Group B Streptococcus Infection in Extremely Preterm Neonates and Neurodevelopmental Outcomes at 2 Years.

BACKGROUND: This study was performed to determine the incidence of group B Streptococcus (GBS) disease among extremely preterm infants and assess to risk of death or neurodevelopmental impairment (NDI) at a corrected age of 18-26 months. METHODS: In this observational cohort study of infants enrolled in a multicenter registry, the incidence of GBS disease was assessed in infants born in 1998-2016 at 22-28 weeks' gestation and surviving for >12 hours. The composite outcome, death or NDI, was assessed in infants born in 1998-2014 at 22-26 weeks' gestation. Infection was defined as GBS isolation in blood or cerebrospinal fluid culture at ≤72 hours (early-onset disease [EOD]) or >72 hours (late-onset disease [LOD]) after birth. Using Poisson regression models, the outcome was compared in infants with GBS disease, infants infected with other pathogens, and uninfected infants. RESULTS: The incidence of GBS EOD (2.70/1000 births [95% confidence interval (CI), 2.15-3.36]) and LOD (8.47/1000 infants [7.45-9.59]) did not change significantly over time. The adjusted relative risk of death/NDI was higher among infants with GBS EOD than in those with other infections (adjusted relative risk, 1.22 [95% CI, 1.02-1.45]) and uninfected infants (1.44 [1.23-1.69]). Risk of death/NDI did not differ between infants with GBS LOD and comparator groups. GBS LOD occurred at a significantly later age than non-GBS late-onset infection. Among infants surviving >30 days, the risk of death was higher with GBS LOD (adjusted relative risk, 1.90 [95% CI, 1.36-2.67]), compared with uninfected infants. CONCLUSIONS: In a cohort of extremely preterm infants, the incidence of GBS disease did not change during the study period. The increased risk of death or NDI with GBS EOD, and of death among some infants with GBS LOD, supports the need for novel preventive strategies for disease reduction. CLINICAL TRIALS REGISTRATION: NCT00063063.

Surgery-Associated Infections among Infants Born Extremely Preterm.

OBJECTIVE: To assess the burden of invasive infection following surgery (surgery-associated infections [SAI]) among infants born extremely premature. STUDY DESIGN: This was an observational, prospective study of infants born at gestational age 22-28 weeks hospitalized for >3 days, between April 1, 2011, to March 31, 2015, in academic centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. SAI was defined by culture-confirmed bacteremia, fungemia, or meningitis ≤14 days following a surgical procedure. RESULTS: Of 6573 infants, 1154 (18%) who underwent surgery were of lower gestational age (mean [SD]: 25.5 [1.6] vs 26.2 [1.6], P < .001), lower birth weight (803 [220] vs 886 [244], P < .001), and more likely to have a major birth defect (10% vs 3%, P < .001); 64% had 1 surgery (range 1-10 per infant). Most underwent gastrointestinal procedures (873, 76%) followed by central nervous system procedures (150, 13%). Eighty-five (7%) infants had 90 SAIs (78 bacteremia, 5 fungemia, 1 bacteremia and meningitis, 6 meningitis alone). Coagulase-negative staphylococci were isolated in 36 (40%) SAI and were isolated with another organism in 5 episodes. Risk of SAI or death ≤14 days after surgery was greater after gastrointestinal compared with central nervous system procedures (16% vs 7%, adjusted relative risk [95% CI]: 1.95 [1.15-3.29], P = .01). Death ≤14 days after surgery occurred in 141 of the 1154 infants; 128 deaths occurred after gastrointestinal surgeries. CONCLUSIONS: Surgical procedures were associated with bacteremia, fungemia, or meningitis in 7% of infants. The epidemiology of invasive postoperative infections as described in this report may inform the selection of empiric antimicrobial therapy and postoperative preventive care.

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

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

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

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

Neurodevelopmental and Growth Outcomes of Extremely Preterm Infants with Short Bowel Syndrome.

OBJECTIVE: To determine if preterm infants with surgical necrotizing enterocolitis (sNEC) or spontaneous intestinal perforation (SIP) with short bowel syndrome (SBS) have worse neurodevelopmental and growth outcomes than those with sNEC/SIP without SBS, and those with no necrotizing enterocolitis, SIP, or SBS. STUDY DESIGN: We undertook a retrospective analysis of prospectively collected data from infants born between 22 and 26 weeks of gestation in the National Institute of Child Health and Human Development Neonatal Research Network centers from January 1, 2008, to December 31, 2016. Survivors were assessed at 18-26 months corrected age by standardized neurologic examination and Bayley Scales of Infant and Toddler Development, Third Edition. The primary outcome was moderate-severe neurodevelopmental impairment. Growth was assessed using World Health Organization z-score standards. Adjusted relative risks were estimated using modified Poisson regression models. RESULTS: Mortality was 32%, 45%, and 21% in the 3 groups, respectively. Eighty-nine percent of survivors were seen at 18-26 months corrected age. Moderate-severe neurodevelopmental impairment was present in 77% of children with SBS compared with 62% with sNEC/SIP without SBS (adjusted relative risk, 1.22; 95% CI, 1.02-1.45; P = .03) and 44% with no necrotizing enterocolitis, SIP, or SBS (adjusted relative risk, 1.60; 95% CI, 1.37-1.88; P < .001). Children with SBS had lowcognitive, language, and motor scores than children with sNEC/SIP without SBS. At follow-up, length and head circumference z-scores remained more than 1 SD below the mean for children with SBS. CONCLUSIONS: Preterm infants with sNEC/SIP and SBS had increased risk of adverse neurodevelopmental outcomes at 18-26 months corrected age and impaired growth compared with peers with sNEC/SIP without SBS or without any of these conditions.

Impact of Early-Onset Sepsis and Antibiotic Use on Death or Survival with Neurodevelopmental Impairment at 2 Years of Age among Extremely Preterm Infants.

OBJECTIVE: To evaluate the hypothesis that early-onset sepsis increases risk of death or neurodevelopmental impairment (NDI) among preterm infants; and that among infants without early-onset sepsis, prolonged early antibiotics alters risk of death/NDI. STUDY DESIGN: Retrospective cohort study of infants born at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers (2006-2014) at 22-26 weeks of gestation and birth weight 401-1000 g. Early-onset sepsis defined as growth of a pathogen from blood or cerebrospinal fluid culture ≤72 hours after birth. Prolonged early antibiotics was defined as antibiotics initiated ≤72 hours and continued ≥5 days without culture-confirmed infection, necrotizing enterocolitis, or spontaneous perforation. Primary outcome was death before follow-up or NDI assessed at 18-26 months corrected age. Poisson regression was used to estimate adjusted relative risk (aRR) and CI for early-onset sepsis outcomes. A propensity score for receiving prolonged antibiotics was derived from early clinical factors and used to match infants (1:1) with and without prolonged antibiotic exposure. Log binomial models were used to estimate aRR for outcomes in matched infants. RESULTS: Among 6565 infants, those with early-onset sepsis had higher aRR (95% CI) for death/NDI compared with infants managed with prolonged antibiotics (1.18 [1.06-1.32]) and to infants without prolonged antibiotics (1.23 [1.10-1.37]). Propensity score matching was achieved for 4362 infants. No significant difference in death/NDI (1.04 [0.98-1.11]) was observed with or without prolonged antibiotics among the matched cohort. CONCLUSIONS: Early-onset sepsis was associated with increased risk of death/NDI among extremely preterm infants. Among matched infants without culture-confirmed infection, prolonged early antibiotic administration was not associated with death/NDI.

Prolonged duration of early antibiotic therapy in extremely premature infants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Risk factors for possible serious bacterial infection in a rural cohort of young infants in central India.

BACKGROUND: Possible serious bacterial infection (PBSI) is a major cause of neonatal mortality worldwide. We studied risk factors for PSBI in a large rural population in central India where facility deliveries have increased as a result of a government financial assistance program. METHODS: We studied 37,379 pregnant women and their singleton live born infants with birth weight ≥ 1.5 kg from 20 rural primary health centers around Nagpur, India, using data from the 2010-13 population-based Maternal and Newborn Health Registry supported by NICHD's Global Network for Women's and Children's Health Research. Factors associated with PSBI were identified using multivariable Poisson regression. RESULTS: Two thousand one hundred twenty-three infants (6 %) had PSBI. Risk factors for PSBI included nulliparity (RR 1.13, 95 % CI 1.03-1.23), parity > 2 (RR 1.30, 95 % CI 1.07-1.57) compared to parity 1-2, first antenatal care visit in the 2nd/3rd trimester (RR 1.46, 95 % CI 1.08-1.98) compared to 1st trimester, administration of antenatal corticosteroids (RR 2.04, 95 % CI 1.60-2.61), low birth weight (RR 3.10, 95 % CI 2.17-4.42), male sex (RR 1.20, 95 % CI 1.10-1.31) and lack of early initiation of breastfeeding (RR 3.87, 95 % CI 2.69-5.58). CONCLUSION: Infants who are low birth weight, born to mothers who present late to antenatal care or receive antenatal corticosteroids, or born to nulliparous women or those with a parity > 2, could be targeted for interventions before and after delivery to improve early recognition of signs and symptoms of PSBI and prompt referral. There also appears to be a need for a renewed focus on promoting early initiation of breastfeeding following delivery in facilities. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov ( NCT01073475 ).

Trends in the incidence of possible severe bacterial infection and case fatality rates in rural communities in Sub-Saharan Africa, South Asia and Latin America, 2010-2013: a multicenter prospective cohort study.

BACKGROUND: Possible severe bacterial infections (pSBI) continue to be a leading cause of global neonatal mortality annually. With the recent publications of simplified antibiotic regimens for treatment of pSBI where referral is not possible, it is important to know how and where to target these regimens, but data on the incidence and outcomes of pSBI are limited. METHODS: We used data prospectively collected at 7 rural community-based sites in 6 low and middle income countries participating in the NICHD Global Network's Maternal and Newborn Health Registry, between January 1, 2010 and December 31, 2013. Participants included pregnant women and their live born neonates followed for 6 weeks after delivery and assessed for maternal and infant outcomes. RESULTS: In a cohort of 248,539 infants born alive between 2010 and 2013, 32,088 (13 %) neonates met symptomatic criteria for pSBI. The incidence of pSBI during the first 6 weeks of life varied 10 fold from 3 % (Zambia) to 36 % (Pakistan), and overall case fatality rates varied 8 fold from 5 % (Kenya) to 42 % (Zambia). Significant variations in incidence of pSBI during the study period, with proportions decreasing in 3 sites (Argentina, Kenya and Nagpur, India), remaining stable in 3 sites (Zambia, Guatemala, Belgaum, India) and increasing in 1 site (Pakistan), cannot be explained solely by changing rates of facility deliveries. Case fatality rates did not vary over time. CONCLUSIONS: In a prospective population based registry with trained data collectors, there were wide variations in the incidence and case fatality of pSBI in rural communities and in trends over time. Regardless of these variations, the burden of pSBI is still high and strategies to implement timely diagnosis and treatment are still urgently needed to reduce neonatal mortality. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT01073475 ).

The Antenatal Corticosteroids Trial (ACT)'s explanations for neonatal mortality - a secondary analysis.

BACKGROUND: The Antenatal Corticosteroid Trial assessed the feasibility, effectiveness, and safety of a multifaceted intervention to increase the use of antenatal corticosteroids (ACS) in mothers at risk of preterm birth at all levels of care in low and middle-income countries. The intervention effectively increased the use of ACS but was associated with an overall increase in neonatal deaths. We aimed to explore plausible pathways through which this intervention increased neonatal mortality. METHODS: We conducted a series of secondary analyses to assess whether ACS or other components of the multifaceted intervention that might have affected the quality of care contributed to the increased mortality observed: 1) we compared the proportion of neonatal deaths receiving ACS between the intervention and control groups; 2) we compared the antenatal and delivery care process in all births between groups; 3) we compared the rates of possible severe bacterial infection between groups; and 4) we compared the frequency of factors related to ACS administration or maternal high risk conditions at administration between the babies who died and those who survived 28 days among all births in the intervention group identified as high risk for preterm birth and received ACS. RESULTS: The ACS exposure among the infants who died up to 28 days was 29 % in the intervention group compared to 6 % in controls. No substantial differences were observed in antenatal and delivery care process between groups. The risk of pSBI plus neonatal death was significantly increased in intervention clusters compared to controls (2.4 % vs. 2.0 %, adjusted RR 1.17, 95 % CI 1.04-1.30, p = 0.008], primarily for infants with birth weight at or above the 25(th) percentile. Regarding factors related to ACS administration, term infants who died were more likely to have mothers who received ACS within 7 days of delivery compared to those who survived 28 days (26.5 % vs 17.9 %, p = 0.014), and their mothers were more likely to have been identified as high risk for hypertension and less likely for signs of preterm labor. CONCLUSIONS: These results suggest that ACS more than other components of the intervention may have contributed to the overall increased neonatal mortality. ACS may have also been involved in the observed increased risk of neonatal infection and death. Further trials are urgently needed to clarify the effectiveness and safety of ACS on neonatal health in low resource settings.

Trends in Care Practices, Morbidity, and Mortality of Extremely Preterm Neonates, 1993-2012.

IMPORTANCE: Extremely preterm infants contribute disproportionately to neonatal morbidity and mortality. OBJECTIVE: To review 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers. DESIGN, SETTING, PARTICIPANTS: Prospective registry of 34,636 infants, 22 to 28 weeks' gestation, birth weight of 401 to 1500 g, and born at 26 network centers between 1993 and 2012. EXPOSURES: Extremely preterm birth. MAIN OUTCOMES AND MEASURES: Maternal/neonatal care, morbidities, and survival. Major morbidities, reported for infants who survived more than 12 hours, were severe necrotizing enterocolitis, infection, bronchopulmonary dysplasia, severe intracranial hemorrhage, cystic periventricular leukomalacia, and/or severe retinopathy of prematurity. Regression models assessed yearly changes and were adjusted for study center, race/ethnicity, gestational age, birth weight for gestational age, and sex. RESULTS: Use of antenatal corticosteroids increased from 1993 to 2012 (24% [348 of 1431 infants]) to 87% (1674 of 1919 infants]; P < .001), as did cesarean delivery (44% [625 of 1431 births] to 64% [1227 of 1921]; P < .001). Delivery room intubation decreased from 80% (1144 of 1433 infants) in 1993 to 65% (1253 of 1922) in 2012 (P < .001). After increasing in the 1990s, postnatal steroid use declined to 8% (141 of 1757 infants) in 2004 (P < .001), with no significant change thereafter. Although most infants were ventilated, continuous positive airway pressure without ventilation increased from 7% (120 of 1666 infants) in 2002 to 11% (190 of 1756 infants) in 2012 (P < .001). Despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age (median, 26 weeks [37% {109 of 296} to 27% {85 of 320}]; adjusted relative risk [RR], 0.93 [95% CI, 0.92-0.94]). Rates of other morbidities declined, but bronchopulmonary dysplasia increased between 2009 and 2012 for infants at 26 to 27 weeks' gestation (26 weeks, 50% [130 of 258] to 55% [164 of 297]; P < .001). Survival increased between 2009 and 2012 for infants at 23 weeks' gestation (27% [41 of 152] to 33% [50 of 150]; adjusted RR, 1.09 [95% CI, 1.05-1.14]) and 24 weeks (63% [156 of 248] to 65% [174 of 269]; adjusted RR, 1.05 [95% CI, 1.03-1.07]), with smaller relative increases for infants at 25 and 27 weeks' gestation, and no change for infants at 22, 26, and 28 weeks' gestation. Survival without major morbidity increased approximately 2% per year for infants at 25 to 28 weeks' gestation, with no change for infants at 22 to 24 weeks' gestation. CONCLUSIONS AND RELEVANCE: Among extremely preterm infants born at US academic centers over the last 20 years, changes in maternal and infant care practices and modest reductions in several morbidities were observed, although bronchopulmonary dysplasia increased. Survival increased most markedly for infants born at 23 and 24 weeks' gestation and survival without major morbidity increased for infants aged 25 to 28 weeks. These findings may be valuable in counseling families and developing novel interventions. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00063063.

Fetal growth and risk of stillbirth: a population-based case-control study.

BACKGROUND: Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. METHODS AND FINDINGS: We conducted a population-based case-control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. CONCLUSIONS: Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies. Please see later in the article for the Editors' Summary.

Early sepsis does not increase the risk of late sepsis in very low birth weight neonates.

OBJECTIVE: To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS). STUDY DESIGN: Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the National Institute of Child Health and Human Development Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤ 72 hours of birth (EOS) or >72 hours (LOS) and antimicrobial therapy for ≥ 5 days or death <5 days while receiving therapy. Regression models were used to assess risk of death or LOS by 120 days and LOS by 120 days among survivors to discharge or 120 days, adjusting for gestational age and other covariates. RESULTS: Of 34,396 infants studied, 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120 days did not differ overall for infants with EOS compared with those without EOS [risk ratio (RR): 0.99 (0.89-1.09)] but was reduced in infants born at <25 weeks gestation [RR: 0.87 (0.76-0.99), P = .048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR: 0.88 (0.75-1.02)], but LOS risk was reduced in infants with birth weight 401-750 g who had EOS [RR: 0.80 (0.64-0.99), P = .047]. CONCLUSIONS: Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.

An algorithm for the estimation of gestational age at the time of fetal death.

BACKGROUND: Accurate assignment of gestational age (GA) at time of fetal death is important for research and clinical practice. An algorithm to estimate GA at fetal death was developed and evaluated. METHODS: The algorithm developed by the Stillbirth Collaborative Research Network (SCRN) incorporated clinical and post-mortem data. The SCRN conducted a population-based case-control study of women with stillbirths and livebirths from 2006 to 2008 in five geographical catchment areas. Rules were developed to estimate a due date, identify an interval during which death likely occurred, and estimate GA at the time of fetal death. Reliability of using fetal foot length to estimate GA at death was assessed. RESULTS: The due date estimated for 620 singleton stillbirths studied was considered clinically reliable for 87%. Only 25.2% of stillbirths were documented alive within 2 days before diagnosis and 47.6% within 1 week of diagnosis. The algorithm-derived estimate of GA at time of fetal death was one or more weeks earlier than the GA at delivery for 43.5% of stillbirths. GA estimated from fetal foot length agreed with GA by algorithm within 2 weeks for 75% within a subset of well-dated stillbirths. CONCLUSIONS: Precise assignment of GA at death, defined as reliable dating criteria and a short interval (≤1 week) during which fetal death was known to have occurred, was possible in 46.6% of cases. Fetal foot length is a relatively accurate measure of GA at death and should be collected in all stillbirth cases.

Bloodstream infections in very low birth weight infants with intestinal failure.

OBJECTIVE: To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSIs) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC). STUDY DESIGN: Infants weighing 401-1500 g at birth who survived for >72 hours and received care at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers were studied. The frequency of culture-positive BSI and pathogens were compared in infants with medically managed NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, the duration of parenteral nutrition (PN) and other outcomes were evaluated. RESULTS: A total of 932 infants were studied (IF, n = 78; surgical NEC without IF, n = 452; medical NEC, n = 402). The proportion with BSI after diagnosis of NEC was higher in the infants with IF than in those with surgical NEC (P = .007) or medical NEC (P < .001). Gram-positive pathogens were most frequent. Among infants with IF, an increased number of infections was associated with longer hospitalization and duration of PN (median stay: 172 for those with 0 infections, 188 days for those with 1 infection, and 260 days for those with ≥2 infections [P = .06]; median duration of PN: 90, 112, and 115 days, respectively [P = .003]) and decreased achievement of full feeds during hospitalization (87%, 67%, and 50%, respectively; P = .03). CONCLUSION: Recurrent BSIs are common in very low birth weight infants with IF. Gram-positive bacteria were the most commonly identified organisms in these infants.

Outcome of extremely preterm infants (<1,000 g) with congenital heart defects from the National Institute of Child Health and Human Development Neonatal Research Network.

Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401-1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998, and December 31, 2005. Neonatal morbidities and 18-22 months' corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index <70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small-for-gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18-22 months' corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20 % of infants survived without NDI.

Neonatal infections: Insights from a multicenter longitudinal research collaborative.

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.

Antimicrobial Susceptibility Profiles Among Neonatal Early-onset Sepsis Pathogens.

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 April 2015-March 2017. Nonsusceptible 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 gentamicin susceptibility data, all were susceptible in vitro to either ampicillin or gentamicin. Among Gram-negative isolates with ampicillin and gentamicin susceptibility data, 72/94 (76.6%) isolates were nonsusceptible to ampicillin, 8/94 (8.5%) were nonsusceptible to gentamicin, and 7/96 (7.3%) isolates were nonsusceptible to both. Five percent or less of tested Gram-negative isolates were nonsusceptible to each of third or fourth generation cephalosporins, piperacillin-tazobactam, and carbapenems. Overall, we estimated that 8% of EOS cases were caused by isolates nonsusceptible 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 1 single antimicrobial agent is likely to provide adequate empiric therapy in all cases.

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

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

T cell cytokines and the risk of blood stream infection in extremely low birth weight infants.

Cytokines mediate the host immune response to infectious micro-organisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6, and IL-10) and inflammatory cytokines (Interferon-γ [INF-γ], tumor necrosis factor-ß [TNF-ß], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the five sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (p=0.01), and higher levels of the regulatory cytokines, IL-6 (p=0.01) and IL-10 (p<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.