To determine in extremely low birth weight (ELBW) infants if elevated blood inteferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-18, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGFβ) are associated with need for shunt following severe intraventricular hemorrhage (IVH), or with ventricular dilation following milder grades /no IVH.
Whole blood cytokines were measured on postnatal days 1, 3, 7, 14, and 21. Maximum IVH grade in the first 28d, and shunt surgery or ventricular dilation on subsequent ultrasound (28d -36 w PMA) were determined.
Of 902 infants in the NICHD NRN Cytokine study who survived to 36w/discharge, 3.1% had shunts. Of the 12% of infants with severe (Gr III–IV) IVH, 26% had a shunt associated with elevated TNF-α. None of the infants without IVH (69%) or with Gr I (12%) or II (7%) IVH received shunts, but 8.4% developed ventricular dilation, associated with lower IFN-γ and higher IL-18.
Statistically significant but clinically non-discriminatory alterations in blood cytokines were noted in infants with severe IVH who received shunts and in those without severe IVH who developed ventricular dilation. Blood cytokines are likely associated with brain injury but may not be clinically useful as biomarkers for white matter damage.
Infant; premature; Cytokines; Hydrocephalus; Intraventricular hemorrhage; Intracranial hemorrhage
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
Candida; neonate; mortality; neurodevelopmental impairment
Permanent ductal closure involves anatomic remodeling, in which transforming growth factor (TGF)-β appears to play a role. Our objective was to evaluate the relationship, if any, between blood spot TGF-β on day 3 and day 7 of life and patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants. Prospective observational study involving ELBW infants (n = 968) in the National Institute of Child Health and Human Development Neonatal Research Network who had TGF-β measured on filter paper spot blood samples using a Luminex assay. Infants with a PDA (n = 493) were significantly more immature, had lower birth weights, and had higher rates of respiratory distress syndrome than those without PDA (n = 475). TGF-β on days 3 and 7 of life, respectively, were significantly lower among neonates with PDA (median 1,177 pg/ml [range 642–1,896]; median 1,386 pg/ml [range 868–1,913]) compared with others without PDA (median 1,334 pg/ml [range 760–2,064]; median 1,712 pg/ml [range 1,014–2,518 pg/ml]). The significant difference persisted when death or PDA was considered a composite outcome. TGF-β levels were not significantly different among subgroups of infants with PDA who were not treated (n = 51) versus those who were treated medically (n = 283) or by surgical ligation (n = 159). TGF-β was not a significant predictor of death or PDA (day 3 odds ratio [OR] 0.99, 95 % confidence interval [CI] 0.83–1.17; day 7 OR 0.88, 95 % CI 0.74–1.04) on adjusted analyses. Our results suggest that blood spot TGF-β alone is unlikely to be a reliable biomarker of a clinically significant PDA or its responsiveness to treatment.
Transforming growth factor; Patent ductus arteriosus; Preterm; Neonate
To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.
This was a prospective pilot RCT of infants 230/7 – 266/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. 161 (44%) infants were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study due to the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.
This pilot RCT was not feasible due to low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.
Extremely preterm infant; hypotension; hydrocortisone; dopamine; informed consent
Methods are required to predict prognosis with changes in clinical course. Death or neurodevelopmental impairment in extremely premature neonates can be predicted at birth/admission to the ICU by considering gender, antenatal steroids, multiple birth, birth weight, and gestational age. Predictions may be improved by using additional information available later during the clinical course. Our objective was to develop serial predictions of outcome by using prognostic factors available over the course of NICU hospitalization.
Data on infants with birth weight ≤1.0 kg admitted to 18 large academic tertiary NICUs during 1998–2005 were used to develop multivariable regression models following stepwise variable selection. Models were developed by using all survivors at specific times during hospitalization (in delivery room [n = 8713], 7-day [n = 6996], 28-day [n = 6241], and 36-week postmenstrual age [n = 5118]) to predict death or death/neurodevelopmental impairment at 18 to 22 months.
Prediction of death or neurodevelopmental impairment in extremely premature infants is improved by using information available later during the clinical course. The importance of birth weight declines, whereas the importance of respiratory illness severity increases with advancing postnatal age. The c-statistic in validation models ranged from 0.74 to 0.80 with misclassification rates ranging from 0.28 to 0.30.
Dynamic models of the changing probability of individual outcome can improve outcome predictions in preterm infants. Various current and future scenarios can be modeled by input of different clinical possibilities to develop individual “outcome trajectories” and evaluate impact of possible morbidities on outcome.
logistic models; premature infant; predictive value of tests; prognosis
We sought to determine if a center’s approach to care of premature infants at the youngest gestational ages (22–24 weeks’ gestation) is associated with clinical outcomes among infants of older gestational ages (25–27 weeks’ gestation).
Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks’ gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks’ gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity.
Our study included 3631 infants 22 to 24 weeks’ gestation and 5227 infants 25 to 27 weeks’ gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22- to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants.
This study suggests that physicians’ willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants.
low-birth weight infant; NICUs; treatment; patient outcome assessment
Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight infants (ELBW), is lacking. We hypothesized that cytokine profiles in the 1st 21 days of life in ELBW with FS differ from those with bacterial sepsis (BS) or no sepsis (NS).
In a secondary analyses of the NICHD Cytokine study, three groups were defined - FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3±1, 7±2, 14±3, and 21±3 and sepsis group was explored.
Of 1066 infants, 89 had FS and 368 had BS. Compared to BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (p<0.05). Analyses controlling for covariates showed significant group differences over time for IFN-γ, IL-10, IL-18, TGF-β and TNF-α (p<0.05).
Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-β and TNF-α in FS, BS or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.
Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24–34 weeks gestational age, but not before 24 weeks because of lack of data. However, many infants born before 24 weeks are provided intensive care now.
To determine if antenatal corticosteroids are associated with improvement in major outcomes in infants born at 22 and 23 weeks.
Design, Setting, Participants
Data for this cohort study were collected prospectively on 401–1000 gram inborn infants (N=10,541) of 22–25 weeks gestation born between 1993–2009 at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4,924 (86.5%) of the infants born in 1993–2008 who survived to 18–22 months. Logistic regression models generated adjusted odds ratios, controlling for maternal and neonatal variables.
Main Outcome Measures
Mortality and neurodevelopmental impairment at 18–22 months corrected age
Death or neurodevelopmental impairment at 18–22 months was lower for infants whose mothers received antenatal corticosteroids born at 23 weeks (antenatal corticosteroids, 83.4% vs no antenatal corticosteroids, 90.5%; adjusted odds ratio 0.58; 95% CI, 0.42–0.80), at 24 weeks (antenatal corticosteroids, 68.4% vs no antenatal corticosteroids, 80.3%; adjusted odds ratio 0.62; 95% CI, 0.49–0.78), and at 25 weeks (antenatal corticosteroids, 52.7% vs no antenatal corticosteroids, 67.9%; adjusted odds ratio 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids, 90.2% vs no antenatal corticosteroids, 93.1%; adjusted odds ratio 0.80; 95% CI, 0.29–12.21). Death by 18–22 months, hospital death, death/intraventricular hemorrhage/periventricular leukomalacia, and death/necrotizing enterocolitis were significantly lower for infants born at 23, 24, and 25 weeks gestational age if the mothers had received antenatal corticosteroids but the only outcome significantly lower at 22 weeks was death/necrotizing enterocolitis (antenatal corticosteroids, 73.5% vs no antenatal corticosteroids, 84.5%; adjusted odds ratio 0.54; 95% CI, 0.30–0.97).
Among infants born at 23–25 weeks gestation, use of antenatal corticosteroids compared to non-use was associated with a lower rate of death or neurodevelopmental impairment at 18–22 months.
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
Extremely low birth weight infants often require rehospitalization during infancy. Our objective was to identify at the time of discharge which extremely low birth weight infants are at higher risk for rehospitalization.
Data from extremely low birth weight infants in Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers from 2002–2005 were analyzed. The primary outcome was rehospitalization by the 18- to 22-month follow-up, and secondary outcome was rehospitalization for respiratory causes in the first year. Using variables and odds ratios identified by stepwise logistic regression, scoring systems were developed with scores proportional to odds ratios. Classification and regression-tree analysis was performed by recursive partitioning and automatic selection of optimal cutoff points of variables.
A total of 3787 infants were evaluated (mean ± SD birth weight: 787 ± 136 g; gestational age: 26 ± 2 weeks; 48% male, 42% black). Forty-five percent of the infants were rehospitalized by 18 to 22 months; 14.7% were rehospitalized for respiratory causes in the first year. Both regression models (area under the curve: 0.63) and classification and regression-tree models (mean misclassification rate: 40%–42%) were moderately accurate. Predictors for the primary outcome by regression were shunt surgery for hydrocephalus, hospital stay of >120 days for pulmonary reasons, necrotizing enterocolitis stage II or higher or spontaneous gastrointestinal perforation, higher fraction of inspired oxygen at 36 weeks, and male gender. By classification and regression-tree analysis, infants with hospital stays of >120 days for pulmonary reasons had a 66% rehospitalization rate compared with 42% without such a stay.
The scoring systems and classification and regression-tree analysis models identified infants at higher risk of rehospitalization and might assist planning for care after discharge.
logistic models; infant; premature; predictive value of tests
To examine the predictive validity of the amplitude integrated electroencephalogram (aEEG) and stage of encephalopathy among infants with hypoxic-ischemic encephalopathy (HIE) eligible for therapeutic whole-body hypothermia.
Neonates were eligible for this prospective study if moderate or severe HIE occurred at <6 hours and an aEEG was obtained at <9 hours of age. The primary outcome was death or moderate/severe disability at 18 months.
There were 108 infants (71 with moderate HIE and 37 with severe HIE) enrolled in the study. aEEG findings were categorized as normal, with continuous normal voltage (n = 12) or discontinuous normal voltage (n = 12), or abnormal, with burst suppression (n = 22), continuous low voltage (n = 26), or flat tracing (n = 36). At 18 months, 53 infants (49%) experienced death or disability. Severe HIE and an abnormal aEEG were related to the primary outcome with univariate analysis, whereas severe HIE alone was predictive of outcome with multivariate analysis. Addition of aEEG pattern to HIE stage did not add to the predictive value of the model; the area under the curve changed from 0.72 to 0.75 (P = .19).
The aEEG background pattern did not significantly enhance the value of the stage of encephalopathy at study entry in predicting death and disability among infants with HIE.
neonatal hypoxic-ischemic encephalopathy; amplitude integrated EEG
Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at https://neonatal.rti.org.
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
bronchopulmonary dysplasia; prematurity; low-birth-weight infant
Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen.
To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers.
Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence.
Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%).
In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
neonatal sepsis; group B streptococcal disease; Escherichia coli infection
To determine (1) the magnitude of clustering of bronchopulmonary dysplasia (36 weeks) or death (the outcome) across centers of the Eunice Kennedy Shriver National Institute of Child and Human Development National Research Network, (2) the infant-level variables associated with the outcome and estimate their clustering, and (3) the center-specific practices associated with the differences and build predictive models.
Data on neonates with a birth weight of <1250 g from the cluster-randomized benchmarking trial were used to determine the magnitude of clustering of the outcome according to alternating logistic regression by using pairwise odds ratio and predictive modeling. Clinical variables associated with the outcome were identified by using multivariate analysis. The magnitude of clustering was then evaluated after correction for infant-level variables. Predictive models were developed by using center-specific and infant-level variables for data from 2001 2004 and projected to 2006.
In 2001–2004, clustering of bronchopulmonary dysplasia/death was significant (pairwise odds ratio: 1.3; P < .001) and increased in 2006 (pairwise odds ratio: 1.6; overall incidence: 52%; range across centers: 32%–74%); center rates were relatively stable over time. Variables that varied according to center and were associated with increased risk of outcome included lower body temperature at NICU admission, use of prophylactic indomethacin, specific drug therapy on day 1, and lack of endotracheal intubation. Center differences remained significant even after correction for clustered variables.
Bronchopulmonary dysplasia/death rates demonstrated moderate clustering according to center. Clinical variables associated with the outcome were also clustered. Center differences after correction of clustered variables indicate presence of as-yet unmeasured center variables.
logistic models; infant; premature; predictive value of tests; clustering
Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low-birth-weight (<1000 g) infants. We quantify risk factors predicting infection in high-risk premature infants and compare clinical judgment with a prediction model of invasive candidiasis.
The study involved a prospective observational cohort of infants <1000 g birth weight at 19 centers of the NICHD Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: 1) potentially modifiable risk factors and 2) a clinical model at time of blood culture to predict candidiasis.
Invasive candidiasis occurred in 137/1515 (9.0%) infants and was documented by positive culture from ≥ 1 of these sources: blood (n=96), cerebrospinal fluid (n=9), urine obtained by catheterization (n=52), or other sterile body fluid (n=10). Mortality was not different from infants who had positive blood culture compared to those with isolated positive urine culture. Incidence varied from 2–28% at the 13 centers enrolling ≥ 50 infants. Potentially modifiable risk factors (model 1) included central catheter, broad-spectrum antibiotics (e.g., third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model (model 2) had an area under the receiver operating characteristic curve of 0.79, and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. Performance of clinical judgment did not vary significantly with level of training.
Prior antibiotics, presence of a central catheter, endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.
Candidiasis; premature infant; risk factors
To examine the impact of birth at night, on the weekend, and during July or August – the first months of the academic year – and the impact of resident duty-hour restrictions on mortality and morbidity of VLBW infants.
Outcomes were analyzed for 11,137 infants with birth weight 501–1250 grams enrolled in the NICHD Neonatal Research Network registry 2001–2005. Approximately half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessment at 18–22 months was completed for 4,508 infants. Mortality (7-day and 28-day), short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth: night vs day, weekend vs weekday, and July or August vs other months, and after vs before implementation of resident duty-hour restrictions.
There was no effect of hour, day, or month of birth on mortality and no impact on the risks of short-term morbidities except the risk of ROP requiring operative treatment was lower for infants born during the late night hours than during the day. There was no impact of timing of birth on neurodevelopmental outcome except the risk of hearing impairment or death was slightly lower among infants born in July or August compared with other months. The introduction of resident and fellow duty-hour restrictions had no impact on mortality or neurodevelopmental outcome. The only change in short-term morbidity after duty-hour restrictions were introduced was an increase in the risk of ROP (stage 2 or higher).
In this network of academic centers, the timing of birth and the introduction of duty-hour restrictions had little effect on the risks of mortality and morbidity of VLBW infants, suggesting that staffing patterns were adequate to provide consistent care.
Neonatal; preterm infants; morbidity/mortality; resident education/training; workforce
The heptavalent pneumococcal-CRM197 conjugate vaccine (PCV-7) has been incompletely studied in very-low-birth-weight (VLBW, ≤1500 grams) infants.
To assess PCV-7 immunogenicity in VLBW, premature infants. We hypothesized that the frequency of post-vaccine antibody concentrations ≥0.15 µg/mL would vary directly with birth weight.
This was a multi-center observational study. Infants 401–1500 grams birth weight and <32 0/7 weeks gestation, stratified by birth weight, were enrolled from 9 NICHD Neonatal Research Network centers. Infants received PCV-7 at 2, 4 and 6 months after birth and had blood drawn 4–6 weeks following the third dose. Antibodies against the 7 vaccine serotypes were measured by enzyme-linked immunosorbent assay.
Of 369 enrolled infants, 244 completed their primary vaccine series by 8 months and had serum obtained. Subjects were 27.8 ± 2.2 (mean ± standard deviation) weeks gestation and 1008 ± 282 grams birth weight. Twenty-six percent had bronchopulmonary dysplasia and 16% had received postnatal glucocorticoids. Infants 1001–1500 grams birth weight were more likely than those 401–1000 grams to achieve antibody concentrations ≥0.15 µg/mL against the least two immunogenic serotypes (6B: 96% v. 85%, P = 0.003 and 23F: 97% v. 88%, P = 0.009). In multiple logistic regression analysis, lower birth weight, postnatal glucocorticoid use, lower weight at blood draw and Caucasian race were each independently associated with antibody concentrations <0.35 µg/mL against serotypes 6B and/or 23F.
When compared with larger premature infants, infants weighing ≤1000 grams at birth have similar antibody responses to most, but not all, PCV-7 vaccine serotypes.
Infant, premature; infant, very low birth weight; pneumococcal vaccines; immunization; vaccines
Matrix metalloproteinases (MMP) and chemokines appear to be induced by hyperoxia in preclinical studies. We hypothesized that O2 exposure immediately after birth is associated with altered blood spot MMP 9 and β chemokine concentrations. The following analytes were measured on blood spots on days 1 and 3 of life, using luminex technology in 1059 infants (birth weights < 1000 grams) in the NICHD Neonatal Research Network: MMP 9, monocyte chemoattractant protein 1 (MCP 1), macrophage inflammatory proteins (MIP 1α and β), and Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES). Infants administered O2 continually from 6 to 24 hours of life (n=729), when compared to those with < 6 hours exposure (n=330), had significantly lower mean birth weight and higher rate of respiratory distress syndrome (p≤ 0.002). On day 3, MCP 1 was higher and RANTES lower among infants with early prolonged O2 exposure. After adjusting for covariates, prolonged early O2 exposure retained a statistically significant association with higher MCP 1 on day 3 (p=0.003). The consistent association between O2 exposure and MCP 1 among extremely preterm infants suggests that further investigation of its role in oxidative injury is warranted.
This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).
Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.
Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤ 12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified.
Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
extremely low gestation; very low birth weight; morbidity; death
Inflammation mediated by cytokines may be important in the pathogenesis of bronchopulmonary dysplasia and the competing outcome of death in extremely low birth weight infants.
To develop multi-variable logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at 36w post-menstrual age using clinical and cytokine data from the first 28 days.
1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development had 25 cytokines measured from blood collected within 4 h of birth and on days 3, 7, 14, and 21. Stepwise regression using peak values of the 25 cytokines and 15 clinical variables identified variables associated with BPD/death. Multi-variable logistic regression was done for bronchopulmonary dysplasia/death using variables selected by stepwise regression. Similar analyses were also done using average cytokine values from days 0–21, days 0–3, and from days 14–21.
Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. Combining results from all models, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukins-1β, -6, -8, -10, and interferon-γ and lower concentrations of interleukin-17, RANTES, and tumor necrosis factor-β. Compared to models with only clinical variables, addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.
The overall pattern of cytokines suggests bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T-lymphocytes.
Logistic models; Infant; premature; Predictive value of tests
To determine the relative contribution of clinical data versus head ultrasound (HUS) in predicting neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
2103 ELBW infants (<1000g) admitted to a National Institute of Child Health and Human Development Neonatal Research Network center who had a HUS within the first 28 days, a repeat one around 36 weeks’ post-menstrual age, and neurodevelopmental assessment at 18–22 months corrected age were selected. Multivariate logistic regression models were developed using clinical and/or HUS variables. The primary outcome was the predictive abilities of the HUS done before 28 days after birth and closer to 36 weeks post-menstrual age, either alone or in combination with “Early” and “Late” clinical variables.
Models using clinical variables alone predicted NDI better than models with only HUS variables at both 28 days and 36 weeks (both p < 0.001), and addition of the HUS data did not improve prediction. NDI was absent in 30% and 28% of the infants with grade IV intracranial hemorrhage or periventricular leukomalacia, respectively, but was present in 39% of the infants with a normal head ultrasound.
Clinical models were better than head ultrasound models in predicting neurodevelopment.
Logistic models; Predictive value of tests; ROC curve; Infant; premature; Intracerebral hemorrhage; Leukomalacia; periventricular
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
Death or severe disability is so common following an Apgar score of 0 at 10 minutes in observational studies that the Neonatal Resuscitation Program suggests considering discontinuation of resuscitation after 10 minutes of effective CPR.
To determine if Apgar scores at 10 minutes are associated with death or disability in early childhood following perinatal hypoxic-ischemic encephalopathy (HIE).
Design, Setting, and Patients
This is a secondary analysis of infants enrolled in the NICHD Neonatal Research Network hypothermia trial. Infants ≥ 36 weeks gestation had clinical and/or biochemical abnormalities at birth, and encephalopathy at < 6 hours. Logistic regression and classification and regression tree (CART) analysis was used to determine associations between Apgar scores at 10 minutes and neurodevelopmental outcome adjusting for covariates. Associations are expressed as odds ratios (OR) and 95% confidence interval (CI).
Main Outcome Measure
Death or disability (moderate or severe) at 18–22 months of age.
Twenty of 208 infants were excluded (missing data). More than 90% of infants had Apgar scores of 0–2 at 1 minute and Apgars at 5 and 10 minutes shifted to progressively higher values; at 10 minutes 27% of infants had Apgar scores of 0–2. After adjustment each point decrease in Apgar score at 10 minutes was associated with a 45% increase in the odds of death or disability (OR 1.45, CI 1.22–1.72). Death or disability occurred in 76, 82 and 80% of infants with Apgar scores at 10 minutes of 0, 1 and 2, respectively. CART analysis indicated that Apgar scores at 10 minutes were discriminators of outcome.
Apgar scores at 10 minutes provide useful prognostic data before other evaluations are available for infants with HIE. Death or moderate/severe disability is common but not uniform with Apgar scores < 3; caution is needed before adopting a specific time interval to guide duration of resuscitation.
Apgar scores; Hypoxic-Ischemic Encephalopathy; cardiopulmonary resuscitation