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1.  Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990–2000: a retrospective cohort study 
BMC Pediatrics  2007;7:20.
It is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23–27 weeks gestation) are changing over time.
Study infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness.
Survival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2.
The probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990's in this regionally based sample of ELGANs.
PMCID: PMC1876228  PMID: 17477872
2.  Trends in socioeconomic inequalities in risk of sudden infant death syndrome, other causes of infant mortality, and stillbirth in Scotland: population based study 
Objectives To compare changes in inequalities in sudden infant death syndrome with other causes of infant mortality and stillbirth in Scotland, 1985-2008.
Design Retrospective cohort study.
Setting Scotland 1985-2008, analysed by four epochs of six years.
Participants Singleton births of infants with birth weight >500 g born at 28-43 weeks’ gestation.
Main outcome measures Sudden infant death syndrome, other causes of postneonatal infant death, neonatal death, and stillbirth. Odds ratios expressed as the association across the range of seven categories of Carstairs deprivation score.
Results The association between deprivation and the risk of all cause stillbirth and infant death varied between the four epochs (P=0.04). This was wholly explained by variation in the risk of sudden infant death syndrome (P<0.001 for interaction). Among women living in areas of low deprivation, there was a sharp decline in the rate of sudden infant death syndrome from 1990 to 1993. Among women living in areas of high deprivation, there was a slower decline in sudden infant death syndrome rates between 1992 and 2004. Consequently, the odds ratio for the association between socioeconomic deprivation and sudden infant death syndrome increased from 2.04 (95% confidence interval 1.53 to 2.72) in 1985-90, to 7.52 (4.62 to 12.25) in 1991-6, and 9.50 (5.46 to 16.53) in 1997-2002 but fell to 1.78 (0.87 to 3.65) in 2002-8. The interaction remained significant after adjustment for maternal characteristics.
Conclusion The rate of sudden infant death syndrome declined throughout Scotland in the early 1990s. The decline had a later onset and was slower among women living in areas of high deprivation, probably because of slower uptake of recommended changes in infant sleeping position. The effect was to create a strong independent association between deprivation and sudden infant death syndrome where one did not exist before.
PMCID: PMC3307809  PMID: 22427307
3.  Risk Factors for Post-NICU Discharge Mortality Among Extremely Low Birth Weight Infants 
The Journal of Pediatrics  2012;161(1):70-74.e2.
To evaluate maternal and neonatal risk factors associated with post-neonatal intensive care unit (NICU) discharge mortality among ELBW infants.
Study design
This is a retrospective analysis of extremely low birth weight (<1,000 g) and <27 weeks' gestational age infants born in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network sites from January 2000 to June 2007. Infants were tracked until death or 18–22 months corrected age. Infants who died between NICU discharge and the 18–22 month follow-up visit were classified as post-NICU discharge mortality. Association of maternal and infant risk factors with post-NICU discharge mortality was determined using logistic regression analysis. A prediction model with six significant predictors was developed and validated.
5,364 infants survived to NICU discharge. 557 (10%) infants were lost to follow-up, and 107 infants died following NICU discharge. Post-NICU discharge mortality rate was 22.3 per 1000 ELBW infants. In the prediction model, African-American race, unknown maternal health insurance, and hospital stay ≥120 days significantly increased risk, and maternal exposure to intra-partum antibiotics was associated with decreased risk of post-NICU discharge mortality.
We identified African-American race, unknown medical insurance and prolonged NICU stay as risk factors associated with post-NICU discharge mortality among ELBW infants.
PMCID: PMC3366175  PMID: 22325187
extremely preterm infants; discharge; mortality; predictive model
4.  Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants 
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
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
PMCID: PMC3136997  PMID: 21471086
bronchopulmonary dysplasia; prematurity; low-birth-weight infant
5.  Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network 
Pediatrics  2010;126(3):443-456.
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.
PMCID: PMC2982806  PMID: 20732945
extremely low gestation; very low birth weight; morbidity; death
6.  Approach to Infants Born at 22 to 24 Weeks’ Gestation: Relationship to Outcomes of More-Mature Infants 
Pediatrics  2012;129(6):e1508-e1516.
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.
PMCID: PMC3362905  PMID: 22641761
low-birth weight infant; NICUs; treatment; patient outcome assessment
7.  Impact of managed clinical networks on NHS specialist neonatal services in England: population based study 
Objective To assess the impact of reorganisation of neonatal specialist care services in England after a UK Department of Health report in 2003.
Design A population-wide observational comparison of outcomes over two epochs, before and after the establishment of managed clinical neonatal networks.
Setting Epoch one: 294 maternity and neonatal units in England, Wales, and Northern Ireland, 1 September 1998 to 31 August 2000, as reported by the Confidential Enquiry into Stillbirths and Sudden Deaths in Infancy Project 27/28. Epoch two: 146 neonatal units in England contributing data to the National Neonatal Research Database at the Neonatal Data Analysis Unit, 1 January 2009 to 31 December 2010.
Participants Babies born at a gestational age of 27+0-28+6 (weeks+days): 3522 live births in epoch one; 2919 babies admitted to a neonatal unit within 28 days of birth in epoch two.
Intervention The national reorganisation of neonatal services into managed clinical networks.
Main outcome measures The proportion of babies born at hospitals providing the highest volume of neonatal specialist care (≥2000 neonatal intensive care days annually), having an acute transfer (within the first 24 hours after birth) and/or a late transfer (between 24 hours and 28 days after birth) to another hospital, assessed by change in distribution of transfer category (“none,” “acute,” “late”), and babies from multiple births separated by transfer. For acute transfers in epoch two, the level of specialist neonatal care provided at the destination hospital (British Association of Perinatal Medicine criteria).
Results After reorganisation, there were increases in the proportions of babies born at 27-28 weeks’ gestation in hospitals providing the highest volume of neonatal specialist care (18% (631/3495) v 49% (1325/2724); odds ratio 4.30, 95% confidence interval 3.83 to 4.82; P<0.001) and in acute and late postnatal transfers (7% (235) v 12% (360) and 18% (579) v 22% (640), respectively; P<0.001). There was no significant change in the proportion of babies from multiple births separated by transfer (33% (39) v 29% (38); 0.86, 0.50 to 1.46; P=0.57). In epoch two, 32% of acute transfers were to a neonatal unit providing either an equivalent (n=87) or lower (n=26) level of specialist care.
Conclusions There is evidence of some improvement in the delivery of neonatal specialist care after reorganisation. The increase in acute transfers in epoch two, in conjunction with the high proportion transferred to a neonatal unit providing an equivalent or lower level of specialist care, and the continued separation of babies from multiple births, are indicative of poor coordination between maternity and neonatal services to facilitate in utero transfer before delivery, and continuing inadequacies in capacity of intensive care cots. Historical data representing epoch one are available only in aggregate form, preventing examination of temporal trends or confounding factors. This limits the extent to which differences between epochs can be attributed to reorganisation and highlights the importance of routine, prospective data collection for evaluation of future health service reorganisations.
PMCID: PMC3318112  PMID: 22490978
8.  Intercenter Differences in Bronchopulmonary Dysplasia or Death Among Very Low Birth Weight Infants 
Pediatrics  2010;127(1):e106-e116.
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.
PMCID: PMC3010091  PMID: 21149431
logistic models; infant; premature; predictive value of tests; clustering
9.  Neonatal Gram Negative and Candida Sepsis Survival and Neurodevelopmental Outcome at the Corrected Age of 24 Months 
PLoS ONE  2013;8(3):e59214.
To evaluate the long term neurodevelopmental outcome of premature infants exposed to either gram- negative sepsis (GNS) or neonatal Candida sepsis (NCS), and to compare their outcome with premature infants without sepsis.
Historical cohort study in a population of infants born at <30 weeks gestation and admitted to the Neonatal Intensive Care Unit (NICU) of the Academic Medical Center in Amsterdam during the period 1997–2007. Outcome of infants exposed to GNS or NCS and 120 randomly chosen uncomplicated controls (UC) from the same NICU were compared. Clinical data during hospitalization and neurodevelopmental outcome data (clinical neurological status; Bayley –test results and vision/hearing test results) at the corrected age of 24 months were collected. An association model with sepsis as the central determinant of either good or adverse outcome (death or severe developmental delay) was made, corrected for confounders using multiple logistic regression analysis.
Of 1362 patients, 55 suffered from GNS and 29 suffered from NCS; cumulative incidence 4.2% and 2.2%, respectively. During the follow-up period the mortality rate was 34% for both GNS and NCS and 5% for UC. The adjusted Odds Ratio (OR) [95% CI] for adverse outcome in the GNS group compared to the NCS group was 1.4 [0.4–4.9]. The adjusted ORs [95% CI] for adverse outcome in the GNS and NCS groups compared to the UC group were 4.8 [1.5–15.9] and 3.2 [0.7–14.7], respectively.
We found no statistically significant difference in outcome at the corrected age of 24 months between neonatal GNS and NCS cases. Suffering from either gram –negative or Candida sepsis increased the odds for adverse outcome compared with an uncomplicated neonatal period.
PMCID: PMC3601057  PMID: 23527140
10.  Validation of the Functional Status II questionnaire in the assessment of extremely-low-birthweight infants 
The increased survival of infants born at extremely low birthweight (ELBW) has been associated with significant morbidity, including higher rates of neurodevelopmental disability. However, formalized testing to evaluate these problems is both time-consuming and costly. The revised Functional Status questionnaire (FS-II) was designed to assess caregivers’ perceptions of the functional status of children with chronic diseases.
We evaluated the reliability and validity of the FS-II for ELBW infants at 18 to 22 months corrected age using data from the US Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN). Exploratory factor analyses were conducted using data from the network’s first follow-up study of 1080 children born in 1993 to 1994 (508 males, 572 females [53%]), and results were confirmed using data from the next network follow-up of 4022 children born in 1995 to 2000 (1864 males, 2158 females [54%]).
Results suggest that a two-factor solution comprising measures of general health and independence is most appropriate for ELBW infants. These factors differed from those found among chronically ill children, and new, more appropriate scales are presented for screening ELBW survivors. Both scales demonstrated good internal consistency: Cronbach’s α=0.87 for general health and α=0.75 for independence. Construct validity of the scales was assessed by comparing mean scores on the scales according to scores on the Bayley Scales of Infant Development, second edition (BSID-II), and medical conditions.
As hypothesized, infants with greater functional impairments according to their BSID-II scores or medical conditions had lower scores on the general health and independence scales, supporting the validity of the scales.
PMCID: PMC3031102  PMID: 19459909
11.  Severe retinopathy of prematurity in infants <30 weeks' gestation in New South Wales and the Australian Capital Territory from 1992 to 2002 
Retinopathy of prematurity (ROP) significantly increased in New South Wales (NSW) from 1986 to 1994, but more recent data suggest that there has now been a decrease.
To study the incidence and treatment of severe ROP (stage ⩾3) in NSW and the Australian Capital Territory (ACT) from 1992 to 2002.
Data collected prospectively from the Neonatal Intensive Care Units' (NICUS) Data Collection over an 11‐year period in infants <30 weeks' gestation were divided into four epochs and analysed retrospectively. The incidence and treatment of severe ROP were compared for gestational ages ⩽24 weeks', 25–26 weeks' and 27–29 weeks' gestation over the four epochs.
In infants ⩽24 weeks' gestation the incidence of severe ROP and those treated increased significantly (stage ⩾3: from 17 (41.5%) to 41 (53.9%), p = 0.052; treated: from 8 (19.5%) to 25 (32.9%), p<0.05 (first and fourth epoch)). In infants 25–26 weeks' gestation the incidence of severe ROP decreased significantly whereas there was a non‐significant increase in those treated (stage ⩾3: from 55 (26.2%) to 46 (19.3%), p<0.05; treated: from 19 (9.0%) to 32 (13.4%)). In infants 27–29 weeks' gestation, there was no significant change in the incidence of severe ROP or those treated (stage ⩾3: from 30 (4.1%) to 17 (2.4%); treated: from 14 (1.9%) to 8 (1.1%)).
In infants ⩽24 weeks' gestation there has been a significant increase in severe ROP, and in infants <27 weeks' gestation the numbers treated for severe ROP increased.
PMCID: PMC2675420  PMID: 17251225
retinopathy of prematurity; preterm infants; cryo‐therapy and laser therapy
12.  Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage 
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.
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.
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.
PMCID: PMC3777699  PMID: 22814942
infant; premature; extremely low birth weight; death; neurodevelopmental impairment
13.  Timing of Elective Repeat Cesarean Delivery at Term and Neonatal Outcomes 
The New England journal of medicine  2009;360(2):111-120.
Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term (37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes.
We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively (i.e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit (ICU).
Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation (6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome (adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend <0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks.
Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.
PMCID: PMC2811696  PMID: 19129525
14.  Death in the neonatal intensive care unit: changing patterns of end of life care over two decades 
Death remains a common event in the neonatal intensive care unit, and often involves limitation or withdrawal of life sustaining treatment.
To document changes in the causes of death and its management over the last two decades.
An audit of infants dying in the neonatal intensive care unit was performed during two epochs (1985–1987 and 1999–2001). The principal diagnoses of infants who died were recorded, as well as their apparent prognoses, and any decisions to limit or withdraw medical treatment.
In epoch 1, 132 infants died out of 1362 admissions (9.7%), and in epoch 2 there were 111 deaths out of 1776 admissions (6.2%; p<0.001). Approximately three quarters of infants died after withdrawal of life sustaining treatment in both epochs. There was a significant reduction in the proportion of deaths from chromosomal abnormalities, and from neural tube defects in epoch 2.
There have been substantial changes in the illnesses leading to death in the neonatal intensive care unit. These may reflect the combined effects of prenatal diagnosis and changing community and medical attitudes.
PMCID: PMC2672727  PMID: 16790729
palliative care; withholding treatment; intensive care
15.  Methicillin-Resistant and Susceptible Staphylococcus aureus Bacteremia and Meningitis in Preterm Infants 
Pediatrics  2012;129(4):e914-e922.
Data are limited on the impact of methicillin-resistant Staphylococcus aureus (MRSA) on morbidity and mortality among very low birth weight (VLBW) infants with S aureus (SA) bacteremia and/or meningitis (B/M).
Neonatal data for VLBW infants (birth weight 401–1500 g) born January 1, 2006, to December 31, 2008, who received care at centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were collected prospectively. Early-onset (≤72 hours after birth) and late-onset (>72 hours) infections were defined by blood or cerebrospinal fluid cultures and antibiotic treatment of ≥5 days (or death <5 days with intent to treat). Outcomes were compared for infants with MRSA versus methicillin-susceptible S aureus (MSSA) B/M.
Of 8444 infants who survived >3 days, 316 (3.7%) had SA B/M. Eighty-eight had MRSA (1% of all infants, 28% of infants with SA); 228 had MSSA (2.7% of all infants, 72% of infants with SA). No infant had both MRSA and MSSA B/M. Ninety-nine percent of MRSA infections were late-onset. The percent of infants with MRSA varied by center (P < .001) with 9 of 20 centers reporting no cases. Need for mechanical ventilation, diagnosis of respiratory distress syndrome, necrotizing enterocolitis, and other morbidities did not differ between infants with MRSA and MSSA. Mortality was high with both MRSA (23 of 88, 26%) and MSSA (55 of 228, 24%).
Few VLBW infants had SA B/M. The 1% with MRSA had morbidity and mortality rates similar to infants with MSSA. Practices should provide equal focus on prevention and management of both MRSA and MSSA infections among VLBW infants.
PMCID: PMC3313632  PMID: 22412036
Staphylococcus aureus; methicillin resistant; infant; newborn
16.  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.
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
17.  Antenatal Antecedents of Cognitive Impairment at 24 Months In Extremely Low Gestational Age Newborns 
Pediatrics  2012;129(3):494-502.
Extremely low gestational age neonates are more likely than term infants to develop cognitive impairment. Few studies have addressed antenatal risk factors of this condition. We identified antenatal antecedents of cognitive impairment determined by the Mental Development Index (MDI) portion of the Bayley Scales of Infant Development, Second Edition (BSID-II), at 24 months corrected age.
We studied a multicenter cohort of 921 infants born before 28 weeks of gestation during 2002 to 2004 and assessed their placentas for histologic characteristics and microorganisms. The mother was interviewed and her medical record was reviewed. At 24 months adjusted age, children were assessed with BSID-II. Multinomial logistic models were used to estimate odds ratios.
A total of 103 infants (11%) had an MDI <55, and 99 infants (11%) had an MDI between 55 and 69. No associations were identified between organisms recovered from the placenta and developmental delay. Factors most strongly associated with MDI <55 were thrombosis of fetal vessels (OR 3.1; 95% confidence interval [CI] 1.2, 7.7), maternal BMI >30 (OR 2.0; 95% CI 1.1, 3.5), maternal education ≤12 years (OR 3.4; 95% CI 1.9, 6.2), nonwhite race (OR 2.2; 95% CI 1.3, 3.8), birth weight z score < −2 (OR 2.8; 95% CI 1.1, 6.9), and male gender (OR 2.7; 95% CI 1.6, 4.5).
Antenatal factors, including thrombosis of fetal vessels in the placenta, severe fetal growth restriction, and maternal obesity, convey information about the risk of cognitive impairment among extremely premature newborns.
PMCID: PMC3289523  PMID: 22331342
prematurity; placenta; chorioamnionitis; fetal growth restriction; mental development
18.  Neurodevelopmental Outcome of Premature Infants after Exposure to Antenatal Indomethacin 
To evaluate the effect of antenatal indomethacin exposure on neurodevelopmental outcomes of premature infants.
Study Design
A retrospective cohort study was performed to compare neurodevelopmental outcomes between premature infants exposed to antenatal indomethacin and infants unexposed to antenatal indomethacin. Inclusion criteria included all 23 – 29 weeks’ gestational age infants delivered between January, 1998 and December, 2002 and who had neurodevelopmental evaluation performed at 16–24 months corrected age. Out born infants and those with major congenital malformations or chromosomal problems were excluded. Continuous and categorical variables were analyzed using t-test and chi-square test, respectively.
87 infants met inclusion criteria. Of 87 infants, 29 infants were exposed to antenatal indomethacin (mean dose 267 mg and median duration 3 days) and 58 infants were unexposed to antenatal indomethacin. There were no significant differences between the two groups in clinical characteristics except for gestational age, mode of delivery and antenatal steroid exposure. There was no significant difference in major neurosensory abnormality (cerebral palsy and/or deafness and/or blindness); however the proportion of infants with sub-normal Bayley-Mental Developmental Index (MDI ≤ 70) and neurodevelopmental impairment (neurosensory abnormality and/or MDI ≤ 70) was significantly less in the group exposed to antenatal indomethacin compared to unexposed group. When controlled for confounders including antenatal steroids, antenatal indomethacin was not associated with MDI ≤ 70 (Odds ratio (OR) 0.44, 95% CI 0.12–1.5) and neurodevelopmental impairment (OR 0.4, 95% CI 0.13–1.2) using logistic regression. Subgroup analysis of 12 infants exposed to antenatal indomethacin within 48 hours of birth was not associated with neurodevelopmental impairment (OR 0.2, 95% CI 0.03–1.02) compared to unexposed group.
Antenatal indomethacin is not associated with abnormal neurodevelopmental outcome in infants ≤ 29 weeks gestational age.
PMCID: PMC2519240  PMID: 18455131
Tocolysis; Antenatal Indomethacin; Neurodevelopment; Premature infants
19.  Identification of Extremely Premature Infants at High Risk of Rehospitalization 
Pediatrics  2011;128(5):e1216-e1225.
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.
PMCID: PMC3208965  PMID: 22007016
logistic models; infant; premature; predictive value of tests
20.  Infant Growth Before and After Term: Effects on Neurodevelopment in Preterm Infants 
Pediatrics  2011;128(4):e899-e906.
To identify sensitive periods of postnatal growth for preterm infants relative to neurodevelopment at 18 months' corrected age.
We studied 613 infants born at <33 weeks' gestation who participated in the DHA for Improvement of Neurodevelopmental Outcome trial. We calculated linear slopes of growth in weight, length, BMI, and head circumference from 1 week of age to term (40 weeks' postmenstrual age), term to 4 months, and 4 to 12 months, and we estimated their associations with Bayley Scales of Infant Development, 2nd Edition, Mental (MDI) and Psychomotor (PDI) Development Indexes in linear regression.
The median gestational age was 30 (range: 2–33) weeks. Mean ± SD MDI was 94 ± 16, and PDI was 93 ± 16. From 1 week to term, greater weight gain (2.4 MDI points per z score [95% confidence interval (CI): 0.8–3.9]; 2.7 PDI points [95% CI: 1.2–.2]), BMI gain (1.7 MDI points [95% CI: 0.4–3.1]; 2.5 PDI points [95% CI: 1.2–3.9]), and head growth (1.4 MDI points [95% CI: −0.0–2.8]; 2.5 PDI points [95% CI: 1.2–3.9]) were associated with higher scores. From term to 4 months, greater weight gain (1.7 points [95% CI: 0.2–3.1]) and linear growth (2.0 points [95% CI: 0.7–3.2]), but not BMI gain, were associated with higher PDI. From 4 to 12 months, none of the growth measures was associated with MDI or PDI score.
In preterm infants, greater weight and BMI gain to term were associated with better neurodevelopmental outcomes. After term, greater weight gain was also associated with better outcomes, but increasing weight out of proportion to length did not confer additional benefit.
PMCID: PMC3182845  PMID: 21949135
growth; motor development; cognitive development; preterm infants
21.  Intensive Care for Extreme Prematurity — Moving Beyond Gestational Age 
The New England journal of medicine  2008;358(16):1672-1681.
Decisions regarding whether to administer intensive care to extremely premature infants are often based on gestational age alone. However, other factors also affect the prognosis for these patients.
We prospectively studied a cohort of 4446 infants born at 22 to 25 weeks' gestation (determined on the basis of the best obstetrical estimate) in the Neonatal Research Network of the National Institute of Child Health and Human Development to relate risk factors assessable at or before birth to the likelihood of survival, survival without profound neurodevelopmental impairment, and survival without neurodevelopmental impairment at a corrected age of 18 to 22 months.
Among study infants, 3702 (83%) received intensive care in the form of mechanical ventilation. Among the 4192 study infants (94%) for whom outcomes were determined at 18 to 22 months, 49% died, 61% died or had profound impairment, and 73% died or had impairment. In multivariable analyses of infants who received intensive care, exposure to antenatal corticosteroids, female sex, singleton birth, and higher birth weight (per each 100-g increment) were each associated with reductions in the risk of death and the risk of death or profound or any neurodevelopmental impairment; these reductions were similar to those associated with a 1-week increase in gestational age. At the same estimated likelihood of a favorable outcome, girls were less likely than boys to receive intensive care. The outcomes for infants who underwent ventilation were better predicted with the use of the above factors than with use of gestational age alone.
The likelihood of a favorable outcome with intensive care can be better estimated by consideration of four factors in addition to gestational age: sex, exposure or nonexposure to antenatal corticosteroids, whether single or multiple birth, and birth weight. ( numbers, NCT00063063 and NCT00009633.)
PMCID: PMC2597069  PMID: 18420500
22.  Vitamin A Supplementation in Extremely Low- Birth-Weight Infants: Subgroup Analysis in Small-for-Gestational-Age Infants 
American journal of perinatology  2013;30(9):771-780.
Preterm infants with intrauterine growth restriction are at increased risk of respiratory distress syndrome and bronchopulmonary dysplasia (BPD). A randomized clinical trial by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network demonstrated that vitamin A supplementation in extremely low-birth-weight (ELBW) preterm infants requiring early respiratory support decreased the risk of developing BPD.
Study Design
A subgroup analysis of small-for-gestational-age (SGA) infants from the original NICHD trial was performed to test the hypothesis that in infants requiring early respiratory support, vitamin A supplementation decreases the relative risk of BPD or death in premature SGA infants to a greater extent than in gestational age–equivalent vitamin A–treated appropriate-for-gestational-age (AGA) infants.
Although vitamin A supplementation significantly increased serum retinol concentrations in AGA ELBW infants (median [5th percentile, 95th percentile]: 16.3 [−7.0, 68.8] versus 2.4 [−13.9, 55.1]; p < 0.001), no increases were noted in SGA ELBW infants.
Given the limited power of this analysis due to a low number of SGA infants, these data did not provide evidence to support the hypothesis that vitamin A supplementation in preterm SGA infants requiring early respiratory support decreases the relative risk of BPD or death as compared with preterm AGA infants.
PMCID: PMC3923571  PMID: 23329565
vitamin A; IUGR–intrauterine growth restriction; BPD–bronchopulmonary dysplasia; SGA–small for gestational age; AGA–appropriate for gestational age
23.  Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants Ventilated With Continuous Positive Airway Pressure vs. Mechanical Ventilation 
Indian journal of pediatrics  2011;79(2):218-223.
To compare continuous positive airway pressure (CPAP) vs. traditional mechanical ventilation (MV) at 24 h of age as predictors of neurodevelopmental (ND) outcomes in extremely low birth weight (ELBW) infants at 18-22 mo corrected gestational age (CGA).
Infants ≤ 1000g birth weight born from January 2000 through December 2006 at two hospitals at the Cincinnati site of the National Institute of Child Health and Human Development Neonatal Research Network were evaluated comparing CPAP (N = 198) vs. MV (N = 109). Primary outcomes included the Bayley Score of Infant Development Version II (BSID-II), presence of deafness, blindness, cerebral palsy, bronchopulmonary dysplasia and death.
Ventilatory groups were similar in gender, rates of preterm prolonged rupture of membranes, antepartum hemorrhage, use of antenatal antibiotics, steroids, and tocolytics. Infants receiving CPAP weighed more, were older, were more likely to be non-Caucasian and from a singleton pregnancy. Infants receiving CPAP had better BSID-II scores, and lower rates of BPD and death.
After adjusting for acuity differences, ventilatory strategy at 24 h of age independently predicts long-term neurodevelopmental outcome in ELBW infants.
PMCID: PMC3498084  PMID: 21853318
24.  Impact of Changes in Perinatal Care on Neonatal Respiratory Outcome and Survival of Preterm Newborns: An Overview of 15 Years 
Survival and outcomes for preterm infants with respiratory distress syndrome (RDS) have improved over the past 30 years. We conducted a study to assess the changes in perinatal care and delivery room management and their impact on respiratory outcome of very low birth weight newborns, over the last 15 years. A comparison between two epochs was performed, the periods before and after 2005, when early nasal continuous positive airway pressure (NCPAP) and Intubation-SURfactant-Extubation (INSURE) were introduced in our center. Three hundred ninety-five clinical records were assessed, 198 (50.1%) females, gestational age 29.1 weeks (22–36), and birth weight 1130 g (360–1498). RDS was diagnosed in 247 (62.5%) newborns and exogenous surfactant was administered to 217 (54.9%). Thirty-three (8.4%) developed bronchopulmonary dysplasia (BPD), and 92 (23%) were deceased. With the introduction of early NCPAP and INSURE, there was a decrease on the endotracheal intubation need and invasive ventilation (P < 0.0001), oxygen therapy (P = 0.002), and mortality (P < 0.0001). The multivariate model revealed a nonsignificant reduction in BPD between the two epochs (OR = 0.86; 95% CI 0.074–9.95; P = 0.9). The changes in perinatal care over the last 15 years were associated to an improvement of respiratory outcome and survival, despite a nonsignificant decrease in BPD rate.
PMCID: PMC3539442  PMID: 23320153
25.  Improving the Neonatal Research Network Annual Certification for Neurologic Examination of the 18–22 month Child 
The Journal of pediatrics  2012;161(6):1041-1046.e2.
To describe the Neonatal Research Network’s (NRN) efforts to improve the certification process for the Follow-up Study neurologic exam and to evaluate inter-rater agreement before and after two annual training workshops.
Study design
The NRN Follow-up Study is a multi-center observational study that has examined more than 11,500 infants from 1998–2010 and born ≤ 26 weeks gestational age at 18 – 22 months corrected age for neurodevelopmental outcome. The percentages of examiners who agreed with the Gold Standard examiner on four neurodevelopmental outcomes on the initial training video and a test video were calculated. Consistency among examiners was assessed with the first-order agreement coefficient (AC1) statistic.
Improvements in agreement among examiners occurred between 2009 and 2010 and between initial training and test. Examiner agreement with the Gold Standard during the initial training was 83% – 91% in 2009 and 89% – 99% in 2010. Examiner agreement on the workshop test video increased from 2009 to 2010 with agreement reaching 100% for all four neurodevelopmental outcomes examined in 2010. AC1 values for the four neurodevelopmental outcomes on the training videos ranged from 0.64 – 0.82 in 2009 and 0.77 – 0.97 in 2010.
We demonstrate the importance of annual certification and the benefits of evaluation and revision of certification protocols to achieve high levels of confidence in neurodevelopmental study outcomes for multi-center networks.
PMCID: PMC3465479  PMID: 22748517
examiner training; neurodevelopmental outcome; inter-rater agreement

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