each., (© 2022 by The Hastings Center. All rights reserved.)

Objective: This study aimed to profile the cytokine/chemokine response from day 0 to 7 in infants (≥36 weeks of gestational age) with neonatal encephalopathy (NE) and to explore the association with long-term outcomes., Study Design: This was a secondary study of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network randomized controlled trial of whole body hypothermia for NE. Eligible infants with moderate-severe NE were randomized to cooling or normothermia. Blood spots were collected on days 0 to 1, 2 to 4, and 6 to 7. Twenty-four cytokines/chemokines were measured using a multiplex platform. Surviving infants underwent neurodevelopmental assessment at 6 to 7 years. Primary outcome was death or moderate-severe impairment defined by any of the following: intelligence quotient <70, moderate-severe cerebral palsy (CP), blindness, hearing impairment, or epilepsy., Results: Cytokine blood spots were collected from 109 participants. In total 99 of 109 (91%) were assessed at 6 to 7 years; 54 of 99 (55%) developed death/impairment. Neonates who died or were impaired had lower early regulated upon activation normal T cell expressed and secreted (RANTES) and higher day 7 monocyte chemotactic protein (MCP)-1 levels than neonates who survived without impairment. Though TNF-α levels had no association with death/impairment, higher day 0 to 1 levels were observed among neonates who died/developed CP. On multiple regression analysis adjusted for center, treatment group, sex, race, and level of hypoxic ischemic encephalopathy, higher RANTES was inversely associated with death/impairment (odds ratio (OR): 0.31, 95% confidence interval [CI]: 0.13-0.74), while day seven MCP-1 level was directly associated with death/impairment (OR: 3.70, 95% CI: 1.42-9.61). Targeted cytokine/chemokine levels demonstrated little variation with hypothermia treatment., Conclusion: RANTES and MCP-1 levels in the first week of life may provide potential targets for future therapies among neonates with encephalopathy., Key Points: · Elevation of specific cytokines and chemokines in neonates with encephalopathy has been noted along with increased risk of neurodevelopmental impairment in infancy.. · Cytokine/chemokines at <7 days were assessed among neonates in a trial of hypothermia for HIE.. · Neonates who died or were impaired at 6 to 7 years following hypoxic-ischemic encephalopathy had lower RANTES and higher MCP-1 levels than those who survived without impairment.., Competing Interests: W.A.C. reports having served on the advisory board of Pediatrix Medical Group and Paradigm Health and holding stock options at the Pediatrix Medical Group. C.M.C. reports having served on the data and safety monitoring board for the Inhibitex phase 3 study of Vernonate for the prevention of infections in preterm infants. E.F.D. reports having received support from the Environmental Protection Agency (Lanphear) and the Gerber Foundation. D.K.S. reports having received research support from Pfizer. The other authors have no relevant financial relationships to disclose. A.P. reports partial salary support for WSU/no direct payment from NRN Network. S.S. reports grants from NICHD NRN partial salary support during the conduct of the study. R.D.H. is the Neonatology Editor-in-Chief but had no role in review of the manuscript for AJP. A.D. reports grants from NIH, during the conduct of the study. W.A.C. reports personal fees from Mednax, outside the submitted work. A.R.L. reports grants from NICHD, during the conduct of the study. J.E.T. reports partial salary support for UT Health/no direct payment from NRN Network., (Thieme. All rights reserved.)

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: The aim of this study was 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 to 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: 0.64-1.04). The Bayesian posterior probability that laparotomy was beneficial (risk difference <0) for a preoperative diagnosis of NEC was 97%. For preoperative diagnosis of IP, death or NDI occurred in 69% after laparotomy versus 63% with drainage (aRR, 1.11; 95% CI: 0.95-1.31); Bayesian probability of benefit with laparotomy = 18%., Conclusions: There was no overall difference in death or NDI rates at 18 to 22 months corrected age between initial laparotomy versus drainage. However, the preoperative diagnosis of NEC or IP modified the impact of initial treatment., Competing Interests: The authors report no conflict of interests., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Telemedicine is widely used but has uncertain value. We assessed telemedicine to further improve outcomes and reduce costs of comprehensive care (CC) for medically complex children., Methods: We conducted a single-center randomized clinical trial comparing telemedicine with CC relative to CC alone for medically complex children in reducing care days outside the home (clinic, emergency department, or hospital; primary outcome), rate of children developing serious illnesses (causing death, ICU admission, or hospital stay >7 days), and health system costs. We used intent-to-treat Bayesian analyses with neutral prior assuming no benefit. All participants received CC, which included 24/7 phone access to primary care providers (PCPs), low patient-to-PCP ratio, and hospital consultation from PCPs. The telemedicine group also received remote audiovisual communication with the PCPs., Results: Between August 22, 2018, and March 23, 2020, we randomly assigned 422 medically complex children (209 to CC with telemedicine and 213 to CC alone) before meeting predefined stopping rules. The probability of a reduction with CC with telemedicine versus CC alone was 99% for care days outside the home (12.94 vs 16.94 per child-year; Bayesian rate ratio, 0.80 [95% credible interval, 0.66-0.98]), 95% for rate of children with a serious illness (0.29 vs 0.62 per child-year; rate ratio, 0.68 [0.43-1.07]) and 91% for mean total health system costs (US$33 718 vs US$41 281 per child-year; Bayesian cost ratio, 0.85 [0.67-1.08])., Conclusion: The addition of telemedicine to CC likely reduced care days outside the home, serious illnesses, other adverse outcomes, and health care costs for medically complex children., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have no conflict of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)