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1.  Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage 
Objective
To determine whether death and/or neurodevelopmental impairment (NDI) after severe intracranial hemorrhage (ICH; grade 3 or 4) differs by gestational age (GA) at birth in extremely low birth weight (ELBW) infants.
Study Design
Demographic, perinatal and neonatal factors potentially contributing to NDI for ELBW infants (23 to 28 weeks gestation) were obtained retrospectively; outcome data came from the ELBW Follow-up Study. NDI was defined at 18 to 22 months corrected age as moderate/severe cerebral palsy, Bayley Scales of Infant Development II cognitive or motor score <70, and/or blindness or deafness. Characteristics of younger versus older infants with no versus severe ICH associated with death or NDI were compared. Generalized linear mixed models predicted death or NDI in each GA cohort.
Result
Of the 6638 infants, 61.8% had no ICH and 13.6% had severe ICH; 39% of survivors had NDI. Risk-adjusted odds of death or NDI and death were higher in the lower GA group. Lower GA increased the odds of death before 30 days for infants with severe ICH. Necrotizing enterocolitis (particularly surgical NEC), late onset infection, cystic periventricular leukomalacia and post-natal steroids contributed to mortality risk. NDI differed by GA in infants without ICH and grade 3, but not grade 4 ICH. Contributors to NDI in infants with severe ICH included male gender, surgical NEC and post-hemorrhagic hydrocephalus requiring a shunt.
Conclusion
GA contributes to the risk of death in ELBW infants, but not NDI among survivors with severe ICH. Male gender, surgical NEC and need for a shunt add additional risk for NDI.
doi:10.1038/jp.2012.91
PMCID: PMC3777699  PMID: 22814942
infant; premature; extremely low birth weight; death; neurodevelopmental impairment
2.  Outcomes of Extremely Low Birth Weight Infants with Acidosis at Birth 
OBJECTIVES
To test the hypothesis that acidosis at birth is associated with the combined primary outcome of death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants, and to develop a predictive model of death/NDI exploring perinatal acidosis as a predictor variable.
STUDY DESIGN
The study population consisted of ELBW infants born between 2002-2007 at NICHD Neonatal Research Network hospitals. Infants with cord blood gas data and documentation of either mortality prior to discharge or 18-22 month neurodevelopmental outcomes were included. Multiple logistic regression analysis was used to determine the contribution of perinatal acidosis, defined as a cord blood gas with a pH<7 or base excess (BE)<-12, to death/NDI in ELBW infants. In addition, a multivariable model predicting death/NDI was developed.
RESULTS
3979 patients were identified of whom 249 had a cord gas pH<7 or BE<-12 mEq/L. 2124 patients (53%) had the primary outcome of death/NDI. After adjustment for confounding variables, pH<7 and BE<-12 mEq/L were each significantly associated with death/NDI (OR=2.5[1.6,4.2]; and OR=1.5[1.1,2.0], respectively). However, inclusion of pH or BE did not improve the ability of the multivariable model to predict death/NDI.
CONCLUSIONS
Perinatal acidosis is significantly associated with death/NDI in ELBW infants. Perinatal acidosis is infrequent in ELBW infants, however, and other factors are more important in predicting death/NDI.
doi:10.1136/archdischild-2013-304179
PMCID: PMC4274605  PMID: 24554564
Cord blood gas; Premature infant; Preterm infant; Neurodevelopmental impairment
3.  Twin Gestation and Neuro-developmental Outcome in Extremely Low Birth Weight Infants 
Pediatrics  2009;123(2):e220-e227.
Objective
To compare the risk-adjusted incidence of death or neuro-developmental impairment at 18–22 months corrected age, between twin and singleton extremely low birth weight infants.
Hypothesis
Twin gestation is independently associated with increased risk of death or adverse neuro-developmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Design/Methods
Retrospective study of inborn extremely low birth weight infants (BW 401– 1000g) admitted to NICHD Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18–22 months corrected age. Neuro-developmental impairment (NDI), the primary outcome variable, was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss needing amplification, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of less than 70. Death was included with NDI as a composite outcome since it is a competing variable. Results were compared for both twins, twin A, twin B, same sex twins, unlike sex twins and singleton infants. Logistic regression analysis was done to control for demographic and clinical factors that were different among the groups.
Results
The cohort of infants who either died or were assessed for NDI consisted of 7,630 singleton infants and 1,376 twins. Logistic regression adjusting for clinical and socio-demographic risk factors showed an increased risk of death or NDI for twins as a group when compared with the singletons (OR-1.39, 95% CI- 1.19–1.63). On analyzing twin A and B separately as well, risk of death or NDI was increased in both twin A (OR-1.32, 95% CI- 1.09–1.59) and for twin B (OR-1.47, 95% CI- 1.21–1.78), when compared with singleton infants.
Conclusions
Twin gestation in ELBW infants is associated with an independent increased risk of death or NDI at 18–22 months corrected age, compared to ELBW singleton gestation infants. Both first and second born twins are at increased risk of death or NDI when compared to singleton ELBW infants.
doi:10.1542/peds.2008-1126
PMCID: PMC2842087  PMID: 19139085
twins; neuro-developmental impairment; extremely low birth weight infants
4.  Is phototherapy exposure associated with better or worse outcomes in 501–1000 gram birth weight infants? 
Aim
To compare risk-adjusted outcomes at 18–22 months corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.
Methods
Outcomes at 18–22 months corrected age included death, neurodevelopmental impairment (NDI), and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for center and other potentially confounding variables.
Results
Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501–1000 g BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI 0.60 –1.20), death, or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).
Conclusions
Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded due to bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501–750g BW NoPTx group is concerning, and consistent with NRN Trial results.
doi:10.1111/j.1651-2227.2011.02175.x
PMCID: PMC3505994  PMID: 21272067
5.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
doi:10.1093/cid/cir800
PMCID: PMC3258271  PMID: 22144537
6.  Spontaneous Intestinal Perforation in Extremely Low Birth Weight Infants: Association with Indometacin Therapy and Effects on Neurodevelopmental Outcomes at 18-22 months Corrected Age 
Background
Spontaneous intestinal perforation (SIP) is associated with the use of postnatal glucocorticoids and indometacin in extremely low birth weight (ELBW) infants. We hypothesized: 1) an association of SIP with the use of antenatal steroids (ANS) and indometacin either as prophylaxis for IVH (P Indo) or for treatment of PDA (Indo/PDA) and 2) an increased risk of death or abnormal neurodevelopmental outcomes in infants with SIP at 18-22 months corrected age.
Design/Methods
We retrospectively identified ELBW infants with SIP in the Neonatal Research Network’s generic database. Unadjusted analysis identified the differences in maternal, neonatal and clinical variables between infants with and without SIP. Logistic regression analysis identified the adjusted odds ratio for SIP with reference to ANS, P Indo and Indo/PDA. Neurodevelopmental outcomes were assessed among survivors at 18 to 22 months corrected age.
Results
Indo/PDA was associated with an increased risk of SIP (adjusted OR 1.61; 95% CI 1.25,2.08), while P Indo and ANS were not. SIP was independently associated with an increased risk of death or NDI (adjusted OR−1.85; 95% CI 1.32,2.60) and NDI among survivors (adjusted OR−1.75, 95% CI 1.20,2.55).
Conclusion
Indometacin used for IVH prophylaxis and ANS were not associated with the occurrence of SIP in ELBW infants. Indometacin used for treatment of symptomatic PDA was however associated with an increased risk of SIP. ELBW infants with SIP have an increased risk of poor neurodevelopmental outcomes.
doi:10.1136/archdischild-2011-300659
PMCID: PMC3753803  PMID: 22684157
extremely low birth weight infant; intestinal perforation; indometacin; cerebral palsy
7.  Clinical Data Predict Neurodevelopmental Outcome Better than Head Ultrasound in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2007;151(5):500-505.e2.
Objective
To determine the relative contribution of clinical data versus head ultrasound (HUS) in predicting neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
Study design
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.
Results
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.
Conclusions
Clinical models were better than head ultrasound models in predicting neurodevelopment.
doi:10.1016/j.jpeds.2007.04.013
PMCID: PMC2879162  PMID: 17961693
Logistic models; Predictive value of tests; ROC curve; Infant; premature; Intracerebral hemorrhage; Leukomalacia; periventricular
8.  Outcome of Extremely Low Birth Weight Infants with Congenital Heart Defects in the Eunice Kennedy Shriver NICHD Neonatal Research Network 
Pediatric cardiology  2012;33(8):1415-1426.
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.
doi:10.1007/s00246-012-0375-8
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
9.  Neurodevelopmental Outcome of Extremely Low Birth Weight Infants from the Vermont Oxford Network: 1998–2003 
Neonatology  2009;97(4):329-338.
Background
Physicians and parents face significant uncertainties when making care decisions for extremely low birth weight (ELBW) infants. Many published estimates of death and developmental outcome are from well-funded university programs and may not reflect outcomes of infants from a variety of settings. The best estimates of the probabilities of death and severe disability combine local experience and published data. Objective: To describe the neurodevelopmental outcome of ELBW infants from centers of the ELBW Infant Follow-Up Group of the Vermont Oxford Network (VON) and to identify characteristics associated with severe disability.
Methods
Predefined measures of living situation, health and developmental outcome were collected at 18–24 months’ corrected age for infants born from July 1, 1998 to December 31, 2003 with birth weights of 401–1,000 g at 33 North American VON centers. Logistic regression was used to identify characteristics associated with severe disability.
Results
6,198 ELBW infants were born and survived until hospital discharge; by the time of follow-up, 88 infants (1.4%) had died. Of the remaining 6,110 infants, 3,567 (58.4%) were evaluated. Severe disability occurred in 34% of the assessed infants. Multivariate logistic regression suggested cystic periventricular leukomalacia, congenital malformation and severe intraventricular hemorrhage were the characteristics most highly associated with severe disability. There were marked variations among the follow-up clinics in the attrition rate.
Conclusion
ELBW infants completing evaluation were at a high risk for severe disability. There are considerable differences among participating centers in attrition at follow-up. Further resources will be needed to study the effect of follow-up care for this group of infants.
doi:10.1159/000260136
PMCID: PMC2889257  PMID: 19940516
Extremely low birth weight infant; Neurodevelopmental outcome; Severe disability; Vermont Oxford Network
10.  Maternal Age, Multiple Birth and Extremely Low Birth Weight Infants 
The Journal of pediatrics  2008;154(4):498-503.e2.
Objectives
To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers ≥ 40 years to the corresponding rates among infants of younger mothers.
Study Design
Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome.
Results
The sample consisted of 14,671 live ELBW births divided into maternal age groups: <20; 20–29; 30–39; and ≥ 40 years. Of infants born to mothers ≥ 40 years, 20% were multiples. Mothers ≥ 40 years had high rates of obstetrical interventions and medical morbidities compared to mothers < 40 years. ELBW live births of mothers ≥ 40 years were 22 % more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared to mothers< 20. Multiple birth, however, was associated with a 10 % greater risk or neurodevelopmental impairment or death.
Conclusion
Although mothers ≥ 40 years had high pregnancy related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.
doi:10.1016/j.jpeds.2008.10.044
PMCID: PMC2834530  PMID: 19111322
outcomes; neurodevelopmental impairment; death
11.  Grade and Laterality of Intraventricular Hemorrhage to Predict 18–22 Month Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
Aims
To determine whether extremely low birth weight (ELBW) infants with bilateral compared to unilateral intraventricular hemorrhage (IVH) have worse neurodevelopmental outcomes at 18–22 months.
Methods
166 ELBW infants (<1000 g) admitted to a Cincinnati NICU from 1998–2005 with a head ultrasound showing Grade I–IV IVH and neurodevelopmental assessment at 18–22 months corrected age were included. Multivariable linear and logistic regression models were developed to determine the impact of laterality and grade of IVH and other clinical variables to predict scores on the Bayley Scales of Infant Development, Second Edition, Mental Development Index (MDI) and Psychomotor Development Index (PDI) and the combined outcome of neurodevelopmental impairment (NDI).
Results
Infants with bilateral grade IV IVH had lower adjusted mean Bayley scores compared with infants with unilateral grade IV IVH. For grades I, II, and III IVH, bilaterality of IVH was not associated with lower mean Bayley scores. Infants with grade IV IVH had the highest odds of NDI. The probability of NDI increased with sepsis and postnatal steroid use.
Conclusions
ELBW infants with bilateral compared to those with unilateral grade IV IVH had worse neurodevelopmental outcomes. Infants with grades I–III IVH had similar outcomes whether they had unilateral or bilateral IVH.
doi:10.1111/j.1651-2227.2011.02584.x
PMCID: PMC3475499  PMID: 22220735
premature; sepsis; steroids; Bayley; cognitive; motor
12.  Neurodevelopmental Outcome of Extremely Low Birth Weight Infants with Candida Infection 
The Journal of pediatrics  2013;163(4):961-967.e3.
Objective
Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birthweight (ELBW) infants enrolled in the Candida study was evaluated based on infection status.
Study design
ELBW infants born at NICHD Neonatal Research Network (NRN) centers between March 2004 and July 2007 screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317/1515 (90%) of the infants enrolled in the Candida study. The Bayley Scales of Infant Development (BSID)-II or the BSID-III was administered at 18 months adjusted age. A secondary comparison with 864 infants registered with NRN enrolled during the same cohort never screened for sepsis and therefore not eligible for the Candida study was performed.
Results
Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83 (1.01,3.33, p=0.047).
Conclusion
In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis.
doi:10.1016/j.jpeds.2013.04.034
PMCID: PMC3786056  PMID: 23726546
Candida; Neonatal sepsis; Neurodevelopmental and Prematurity
13.  Adverse Events After Routine Immunization of Extremely Low Birth Weight Infants 
JAMA pediatrics  2015;169(8):740-745.
Importance
Immunization of extremely low birth weight (ELBW) infants in the neonatal intensive care unit (NICU) is associated with adverse events including fever and apnea/bradycardia in the immediate post-immunization period. This presents a diagnostic dilemma for clinicians, leading to the potential for immunization delay and sepsis evaluations.
Objective
To compare the incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death among immunized ELBW infants in the 3 days pre- and post-immunization.
Design
Multicenter retrospective cohort study.
Setting
348 NICUs managed by the Pediatrix Medical Group.
Participants
13,926 ELBW infants ≤28 weeks gestation who were discharged between 2007 and 2012.
Exposure
At least one immunization between day of life 53 and 110.
Main Outcomes and Measures
Incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death.
Results
Most (91%) of the infants received 3 or more immunizations. The incidence of sepsis evaluations increased from 5.4/1000 patient days in the pre-immunization period to 19.3/1000 patient days post-immunization (adjusted rate ratio [ARR], 3.7; 95% CI, 3.2–4.4). The need for increased respiratory support increased from 6.6/1000 patient days in the pre-immunization period to 14.0/1000 patient days post-immunization (ARR, 2.1; 95% CI, 1.9–2.5), and intubation increased from 2.0/1000 patient days to 3.6/1000 patient days (ARR, 1.7; 95% CI, 1.3–2.2). The post-immunization incidence of adverse events was similar across immunization types, including combination vaccines when compared to single-dose vaccines. Infants who were 23–24 weeks gestation had a higher risk of sepsis evaluation and intubation post-immunization. A prior history of sepsis was associated with higher risk of sepsis evaluation post-immunization.
Conclusion
ELBW infants in the NICU had an increased incidence of sepsis evaluations as well as increased respiratory support and intubation after routine immunization. Our findings provide no evidence to suggest that clinicians should not use combination vaccines in ELBW infants. Further studies are needed to determine whether timing or spacing of immunization administrations confers risk for the developing adverse events and whether a prior history of sepsis confers risk for an altered immune response in ELBW infants.
doi:10.1001/jamapediatrics.2015.0418
PMCID: PMC4523398  PMID: 26030302
14.  Mortality and Morbidity of Extremely Low Birth Weight Infants in the Mainland of China: A Multi-center Study 
Chinese Medical Journal  2015;128(20):2743-2750.
Background:
With the progress of perinatal medicine and neonatal technology, more and more extremely low birth weight (ELBW) survived all over the world. This study was designed to investigate the short-term outcomes of ELBW infants during their Neonatal Intensive Care Unit (NICU) stay in the mainland of China.
Methods:
All infants admitted to 26 NICUs with a birth weight (BW) < l000 g were included between January l, 2011 and December 31, 2011. All the data were collected retrospectively from clinical records by a prospectively designed questionnaire. The data collected from each NICU transmitted to the main institution where the results were aggregated and analyzed. Categorical variables were performed with Pearson Chi-square test. Binary Logistic regression analysis was used to detect risk factors.
Results:
A total of 258 ELBW infants were admitted to 26 NICUs, of whom the mean gestational age (GA) was 28.1 ± 2.2 weeks, and the mean BW was 868 ± 97 g. The overall survival rate at discharge was 50.0%. Despite aggressive treatment 60 infants (23.3%) died and another 69 infants (26.7%) died after medical care withdrawal. Furthermore, the survival rate was significantly higher in coastal areas than inland areas (53.6% vs. 35.3%, P = 0.019). BW < 750 g and GA < 28 weeks were the largest risk factors, and being small for gestational age was a protective factor related to mortality. Respiratory distress syndrome was the most common complication. The incidence of patent ductus arteriosus, intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia, retinopathy of prematurity was 26.2%, 33.7%, 6.7%, 48.1%, and 41.4%, respectively. Ventilator associated pneumonia was the most common hospital acquired infection during hospitalization.
Conclusions:
Our study was the first survey that revealed the present status of ELBW infants in the mainland of China. The mortality and morbidity of ELBW infants remained high as compared to other developed countries.
doi:10.4103/0366-6999.167312
PMCID: PMC4736874  PMID: 26481740
Extremely Low Birth Weight; Infant; Mortality; National Survey
15.  Early cortisol values and long-term outcomes in extremely low birth weight infants 
Objective
Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment.
Study Design
As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile.
Result
Median cortisol value was 16.0 μg per 100 ml at baseline for all infants, and 13.1 μg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia.
Conclusion
Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone.
doi:10.1038/jp.2009.191
PMCID: PMC3586211  PMID: 20010616
bronchopulmonary dysplasia; extremely preterm infants; hydrocortisone; outcomes of high-risk infants
16.  Impact of Postnatal Corticosteroid (PNS) Use on Neurodevelopment at 18-22 Months Adjusted Age: Effects of Dose, Timing and Risk of Bronchopulmonary Dysplasia in Extremely Low Birthweight Infants (ELBW) 
Pediatrics  2009;123(3):e430-e437.
Objective:
Postnatal steroid use in bronchopulmonary dysplasia (BPD) decreases lung inflammation but increases impairment (NDI). We hypothesized that increased dose is associated with increased NDI, lower postmenstrual age (PMA) at exposure increases NDI and risk of BPD modifies the effect of PNS.
Methods:
Steroid dose and timing of exposure beyond 7 days was assessed among 2358 ELBW nested in a prospective trial, with 1667 (84%) survivors examined at 18-22 months PMA. Logistic regression tested the relationship between NDI (Bayley MDI/PDI < 70, disabling cerebral palsy (CP) or sensory impairment), total dose (tertiles < 0.9, 0.9-1.9, ≥ 1.9 mg/kg) and PMA at first dose. Separate logistic regression tested effect modification by BPD severity (Romagnoli Risk > 0.5 as high risk, n=2336 (99%) for days of life 4-7).
Results:
366 neonates (16%) were steroid treated (94% dexamethasone). Treated neonates were smaller and less mature. 72% of those treated were high risk for BPD. PNS exposure was associated with NDI/death (61 vs. 44%, p < 0.001). NDI increased with higher dose; 71% dead or impaired at highest dose tertile. Each 1 mg/kg was associated with a 2.0 point reduction in MDI and a 40% risk increase in disabling CP. (OR 1.4, 95% CI: 1.2-1.6). Older PMA did not mitigate the harm. Treatment after 33 weeks PMA was associated with greatest harm (NDI/death OR 2.5, 95% CI: 1.1-5.5) despite not receiving highest dose. The relationship of PNS to NDI was modified by BPD risk, (High risk OR 1.9, 95% CI: 1.4-2.6; Low risk OR 2.9, 95% CI: 1.8-4.8) with those at highest risk experiencing less harm.
Conclusion:
Higher PNS dose was associated with increased NDI. There is no “safe” window for PNS use in ELBWs. Neonates with low BPD risk should not be exposed. A randomized trial of PNS for infants at highest risk is warranted.
doi:10.1542/peds.2008-1928
PMCID: PMC2846831  PMID: 19204058
postnatal corticosteroids; neurodevelopmental impairment; extremely low birth weight infants
17.  Failed Endotracheal Intubation and Adverse Outcomes Among Extremely Low Birth Weight Infants 
OBJECTIVE
To quantify the importance of successful endotracheal intubation on the first attempt among extremely low birth weight (ELBW) infants who require resuscitation after delivery.
STUDY DESIGN
A retrospective chart review was conducted for all ELBW infants ≤1000 g born between January 2007 and May 2014 at a level IV neonatal intensive care unit. Infants were included if intubation was attempted during the first five minutes of life, or if intubation was attempted during the first 10 minutes of life with heart rate < 100. The primary outcome was death or neurodevelopmental impairment. The association between successful intubation on the first attempt and the primary outcome was assessed using multivariable logistic regression with adjustment for birth weight, gestational age, gender, and antenatal steroids.
RESULTS
The study sample included 88 ELBW infants. Forty-percent were intubated on the first attempt and 60% required multiple intubation attempts. Death or neurodevelopmental impairment occurred in 29% of infants intubated on the first attempt, compared to 53% of infants that required multiple attempts, adjusted odds ratio 0.4 (95% confidence interval 0.1 - 1.0), p < 0.05.
CONCLUSION
Successful intubation on the first attempt is associated with improved neurodevelopmental outcomes among ELBW infants. This study confirms the importance of rapid establishment of a stable airway in ELBW infants requiring resuscitation after birth and has implications for personnel selection and role assignment in the delivery room.
doi:10.1038/jp.2015.158
PMCID: PMC4731260  PMID: 26540244
Extremely low birth weight; endotracheal intubation; neurodevelopmental impairment; resuscitation; failed intubation; intubation attempt
18.  Outcomes of extremely preterm infants following severe intracranial hemorrhage 
Objective
Severe intracranial hemorrhage (ICH) is an important prognostic variable in extremely preterm (EPT) infants. We examined imaging and clinical variables that predict outcomes in EPT infants with severe ICH.
Study design
Retrospective analysis of 353 EPT infants with severe ICH. Outcomes were compared by examining: i) unilateral vs. bilateral ICH; and ii) presence vs. absence of hemorrhagic parenchymal infarction (HPI). Regression analyses identified variables associated with death or neurodevelopmental impairment (NDI).
Results
Bilateral ICH and HPI had higher rates of adverse outcomes and were independently associated with death/NDI. HPI was the most important variable for infants of lower birth weight, and bilateral ICH for larger infants. For infants surviving to 36 weeks, shunt placement was most associated with death/NDI.
Conclusions
Bilateral ICH and the presence of HPI in EPT infants with severe ICH are associated with death/NDI, though the importance depends on birth weight and survival to 36 weeks.
doi:10.1038/jp.2013.162
PMCID: PMC4143234  PMID: 24370654
intraventricular hemorrhage; neurodevelopmental impairment; extremely low birth weight; cranial ultrasound
19.  Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation 
Objective
We sought to determine the incidence of necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) in surviving extremely low-birth-weight (ELBW, <1000 g birth weight) infants and to establish the impact of NEC on outcomes by hospital discharge and at 18 to 22 months adjusted age in a large, contemporary, population-based practice.
Study Design
Hospital outcome data for all ELBW infants born in the greater Cincinnati region from 1998 to 2009 were extracted from the National Institute of Child Health Neonatal Research Network Database. Neurodevelopmental outcome at 18 to 22 months was assessed using Bayley Scales of Infant Development-II scores for Mental Developmental Index and Psychomotor Developmental Index. Multivariable logistic regression was used and adjusted odds ratios reported to control for confounders.
Result
From 1998 to 2009, ELBW infants accounted for 0.5% of the 352 176 live-born infants in greater Cincinnati. The incidence of NEC was 12%, with a 50% case-fatality rate. Death before discharge, morbid complications of prematurity and neurodevelopmental impairment were all increased among infants diagnosed with NEC. Infants with surgical NEC and SIP had a higher incidence of death, but long-term neurodevelopmental outcomes were not different comparing surviving ELBW infants with medical NEC, surgical NEC and SIP.
Conclusion
Although ELBW infants comprise a very small proportion of live-born infants, those who develop NEC and SIP are at an increased risk for death, morbid complications of prematurity and neurodevelopmental impairment. No significant differences in neurodevelopmental outcomes were observed between the medical and surgical NEC and SIP groups.
doi:10.1038/jp.2011.176
PMCID: PMC3496418  PMID: 22157625
necrotizing enterocolitis; extremely low-birth-weight; neurodevelopmental outcome; Bayley scales of infant development
20.  Outcomes of Extremely Low Birth Weight Infants with Bronchopulmonary Dysplasia: Impact of the Physiologic Definition 
Early human development  2012;88(7):509-515.
Aims
We compared neurodevelopmental outcomes of extremely low birth weight (ELBW) infants with and without bronchopulmonary dysplasia (BPD), using the physiologic definition.
Study Design
ELBW (birth weights <1000 grams) infants admitted to the Neonatal Research Network centers and hospitalized at 36 weeks postmenstrual age (n=1,189) were classified using the physiologic definition of BPD. Infants underwent Bayley III assessment at 18-22 months corrected age. Multivariable logistic regression was used to determine the association between physiologic BPD and cognitive impairment (score < 70).
Results
BPD by the physiologic definition was diagnosed in 603 (52%) infants, 537 of whom were mechanically ventilated or on FiO2 > 30% and 66 who failed the room air challenge. Infants on room air (n=505) and those who passed the room air challenge (n=51) were classified as “no BPD” (n=556). At follow up, infants with BPD had significantly lower mean weight and head circumference. Moderate to severe cerebral palsy (7 vs. 2.1%) and spastic diplegia (7.8 vs. 4.1%) and quadriplegia (3.9 vs. 0.9%) phenotypes as well as cognitive (12.8 vs. 4.6%) and language scores < 70 (24.2 vs. 12.3%) were significantly more frequent in those with BPD compared to those without BPD. BPD was independently associated (adjusted OR 2.4; 95% CI 1.40-4.13) with cognitive impairment.
Conclusions
Rates of adverse neurodevelopmental outcomes in early childhood were significantly higher in those with BPD. BPD by the physiologic definition was independently associated with cognitive impairment using Bayley Scales III. These findings have implications for targeted post-discharge surveillance and early intervention.
doi:10.1016/j.earlhumdev.2011.12.013
PMCID: PMC3686277  PMID: 22236557
Outcome; preterm; bronchopulmonary dysplasia; physiologic definition
21.  PaCO2 in Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) 
Objective
To determine the association of PaCO2 with severe intraventricular hemorrhage (sIVH), bronchopulmonary dysplasia (BPD), and neurodevelopmental impairment (NDI) at 18–22 months in premature infants.
Design
Secondary exploratory data analysis of SUPPORT.
Setting
Multiple referral NICUs.
Patients
1316 infants 24 0/7 to 27 6/7 weeks gestation randomized to different oxygenation (SpO2 target 85–89% vs 91–95%) and ventilation strategies.
Main Outcome Measures
Blood gases from postnatal days 0–14 were analyzed. Five PaCO2 variables were defined: minimum [Min], maximum [Max], standard deviation, average (time-weighted), and a 4 level categorical variable (hypercapnic [highest quartile of Max PaCO2], hypocapnic [lowest quartile of Min PaCO2], fluctuators [both hypercapnia and hypocapnia], and normocapnic [middle two quartiles of Max and Min PaCO2]). PaCO2 variables were compared for infants with and without sIVH, BPD, and NDI (+/− death). Multivariable logistic regression models were developed for adjusted results.
Results
sIVH, BPD, and NDI (+/− death) were associated with hypercapnic infants and fluctuators. Association of Max PaCO2 and outcomes persisted after adjustment (Per 10 mmHg increase: sIVH/death: OR 1.27 [1.13–1.41]; BPD/death: OR 1.27 [1.12–1.44]; NDI/death: OR 1.23 [1.10–1.38], Death: OR 1.27 [1.12–1.44], all p <0.001). No interaction was found between PaCO2 category and SpO2 treatment group for sIVH/death, NDI/death, or death. Max PaCO2 was positively correlated with maximum FiO2 (rs0.55, p<0.0001) & ventilator days (rs0.61, p<0.0001).
Conclusions
Higher PaCO2 was an independent predictor of sIVH/death, BPD/death, and NDI/death. Further trials are needed to evaluate optimal PaCO2 targets for high risk infants.
doi:10.1136/archdischild-2014-306802
PMCID: PMC4336211  PMID: 25425651
Infant; premature; Infant mortality; Infant; Premature; Diseases/epidemiology; Predictive value of tests; Prognosis; Intracranial hemorrhage; Blood Gas Analysis
22.  Developmental Outcomes of Very Preterm Infants with Tracheostomies 
The Journal of pediatrics  2014;164(6):1303-1310.e2.
Objectives
To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy.
Study design
Retrospective cohort study from 16 centers of the NICHD Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N=8,683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI, a composite of one or more of: developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed impact of timing, by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life.
Results
Tracheostomies were associated with all neonatal morbidities examined, and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without [odds ratio (OR) adjusted for center 7.0 (95%CI, 5.2-9.5)]. After adjustment for potential confounders, odds of death or NDI remained higher [OR 3.3 (95%CI, 2.4-4.6)], but odds of death alone were lower [OR 0.4 (95%CI, 0.3-0.7)], among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life [adjusted OR 0.5 (95%CI, 0.3-0.9)].
Conclusions
Tracheostomy in preterm infants is associated with adverse developmental outcomes, and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population.
doi:10.1016/j.jpeds.2013.12.014
PMCID: PMC4035374  PMID: 24472229
newborn; very low birth weight infant; neurodevelopmental impairment; tracheotomy; bronchopulmonary dysplasia; prematurity
23.  Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants 
Pediatrics  2015;135(1):e32-e42.
BACKGROUND:
Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months’ corrected age.
METHODS:
Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks’ gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors.
RESULTS:
Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3–6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8–35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes.
CONCLUSIONS:
Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.
doi:10.1542/peds.2014-0898
PMCID: PMC4279063  PMID: 25554820
MRI; neurodevelopmental; neuroimaging; preterm infant; ultrasound
24.  Invasive candidiasis in low birth weight preterm infants: risk factors, clinical course and outcome in a prospective multicenter study of cases and their matched controls 
BMC Infectious Diseases  2014;14:327.
Background
This multicenter prospective study of invasive candidiasis (IC) was carried out to determine the risk factors for, incidence of, clinical and laboratory features, treatment and outcome of IC in infants of birth weight <1250 g.
Methods
Neonates <1250 g with IC and their matched controls (2:1) were followed longitudinally and descriptive analysis was performed. Survivors underwent neurodevelopmental assessment at 18 to 24 months corrected age. Neurodevelopmental impairment (NDI) was defined as blindness, deafness, moderate to severe cerebral palsy, or a score <70 on the Bayley Scales of Infant Development 2nd edition. Multivariable analyses were performed to determine risk factors for IC and predictors of mortality and NDI.
Results
Cumulative incidence rates of IC were 4.2%, 2.2% and 1.5% for birth-weight categories <750 g, <1000 g, <1500 g, respectively. Forty nine infants with IC and 90 controls were enrolled. Necrotizing enterocolitis (NEC) was the only independent risk factor for IC (p = 0.03). CNS candidiasis occurred in 50% of evaluated infants, while congenital candidiasis occurred in 31%. Infants with CNS candidiasis had a higher mortality rate (57%) and incidence of deafness (50%) than the overall cohort of infants with IC. NDI (56% vs. 33%; p = 0.017) and death (45% vs. 7%; p = 0.0001) were more likely in cases than in controls, respectively. IC survivors were more likely to be deaf (28% vs. 7%; p = 0.01). IC independently predicted mortality (p = 0.0004) and NDI (p = 0.018).
Conclusion
IC occurred in 1.5% of VLBW infants. Preceding NEC increased the risk of developing IC. CNS candidiasis is under-investigated and difficult to diagnose, but portends a very poor outcome. Mortality, deafness and NDI were independently significantly increased in infants with IC compared to matched controls.
doi:10.1186/1471-2334-14-327
PMCID: PMC4063435  PMID: 24924877
Invasive candidiasis; Neurodevelopmental outcome; Risk factors; Neonatal; Prematurity
25.  Bronchopulmonary dysplasia and neurodevelopmental outcome in extremely preterm neonates 
European Journal of Pediatrics  2013;172(9):1173-1180.
We tested the hypothesis that the use of supplemental oxygen (sO2) at discharge from the NICU in extremely preterm neonates is associated with a greater risk of neurodevelopmental impairment (NDI) at 18 months corrected gestational age (CGA) than the risk of NDI of those neonates discharged in room air. Four hundred twenty-four charts were retrospectively reviewed from infants born at <27 weeks and transferred to Nationwide Children’s Hospital from December 1, 2004 to June 14, 2010. Use of sO2 was evaluated on day of life (dol) 28, at 36 weeks post-menstrual age (PMA), and at discharge. Logistic regression was used to identify postnatal risk factors associated with sO2 at discharge and NDI. At dol 28, 96 % of surviving patients received sO2, and therefore had bronchopulmonary dysplasia (BPD) by definition from a National Institutes of Child Health and Human Development workshop. At 36 weeks PMA, 89 % continued on sO2 (moderate/severe BPD), and at discharge, 74 % continued on sO2. When factors associated with NDI were examined, the need for mechanical ventilation ≥28 days (adjOR = 3.21, p = 0.01), grade III–IV intraventricular hemorrhage (IVH) (adjOR = 4.61, p < 0.01), and discharge at >43 weeks PMA (adjOR = 2.12, p = 0.04) were the strongest predictors of NDI at 18 months CGA. There was no difference in Bayley Scales of Infant Development, third edition composite scores between patients with no/mild BPD and patients with moderate/severe BPD (cognitive p = 0.60, communication p = 0.53, motor p = 0.19) or those scores between patients on and off oxygen at discharge (cognitive p = 0.58, communication p = 0.70, motor p = 0.62). Conclusions: The need for sO2 at discharge is not associated with an increased risk of NDI in these patients. The strongest predictors of poor neurodevelopmental outcome in this population were prolonged positive pressure support, grade III–IV IVH, and discharge at >43 weeks PMA.
doi:10.1007/s00431-013-2016-5
PMCID: PMC3742432  PMID: 23644648
Mechanical ventilation; Supplemental oxygen; Very low birth weight; Intraventricular hemorrhage; Necrotizing enterocolitis

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