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

In a prospective cohort study of 65 inborn infants who were evaluated for late-onset sepsis at72 hours of age in 2 academic neonatal intensive care units, none had parechovirus or enterovirus RNA detected by polymerase chain reaction performed on nasopharyngeal specimens during the first or subsequent sepsis evaluations (n = 80).

BACKGROUND: Empiric administration of ampicillin and gentamicin is recommended for newborns at risk of early-onset sepsis (EOS). There are limited data on antimicrobial susceptibility of all EOS pathogens. METHODS: Retrospective review of antimicrobial susceptibility data from a prospective EOS surveillance study of infants born ≥22 weeks’ gestation and cared for in Neonatal Research Network centers 4/2015–3/2017. Non-susceptible was defined as intermediate or resistant on final result. RESULTS: We identified 239 pathogens (235 bacteria, 4 fungi) in 235 EOS cases among 217,480 live-born infants. Antimicrobial susceptibility data were available for 189/239 (79.1%) isolates. Among 81 gram-positive isolates with ampicillin and/or gentamicin susceptibility data, all were susceptible in vitro to either ampicillin or gentamicin. Among gram-negative isolates with ampicillin and/or gentamicin susceptibility data, 72/94 (76.6%) isolates were non-susceptible to ampicillin, 8/94 (8.5%) were non-susceptible to gentamicin, and 7/96 (7.3%) isolates were non-susceptible to both. Five percent or less of tested gram-negative isolates were non-susceptible to each of 3(rd) or 4(th) generation cephalosporins, piperacillin-tazobactam and carbapenems. Overall, we estimated that 8% of EOS cases were caused by isolates non-susceptible to both ampicillin and gentamicin; these were most likely to occur among preterm, very-low birth weight infants. CONCLUSIONS: The vast majority of contemporary EOS pathogens are susceptible to the combination of ampicillin and gentamicin. Clinicians may consider the addition of broader-spectrum therapy among newborns at highest risk of EOS, but we caution that neither the substitution nor the addition of one single antimicrobial agent is likely to provide adequate empiric therapy in all cases.

For more than 30 years, the Neonatal Research Network (NRN) has conducted studies addressing the epidemiology of neonatal infections, including incidence, microbiology, maternal and neonatal risk factors, associated clinical findings, and outcomes. These studies have provided clinicians and policymakers critical data needed to inform national guidance for infection risk assessment and support daily practice. Further, NRN studies have prompted research into optimal approaches to infection diagnosis, treatment, and antimicrobial stewardship. In this article, we summarize the key findings of NRN infection-related studies, with an emphasis on those published in 2000 or later.

ObjectiveDetermine risk of death or neurodevelopmental impairment (NDI) in infants with late-onset sepsis (LOS) versus late-onset, antibiotic-treated, blood culture-negative conditions (LOCNC).DesignRetrospective cohort study.Setting24 neonatal centres.PatientsInfants born 1/1/2006–31/12/2014, at 22–26 weeks gestation, with birth weight 401–1000 g and surviving >7 days were included. Infants with early-onset sepsis, necrotising enterocolitis, intestinal perforation or both LOS and LOCNC were excluded.ExposuresLOS and LOCNC were defined as antibiotic administration for ≥5 days with and without a positive blood/cerebrospinal fluid culture, respectively. Infants with these diagnoses were also compared with infants with neither condition.OutcomesDeath or NDI was assessed at 18–26 months corrected age follow-up. Modified Poisson regression models were used to estimate relative risks adjusting for covariates occurring ≤7 days of age.ResultsOf 7354 eligible infants, 3940 met inclusion criteria: 786 (20%) with LOS, 1601 (41%) with LOCNC and 1553 (39%) with neither. Infants with LOS had higher adjusted relative risk (95% CI) for death/NDI (1.14 (1.05 to 1.25)) and death before follow-up (1.71 (1.44 to 2.03)) than those with LOCNC. Among survivors, risk for NDI did not differ between the two groups (0.99 (0.86 to 1.13)) but was higher for LOCNC infants (1.17 (1.04 to 1.31)) compared with unaffected infants.ConclusionsInfants with LOS had higher risk of death, but not NDI, compared with infants with LOCNC. Surviving infants with LOCNC had higher risk of NDI compared with unaffected infants. Improving outcomes for infants with LOCNC requires study of the underlying conditions and the potential impact of antibiotic exposure.

Congenital CMV infection (cCMVi) affects 0.5–1% of all live births worldwide, making it the leading cause of sensorineural hearing loss (SNHL) in childhood. The majority of infants with cCMVi have normal hearing at birth, but are at risk of developing late-onset SNHL. Currently, we lack reliable biomarkers to predict the development of SNHL in these infants. Here, we evaluate blood transcriptional profiles in 80 infants with cCMVi (49 symptomatic, 31 asymptomatic), enrolled in the first 3 weeks of life, and followed for 3 years to assess emergence of late-onset SNHL. The biosignatures of symptomatic and asymptomatic cCMVi are indistinguishable, suggesting that immune responses of infants with asymptomatic and symptomatic cCMVi are not different. Random forest analyses of initial samples in infants with cCMVi, irrespective of their clinical classification, identify a 16-gene classifier signature associated with the development of SNHL with 92% accuracy, suggesting its potential value as a biomarker., Congenital CMV infection can result in sensorineural hearing loss, but predicting this outcome is not yet possible. Here, the authors show that while blood gene expression profiles are not substantially different between symptomatic and asymptomatic infants with congenital CMV infection, a 16-gene signature is identified and able to predict late-onset hearing loss in these children.

BACKGROUND AND OBJECTIVE In 2014 at Nationwide Children’s Hospital, the Neonatal Antimicrobial Stewardship Program recommended nafcillin over vancomycin for empirical therapy of possible late-onset sepsis (LOS) in infants without a history of methicillin-resistant Staphylococcus aureus colonization or infection. We report our experience with this guideline and assess its safety. METHODS We retrospectively reviewed all infants who received nafcillin or vancomycin for empirical treatment of possible LOS at 3 NICUs before (January 2013–May 2014) and after (January 2017–March 2019) implementation of a vancomycin reduction guideline. Safety measures included duration of blood culture positivity, recurrence of infection with the same previously identified pathogen in the 14 days after discontinuation of antibiotic therapy, and mortality. RESULTS Among 366 infants who received a first antibiotic course for possible LOS, 84% (95 of 113) and 25% (62 of 253) received empirical therapy with vancomycin before and after the guideline implementation, respectively, representing a 70% reduction. Nafcillin use increased by 368%. Duration of blood culture positivity did not differ before and after the guidance. In 2 infants, antibiotic therapy was restarted within 14 days of discontinuation of the initial therapy for recurrence of the same infection; both had received empirical vancomycin. Overall in-hospital mortality was 10%, and there was no difference before (9%) and after (10%) implementation of the vancomycin reduction guidance (odds ratio, 0.97). CONCLUSIONS Nafcillin can be a safe alternative to vancomycin for empirical therapy of LOS among NICU infants who do not have a history of methicillin-resistant S aureus infection or colonization.

Objective To determine the frequency of abnormal findings on evaluation of neonates with congenital CMV infection who have a normal physical examination Study design Retrospective, 2-center study (1996–2017) that reviewed results of complete blood cell count and platelets, serum alanine aminotransferase (ALT) and bilirubin concentrations, eye examination, cranial ultrasonography or other neuroimaging, and brainstem evoked responses performed on neonates with congenital CMV infection and a normal physical examination Results Of 34 infants with congenital CMV infection and a normal physical examination, 56% (19/34) had ≥1 abnormality: 39%, elevated ALT concentration; 45%, abnormal neuroimaging (five, lenticulostriate vasculopathy; six, intraventricular hemorrhage; four, calcifications); 12%, anemia; 16%, thrombocytopenia; and 3%, chorioretinitis. Seven (21%) infants had sensorineural hearing loss, and 18 infants received antiviral therapy. Conclusion Some infants with congenital CMV infection and a normal physical examination had abnormalities on laboratory or neuroimaging evaluation, which in some cases prompted antiviral treatment.

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.

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

Syphilis in neonates and infants remains a significant public health problem because it is a major cause of fetal and neonatal morbidity and mortality globally. Despite decades of experience with syphilis in adults and infants, maternal and congenital syphilis are increasing substantially in the United States. The vertical transmission, clinical manifestations, diagnosis, evaluation, treatment, and follow-up are reviewed to guide the health care professional in understanding the optimal management of this preventable disease.

Infants born preterm are affected by a hypothalamic-pituitary-thyroid axis that is immature and still developing as they progress closer to corrected term gestation. Multiple risk factors place preterm infants at risk for a hypothyroid state. However, there is variability in thyroid-stimulating hormone cutoff values and limited data on free thyroxine reference intervals to guide clinicians.1584 thyroid-stimulating hormone and 1576 free thyroxine laboratory samples that were originally collected to screen hospitalized infants for delayed-onset of hypothyroidism were retrospectively evaluated from a group of 1087 infants who ranged in postmenstrual age from 25 to 43 weeks gestation at the time of laboratory sample collection. Median thyroid hormone values and reference intervals were established using R and the mixtools package.Thyroid-stimulating hormone reference intervals remained similar across gestational ages from 0.340-9.681 µIU/mL in 25-27 6/7-week infants to 1.090-7.627 µIU/mL in 40-43-weeks infants. For the same age groups, free thyroxine reference intervals increased from 0.42-0.91 ng/dL to 0.87-1.32 ng/dL.The reference intervals identified suggest that infants31 weeks gestation have a higher thyroid-stimulating hormone and lower free thyroxine level at baseline than previously anticipated.The increasing free thyroxine values in preterm to term infants indicate a maturing hypothalamic-pituitary-thyroid axis. Clinicians need thyroid hormone reference intervals that also vary by postmenstrual age to aid the evaluation of sick preterm infants who are at risk of a delayed hypothyroidism diagnosis that can be missed on the initial newborn screen. This study provides one of the largest samples of thyroid-stimulating hormone and free thyroxine data to establish reference intervals in preterm infants. Clinicians may utilize the identified postmenstrual age-based reference intervals to inform follow-up thyroid testing in preterm infants at several weeks postnatal age.

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

BACKGROUND AND OBJECTIVES: Variation in pediatric medical care is common and contributes to differences in patient outcomes. Site-to-site variation in the characteristics and care of infants with neonatal opioid withdrawal syndrome (NOWS) has yet to be quantified. Our objective was to describe site-to-site variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS. METHODS: Cross-sectional study of 1377 infants born between July 1, 2016, and June 30, 2017, who were ≥36 weeks’ gestation, with NOWS (evidence of opioid exposure and NOWS scoring within the first 120 hours of life) born at or transferred to 1 of 30 participating hospitals nationwide. Site-to-site variation for each parameter within the 3 domains was measured as the range of individual site-level means, medians, or proportions. RESULTS: Sites varied widely in the proportion of infants whose mothers received adequate prenatal care (31.3%–100%), medication-assisted treatment (5.9%–100%), and prenatal counseling (1.9%–75.5%). Sites varied in the proportion of infants with toxicology screening (50%–100%) and proportion of infants receiving pharmacologic therapy (6.7%–100%), secondary medications (1.1%–69.2%), and nonpharmacologic interventions including fortified feeds (2.9%–90%) and maternal breast milk (22.2%–83.3%). The mean length of stay varied across sites (2–28.8 days), as did the proportion of infants discharged with their parents (33.3%–91.1%). CONCLUSIONS: Considerable site-to-site variation exists in all 3 domains. The magnitude of the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS. This variation should be considered in future clinical trial development, practice implementation, and policy development.

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.

To determine when infants in the neonatal intensive care unit (NICU) have the first hearing screen performed, and thus inform targeted testing for cytomegalovirus (CMV)-related hearing loss.Retrospective review of electronic health records of infants admitted to a Level 4 outborn NICU and had a first hearing screen performed from 8/2016-8/2018.Among 1498 infants, 546 (36%) had a first hearing screen performed at age21 days when a positive CMV PCR test cannot distinguish congenital from postnatal CMV acquisition. While most infants tested at21 days of age were34 weeks' gestational age (71%), 18% (n = 100) and 11% (n = 59) were ≥34 and ≥37 weeks' gestation, respectively.Targeted CMV testing for failed hearing screen in the NICU is problematic as 36% of infants did not have a hearing screen performed before 21 days of age, supporting the need for CMV screening at NICU admission.

Objectives To determine whether antibiotic use in the first 14 postnatal days in preterm, very low birth weight (birth weight of ≤1500 g) infants is associated with risk after 14 days of age for late-onset sepsis, necrotizing enterocolitis (NEC), or death after controlling for severity of illness using the Clinical Risk Index in Babies II score, and determine whether duration of antibiotic exposure was associated with risk of adverse outcomes. Study design This retrospective cohort study included very low birth weight infants born at ≤326/7 weeks of gestation admitted to the neonatal intensive care unit from September 2010 to June 2014. Infants were excluded if they had major congenital anomalies or culture-proven sepsis, NEC, or death during the first 14 days of life. Antibiotic exposure was recorded as days of therapy and length of therapy in days. Results Of 374 infants, 70 (19%) had late-onset sepsis, NEC, or death after 14 days of age. The median number of antibiotic days of therapy and length of therapy were 5.5 and 3.0, respectively. In multivariate analysis after controlling for severity of illness, each antibiotic day of therapy was associated with a 1.24 times increased risk of sepsis, NEC, or death (OR, 1.24; 95% CI, 1.17-1.31). Risk was similar when length of therapy was used (OR, 1.47; 95% CI, 1.32-1.64). Conclusions After controlling for severity of illness, each day of antibiotic therapy provided to preterm, very low birth weight infants in the first 2 weeks of age is associated with an increased risk of late-onset sepsis, NEC, or death.

A review of the conundrum called mild hypoxic-ischemic encephalopathy (HIE) is provided. During the past decades, the definition of HIE has evolved to accommodate the short window of time required for the initiation of therapeutic hypothermia. Also, neurological evaluations have changed with the use of simpler staging systems that can be applied within the first 6 h of life. In this review, we discuss the challenges in the identification of newborns with “mild HIE” within 6 h after birth, the limitations in the existing early biomarkers of brain injury, and the current knowledge gaps in the long term neurodevelopmental outcomes of infants diagnosed with mild HIE. Progress in the understanding of mild HIE and its sequelae continues to be hindered by the lack of a standardized definition for mild HIE that will reliably identify at-risk infants who may benefit from neuroprotective strategies.

Real-time polymerase chain reaction (PCR) of saliva is highly sensitive for newborn congenital cytomegalovirus (CMV) screening. This study uses nationally published CMV seroprevalence and breastfeeding rates to estimate the contribution of CMV DNA in breast milk to false-positive saliva PCR results. The false-positive rates adjusted for breastfeeding ranged from 0.03% in white Hispanic persons to 0.14% in white non-Hispanic persons. Saliva CMV PCR for newborn screening is highly sensitive, and the low false-positive rates in this study suggest that saliva PCR results are unlikely to be significantly influenced by breastfeeding or other perinatal exposures.

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.

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

Optimal management of the patent ductus arteriosus (PDA) in preterm infants remains controversial. Therefore, studies identifying infants who are most likely to benefit from PDA treatment are needed.We sought to examine if significant intrauterine growth restriction, defined by birth weight z-score, reduces the efficacy of PDA closure with indomethacin or ibuprofen and thereby increases the need for surgical closure of PDA after pharmacologic treatment.We studied infants 23-28weeks' gestation born 2006-2013 at NICHD Neonatal Research Network centers. We examined the responses to PDA treatment with indomethacin and/or ibuprofen and whether the PDA was subsequently closed surgically. Logistic regression generated adjusted odds ratios (ORs) for the associations between the z-score groups (-2, -2 to -0.5, and-0.5) and PDA surgery following pharmacologic treatment.5606 infants were diagnosed with PDA; 3587 (64.0%) received indomethacin or ibuprofen or both, and 909 (25.3%) underwent PDA surgery. Mothers of infants with PDA non-closure were less likely to have hypertension (19% vs. 28%). Infants with non-closure were more likely to be female (53% vs. 49%), have lower gestational age and birth weight and to develop sepsis (42% vs. 31%). Compared to infants with z-score-0.5, PDA surgery was increased among infants with z-score -2 to -0.5 (OR=1.23; 95% CI 1.02-1.47) but not among infants with z-score-2.Infants with birth weight z-score -2 to -0.5 are more likely than normally grown infants to require PDA surgery following pharmacologic treatment.

Objective To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants. Study design Previously generated GWA data from the Neonatal Research Network9s anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p −5 . Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points. Results Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10 −8 ); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values Conclusions No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.

Objective This study aims to describe the frequency and characteristics of anticonvulsant medication treatments initiated in the neonatal period. Study Design We analyzed a cohort of neonates with a seizure diagnosis who were discharged from institutions in the Pediatric Health Information System between 2007 and 2016. Adjusted risk ratios and 95% confidence intervals for characteristics associated with neonatal (≤ 28 days postnatal) anticonvulsant initiation were calculated via modified Poisson regression. Results A total of 6,245 infants from 47 institutions were included. There was a decrease in both phenobarbital initiation within the neonatal period (96.9 to 91.3%, p = 0.015) and continuation at discharge (90.6 to 68.6%, p Conclusion Phenobarbital remains the most widely used neonatal seizure treatment. Levetiracetam is increasingly used as a second line therapy. Increasing levetiracetam use indicates a need for additional study to determine its effectiveness in reducing seizure burden and improving long-term outcomes.

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: Among extremely preterm infants, we evaluated whether bevacizumab therapy compared with surgery for retinopathy of prematurity (ROP) is associated with adverse outcomes in early childhood. METHODS: This study was a retrospective analysis of prospectively collected data on preterm (22–26 + 6/7 weeks’ gestational age) infants admitted to the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers who received bevacizumab or surgery exclusively for ROP. The primary outcome was death or severe neurodevelopmental impairment (NDI) at 18 to 26 months’ corrected age (Bayley Scales of Infant and Toddler Development, Third Edition cognitive or motor composite score RESULTS: The cohort (N = 405; 214 [53%] boys; median [interquartile range] gestational age: 24.6 [23.9–25.3] weeks) included 181 (45%) infants who received bevacizumab and 224 (55%) who underwent ROP surgery. Infants treated with bevacizumab had a lower median (interquartile range) birth weight (640 [541–709] vs 660 [572.5–750] g; P = .02) and longer durations of conventional ventilation (35 [21–58] vs 33 [18–49] days; P = .04) and supplemental oxygen (112 [94–120] vs 105 [84.5–120] days; P = .01). Death or severe NDI (adjusted odds ratio [aOR] 1.42; 95% confidence interval [CI] 0.94 to 2.14) and severe NDI (aOR 1.14; 95% CI 0.76 to 1.70) did not differ between groups. Odds of death (aOR 2.54 [95% CI 1.42 to 4.55]; P = .002), a cognitive score CONCLUSIONS: In this multicenter cohort of preterm infants, ROP treatment modality was not associated with differences in death or NDI, but the bevacizumab group had higher mortality and poor cognitive outcomes in early childhood. These data reveal the need for a rigorous appraisal of ROP therapy.

Respiratory syncytial virus (RSV) remains the leading cause for hospitalizations in infants worldwide, resulting in significant health and financial burden. Since 1998, the humanized monoclonal antibody palivizumab remains the only available option licensed for the prevention of severe RSV disease in high-risk children, namely premature infants and those with chronic lung disease and congenital heart disease. In 2014, the American Academy of Pediatrics modified the recommendations on the use of RSV prophylaxis in these high-risk children, and limited its use to premature infants born at

Objective To determine the frequency of detection of cytomegalovirus (CMV) in surgical or autopsy intestinal tissue from infants with necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP) of the small bowel. Study design This was a retrospective cohort study of infants in the neonatal intensive care unit at Nationwide Children's Hospital, Columbus, Ohio, with NEC (Bell stage ≥2B) or SIP from 2000 to 2016. Paraffin-embedded surgical or autopsy intestinal tissues were examined for CMV by polymerase chain reaction (PCR) and immunohistochemistry (IHC), and clinical characteristics of CMV-positive vs CMV-negative cases were compared. Results CMV was detected by PCR or IHC in 7 (4%) of 178 infants with surgical or autopsy- confirmed NEC (n = 6) or SIP (n = 1). Among 143 NEC cases (123 surgical, 20 autopsy), CMV was detected in 6 (4%): 4 (2 surgical, 2 autopsy) by both PCR and IHC, and 2 (surgical) by PCR only. Among 35 SIP cases (32 surgical, 3 autopsy), 1 (3%) surgical case was positive, by PCR only. CMV-associated NEC cases had lower median gestational age (24 vs 28 weeks; P = .02), birth weight (649 vs 1121 g; P = .04), and platelet count (16 000/mm3 vs 50 000/mm3; P = .018) compared with CMV-negative cases, respectively. No association was found with receipt of maternal milk, age at NEC diagnosis, male sex, cholestasis, or mortality. Conclusions CMV was detected in intestinal tissue from 4% of NEC or SIP cases (NEC, 4%; SIP, 3%). Lower gestational age, lower birth weight, and thrombocytopenia were significantly associated with detection of CMV in NEC or SIP cases.

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 .

Background Invasive candidiasis (IC) is an important cause of sepsis in premature infants and is associated with a high risk of death and neurodevelopmental impairment. Prevention of IC has become a major focus in very low birth weight infants, with fluconazole increasingly used as prophylaxis. Methods We identified all randomized, placebo-controlled trials evaluating fluconazole prophylaxis in premature infants conducted in the United States. We obtained patient-level data from the study investigators and performed an aggregated analysis. The occurrence of each endpoint in infants who received prophylaxis with fluconazole vs placebo was compared. Endpoints evaluated were IC or death, IC, death, Candida colonization, and fluconazole resistance among tested isolates. Safety endpoints evaluated included clinical and laboratory parameters. Results Fluconazole prophylaxis reduced the odds of IC or death, IC, and Candida colonization during the drug exposure period compared with infants given placebo: odds ratios of 0.48 (95% confidence interval [CI], .30-.78), 0.20 (95% CI, .08-.51), and 0.28 (95% CI, .18-.41), respectively. The incidence of clinical and laboratory adverse events was similar for infants who received fluconazole compared with placebo. There was no statistically significant difference in the proportion of tested isolates that were resistant to fluconazole between the fluconazole and placebo groups. Conclusions Fluconazole prophylaxis is effective and safe in reducing IC and Candida colonization in premature infants, and has no impact on resistance.

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.

Prolonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.Cohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.A total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC.The proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC.

Objectives Extremely premature infants are at high risk of developing invasive candidiasis; fluconazole prophylaxis is safe and effective for reducing invasive candidiasis in this population but further study is needed. We sought to better understand the effect of prophylactic fluconazole on a selection of fluconazole-resistant Candida species. Methods We evaluated the susceptibility to fluconazole of Candida isolates from premature infants ( Results Three hundred and sixty-one infants received fluconazole (n = 188) or placebo (n = 173). After the baseline period, Candida colonization was significantly lower in the fluconazole group compared with placebo during periods 1 (5% versus 27%; P Conclusions Fluconazole prophylaxis decreased Candida albicans and ‘non-albicans’ Candida colonization and was associated with a slightly higher fluconazole MIC for colonizing Candida isolates.

BackgroundViral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear.MethodsPost hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy.ResultsHigher baseline VL was associated with central nervous system involvement (3.82 log, range 1–5.65 vs 3.32 log, range 1–5.36; P = .001), thrombocytopenia (3.68 log, range 1–5.65 vs 3.43 log, range 1–5.36; P = .03), and transaminitis at presentation (3.73 log, range 1–5.60 vs 3.39 log, range 1–5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing.ConclusionsIn infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes.

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

Congenital syphilis remains a major public health problem worldwide, and its incidence is increasing in the United States. This review highlights the ongoing problem of this preventable infection, and discusses vertical transmission and clinical manifestations while providing a practical algorithm for the evaluation and management of infants born to mothers with reactive serologic tests for syphilis. Every case of congenital syphilis must be seen as a failure of our public health system to provide optimal prenatal care to pregnant women, as congenital syphilis can be prevented by early and repeated prenatal serologic screening of mothers and penicillin treatment of infected women, their sexual partners, and their newborn infants.

BACKGROUND The recent occurrence of congenital syphilis in Columbus, OH, raised concern for an increase in syphilis among women and infants. The objectives were to examine the rates of syphilis among men, women and infants in Ohio from 2003 to 2016 and compare these rates to the rest of the United States. METHODS This retrospective study evaluated cases of syphilis among men, women and infants from 2003 to 2016 using data from the Ohio Department of Health and the Centers for Disease Control and Prevention. RESULTS In Ohio from 2003 to 2016, the number of all syphilis cases among women significantly increased from 153 (2.6/100,000) to 294 (5.2/100,000), respectively (b = 0.26; P = 0.001; 95% confidence interval [CI]: 0.137-0.382). From 2003 to 2016, congenital syphilis in Ohio also increased significantly from 3 (2/100,000) to 13 cases (9.3/100,000), respectively (b = 1.05; P ≤ 0.001; 95% CI: 0.687-1.408). The increase in congenital syphilis mirrored the increase in all cases of syphilis in women but not with the rates of primary and secondary syphilis. Among men, cases of primary and secondary syphilis increased significantly in Ohio and the rest of the United States, from 156 (2.8/100,000) and 5956 (4.2/100,000) in 2003 to 622 (10.5/100,000) and 24,724 (15.6/100,000) in 2016, respectively (Ohio: b = 0.55; P < 0.001; 95% CI: 0.426-0.679; United States: b = 0.77; P < 0.001; 95% CI: 0.629-0.916). CONCLUSIONS The association of congenital syphilis with all syphilis cases in women highlights the importance of reporting all cases and not just primary and secondary syphilis. The increase in congenital syphilis reinforces the recommendation for repeat maternal screening during pregnancy.

Background/Purpose A non-standardized approach to caring for infants after pyloromyotomy for pyloric stenosis was associated with prolonged postoperative length of stay (pLOS) at our institution. We studied the impact of a standardized postoperative care protocol on pLOS, patients' clinical course, and nursing care. Methods A retrospective chart review identified that 27% of infants who underwent uncomplicated pyloromyotomy had prolonged pLOS, defined as more than one postoperative midnight. A comprehensive postoperative care protocol was developed for infants undergoing pyloromyotomy. Patients were recruited prospectively and those with complications were excluded. A sample size of 70 in each cohort (historic and prospective) allowed 80% power to detect a 50% reduction in the proportion of patients with prolonged pLOS (α=0.05). The prospective group and historic cohort were compared using nonparametric statistics. Results The historic cohort had 70 patients and the prospective cohort had 66. Protocol implementation resulted in fewer patients with prolonged pLOS, shorter time to feeds, fewer feeds to discharge, less emesis, and improved nursing documentation. Conclusion Implementation of a postoperative care protocol improved various aspects of patient care and nursing care studied. Protocols outline a patient's course and serve as a common platform for communication among care providers; they can facilitate, expedite, and enhance patient care.

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.

Prolonged or unnecessary antibiotic use is associated with adverse outcomes in neonates. Our objectives were to quantify all antibiotic use in a Level-III neonatal intensive care unit and to identify scenarios where their use could be reduced.Surveillance and evaluation of all antibiotic use provided to every infant admitted to a Level-III neonatal intensive care unit from 10/3/11 to 11/30/12 was performed. Types of antibiotics, reasons for their initiation, discontinuation and duration, as well as clinical, laboratory and outcome data were recorded. Antibiotic use was quantified by days of therapy (DOT) per 1000 patient-days (PD).A total of 1607 infants were included. The total antibiotic use was 9165 DOT (343.2 DOT/1000 PD; 5.7 DOT/infant). Seventy-two percent of infants received 1 (43%) or more (29%) courses of antibiotics. Gentamicin (46%), ampicillin (39%) and oxacillin (8%) were the most frequently used agents. Ninety-four percent of antibiotic use (323 DOT/1000 PD) was empiric therapy for suspected infection. Sixty-three percent (216.2 DOT/1000 PD) was discontinued at approximately 48 hours when cultures were sterile (68%48 hours, 32%≤48 hours). Twenty-six percent of all antibiotic use (89.4 DOT/1000 PD) was therapy for ≥5 days despite sterile cultures; pneumonia (16%) and "culture-negative" sepsis (8%) were the major contributors. Five percent (17.4 DOT/1000 PD) of antibiotic use was for culture-proven sepsis, 5% (16.6 DOT/1000 PD) was penicillin prophylaxis for group B Streptococcus and 1% (3.5 DOT/1000 PD) was preprocedural prophylaxis.Narrow-spectrum therapy accounted for92% of antibiotic use and would not be monitored by most stewardship programs. Only 5% of antibiotic usage was due to culture-proven infection. Pneumonia and "culture-negative" sepsis were frequent reasons for prolonged therapy; further study of these conditions may allow reduction in treatment duration.

A 35-day-old female with severe combined immunodeficiency developed cytomegalovirus (CMV) meningitis before undergoing hematopoietic stem cell transplantation. Strategies for timely diagnosis of neonates with congenital or acquired CMV infection and prevention of CMV acquisition in the era of universal newborn severe combined immunodeficiency screening are needed.

Objective To determine the frequency of detection of cytomegalovirus (CMV) among infants evaluated for late-onset sepsis in the neonatal intensive care unit (NICU). Methods This study was a prospective cohort study. Results During the 13-month study, 84 infants underwent 116 sepsis evaluations, and CMV DNA was detected in saliva in three (4%) infants (median: gestational age 28 weeks, birth weight 950 g), representing 5% (n=6) of all sepsis evaluations. One infant had CMV DNA detected in saliva in all four sepsis evaluations. Two infants had acquired CMV infection, while the timing of CMV acquisition could not be determined in one infant. Two of the three infants had concomitant Gram-negative bacteremia and urinary tract infections (UTIs), two developed severe bronchopulmonary dysplasia (BPD) and none died. Conclusion Detection of CMV DNA in saliva occurred in 4% of infants and 5% of sepsis evaluations. Persistence of CMV DNA shedding in saliva made attribution of clinical illness difficult to ascertain.

Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).

Importance Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective To characterize the outcomes of extremely preterm neonates younger than 27 weeks’ gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks’ postmenstrual age. Design, Setting, and Participants This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks’ gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks’ postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

BACKGROUND: Premature infants are at high risk of early-onset sepsis (EOS) relative to term infants, and most are administered empirical antibiotics after birth. We aimed to determine if factors evident at birth could be used to identify premature infants at lower risk of EOS. METHODS: Study infants were born at 22 to 28 weeks’ gestation in Neonatal Research Network centers from 2006 to 2014. EOS was defined by isolation of pathogenic species from blood or cerebrospinal fluid culture at ≤72 hours age. Infants were hypothesized as “low risk” for EOS when delivered via cesarean delivery, with membrane rupture at delivery, and absence of clinical chorioamnionitis. Frequency of prolonged antibiotics (≥5 days) was compared between low-risk infants and all others. Risks of mortality, EOS, and other morbidities were assessed by using regression models adjusted for center, race, antenatal steroid use, multiple birth, sex, gestation, and birth weight. RESULTS: Of 15 433 infants, 5759 (37%) met low-risk criteria. EOS incidence among infants surviving >12 hours was 29 out of 5640 (0.5%) in the low-risk group versus 209 out of 8422 (2.5%) in the comparison group (adjusted relative risk = 0.24 [95% confidence interval, 0.16–0.36]). Low-risk infants also had significantly lower combined risk of EOS or death ≤12 hours. Prolonged antibiotics were administered to 34% of low-risk infants versus 47% of comparison infants without EOS. CONCLUSIONS: Delivery characteristics of extremely preterm infants can be used to identify those with significantly lower incidence of EOS. Recognition of differential risk may help guide decisions to limit early antibiotic use among approximately one-third of these infants.

Objective To analyze reasons for low enrollment in an RCT of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late-preterm newborns. Study Design The original study was a multicenter RCT. Eligibility: ≥34 weeks’ gestation

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