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1.  Ten-Year Review of Major Birth Defects in VLBW Infants 
Pediatrics  2013;132(1):49-61.
OBJECTIVE:
Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care.
METHODS:
Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics.
RESULTS:
A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41–3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001).
CONCLUSIONS:
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
doi:10.1542/peds.2012-3111
PMCID: PMC3691532  PMID: 23733791
birth defects; prematurity; Neonatal Research Network; low birth weight
2.  Early sepsis does not increase the risk of late sepsis in very low birth weight neonates 
The Journal of pediatrics  2013;162(5):942-948.e3.
Objective
To examine whether preterm very low birth weight (VLBW) infants have an increased risk of late-onset sepsis (LOS) following early-onset sepsis (EOS).
Study design
Retrospective analysis of VLBW infants (401-1500 g) born September 1998 through December 2009 who survived >72 hours and were cared for within the NICHD Neonatal Research Network. Sepsis was defined by growth of bacteria or fungi in a blood culture obtained ≤72 hr of birth (EOS) or >72 hr (LOS) and antimicrobial therapy for ≥5 days or death <5 d while receiving therapy. Regression models were used to assess risk of death or LOS by 120d and LOS by 120d among survivors to discharge or 120d, adjusting for gestational age and other covariates.
Results
Of 34,396 infants studied 504 (1.5%) had EOS. After adjustment, risk of death or LOS by 120d did not differ overall for infants with EOS compared with those without EOS [RR:0.99 (0.89-1.09)] but was reduced in infants born at <25wk gestation [RR:0.87 (0.76-0.99), p=0.048]. Among survivors, no difference in LOS risk was found overall for infants with versus without EOS [RR:0.88 (0.75-1.02)], but LOS risk was shorter in infants with BW 401-750 g who had EOS [RR:0.80 (0.64-0.99), p=0.047].
Conclusions
Risk of LOS after EOS was not increased in VLBW infants. Surprisingly, risk of LOS following EOS appeared to be reduced in the smallest, most premature infants, underscoring the need for age-specific analyses of immune function.
doi:10.1016/j.jpeds.2012.11.027
PMCID: PMC3622770  PMID: 23295144
Very low birth weight; early-onset sepsis; late-onset sepsis
3.  Fetal Growth and Risk of Stillbirth: A Population-Based Case–Control Study 
PLoS Medicine  2014;11(4):e1001633.
Radek Bukowski and colleagues conducted a case control study in 59 US hospitals to determine the relationship between fetal growth and stillbirth, and find that both restrictive and excessive growth could play a role.
Please see later in the article for the Editors' Summary
Background
Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth.
Methods and Findings
We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (<10th percentile) or large for gestational age (LGA) (>90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (<5th and >95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings.
Conclusions
Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pregnancy is usually a happy time, when the parents-to-be anticipate the arrival of a new baby. But, sadly, about 20% of pregnancies end in miscarriage—the early loss of a fetus (developing baby) that is unable to survive independently. Other pregnancies end in stillbirth—fetal death after 20 weeks of pregnancy (in the US; after 24 weeks in the UK). Stillbirths, like miscarriages, are common. In the US, for example, one in every 160 pregnancies ends in stillbirth. How women discover that their unborn baby has died varies. Some women simply know something is wrong and go to hospital to have their fears confirmed. Others find out when a routine check-up detects no fetal heartbeat. Most women give birth naturally after their baby has died, but if the mother's health is at risk, labor may be induced. Common causes of stillbirth include birth defects and infections. Risk factors for stillbirth include being overweight and smoking during pregnancy.
Why Was This Study Done?
Stillbirths are often associated with having a “small for gestational age” (SGA) fetus. Gestation is the period during which a baby develops in its mother's womb. Gestational age is estimated from the date of the woman's last menstrual period and/or from ultrasound scans. An SGA fetus is lighter than expected for its age based on observed distributions (norms) of fetal weights for gestational age. Although stillbirth is clearly associated with impaired fetal growth, the exact relationship between fetal growth and stillbirth remains unclear for two reasons. First, studies investigating this relationship have used gestational age at delivery rather than gestational age at death as an estimate of fetal age, which overestimates the gestational age of stillbirths and leads to errors in estimates of the proportions of SGA and “large for gestational age” (LGA) stillbirths. Second, many characteristics that affect normal fetal growth are also associated with the risk of stillbirth, and this has not been allowed for in previous studies. In this population-based case–control study, the researchers investigate the fetal growth abnormalities associated with stillbirth using a new approach to estimate gestational age and accounting for the effect of characteristics that affect both fetal growth and stillbirth. A population-based case–control study compares the characteristics of patients with a condition in a population with those of unaffected people in the same population.
What Did the Researchers Do and Find?
The researchers investigated all the stillbirths and a sample of live births that occurred over 2.5 years at 59 hospitals in five US regions. They used a formula developed by the Stillbirth Collaborative Research Network to calculate the gestational age at death of the stillbirths. They categorized fetuses as SGA if they had a weight for gestational age within the bottom 10% (below the 10th percentile) of the population and as LGA if they had a weight for gestational age above the 90th percentile at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms of fetal weight for gestational age. Population norms incorporate weights for gestational age from normal pregnancies and from pregnancies complicated by growth abnormalities, whereas the other two norms include weights for gestational age from normal pregnancies only. Having an SGA fetus was associated with a 3- to 4-fold increased risk of stillbirth compared to having a fetus with “appropriate” weight for gestational age based on all three norms. LGA was associated with an increased risk of stillbirth based on the ultrasound and individualized norms but not the population norms. Being more severely SGA or LGA (below the 5th percentile or above the 95th percentile) was associated with an increased risk of stillbirth.
What Do These Findings Mean?
These findings indicate that, when the time of death is accounted for and norms for weight for gestational age only from uncomplicated pregnancies are used, stillbirth is associated with both restricted and excessive fetal growth. Overall, abnormal fetal growth was identified in 25% of stillbirths using population norms and in about 50% of stillbirths using ultrasound or individualized norms. Although the accuracy of these findings is likely to be affected by aspects of the study design, these findings suggest that, contrary to current practices, strategies designed to prevent stillbirth should focus on identifying both severely SGA and severely LGA fetuses and should use norms for the calculation of weight for gestational age based on normal pregnancies only. Such an approach has the potential to identify almost half of the pregnancies likely to result in stillbirth.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001633.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on stillbirth
Tommy's, a UK nonprofit organization that funds research into stillbirth, premature birth, and miscarriage and provides information for parents-to-be, also provides information on stillbirth (including personal stories)
The UK National Health Service Choices website provides information about stillbirth (including a video about dealing with grief after a stillbirth)
MedlinePlus provides links to other resources about stillbirth (in English and Spanish)
Information about the Stillbirth Collaborative Research Network is available
doi:10.1371/journal.pmed.1001633
PMCID: PMC3995658  PMID: 24755550
4.  AN ALGORITHM FOR THE ESTIMATION OF GESTATIONAL AGE AT THE TIME OF FETAL DEATH 
Background
Accurate assignment of gestational age at time of fetal death is important for research and clinical practice. An algorithm to estimate gestational age (GA) at fetal death was developed and evaluated.
Methods
The algorithm developed by the Stillbirth Collaborative Research Network (SCRN) incorporated clinical and postmortem data. The SCRN conducted a population-based case-control study of women with stillbirths and live births from 2006 to 2008 in five geographic catchment areas. Rules were developed to estimate a due date, identify an interval during which death likely occurred, and estimate GA at the time of fetal death. Reliability of using fetal foot length to estimate GA at death was assessed.
Results
The due date estimated for 620 singleton stillbirths studied was considered clinically reliable for 87%. Only 25.2% of stillbirths were documented alive within two days before diagnosis and 47.6% within one week of diagnosis. The algorithm-derived estimate of GA at time of fetal death was 1 or more weeks earlier than the GA at delivery for 43.5% of stillbirths. GA estimated from fetal foot length agreed with GA by algorithm within two weeks for 75% within a subset of well-dated stillbirths.
Conclusions
Precise assignment of GA at death, defined as reliable dating criteria and a short interval (≤1 week) during which fetal death was known to have occurred, was possible in 46.6% of cases. Fetal foot length is a relatively accurate measure of GA at death and should be collected in all stillbirth cases.
doi:10.1111/ppe.12037
PMCID: PMC3564237  PMID: 23374059
5.  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
6.  Methicillin-Resistant and Susceptible Staphylococcus aureus Bacteremia and Meningitis in Preterm Infants 
Pediatrics  2012;129(4):e914-e922.
BACKGROUND:
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).
METHODS:
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.
RESULTS:
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%).
CONCLUSIONS:
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.
doi:10.1542/peds.2011-0966
PMCID: PMC3313632  PMID: 22412036
Staphylococcus aureus; methicillin resistant; infant; newborn
7.  Bloodstream infections in very low birth weight infants with intestinal failure 
The Journal of pediatrics  2011;160(1):54-9.e2.
Objective
To examine pathogens and other characteristics associated with late-onset bloodstream infections (BSI) in infants with intestinal failure (IF) as a consequence of necrotizing enterocolitis (NEC).
Study design
Infants 401–1500 grams at birth who survived >72 hours and received care at NICHD Neonatal Research Network centers were studied. Frequency of culture positive BSI and pathogens were compared for infants with medical NEC, NEC managed surgically without IF, and surgical IF. Among infants with IF, duration of parenteral nutrition (PN) and other outcomes were evaluated.
Results
932 infants were studied (IF, n=78; surgical NEC without IF, n=452; medical NEC, n=402). The proportion with BSI after NEC diagnosis was higher in infants with IF than with surgical NEC (p=0.007) or medical NEC (p<0.001). Gram positive pathogens were most frequent. Among infants with IF, increased number of infections was associated with longer hospitalization and duration on PN (0, 1, ≥2 infections; median stay (days): 172, 188, 260, p=0.06; median days on PN: 90, 112, 115, p=0.003), and the proportion who achieved full feeds during hospitalization decreased (87%, 67%, 50%, p=0.03).
Conclusion
Recurrent BSIs are common in VLBW infants with IF. Gram positive bacteria were most commonly identified in these infants.
doi:10.1016/j.jpeds.2011.06.034
PMCID: PMC3419271  PMID: 21840538
Short bowel syndrome; Bloodstream infections; Late onset sepsis; Very low birth weight; Nutrition; Intestinal failure
8.  The Burden of Invasive Early-Onset Neonatal Sepsis in the United States, 2005–2008 
Background
Sepsis in the first 3 days of life is a leading cause of morbidity and mortality among infants. Group B Streptococcus (GBS), historically the primary cause of early-onset sepsis, has declined through widespread use of intrapartum chemoprophylaxis. We estimated the national burden of invasive early-onset sepsis (EOS) cases and deaths in the era of GBS prevention.
Methods
Population-based surveillance for invasive EOS was conducted in 4 of CDC’s Active Bacterial Core surveillance (ABCs) sites from 2005–2008. We calculated incidence using state and national live birth files. Estimates of the national number of cases and deaths were calculated, standardizing by race and gestational age.
Results
ABCs identified 658 cases of EOS; 72 (10.9%) were fatal. Overall incidence remained stable during the three years (2005:0.77 cases/1,000 live births; 2008:0.76 cases/1,000 live births). GBS (~38%) was the most commonly reported pathogen followed by Escherichia coli (~24%). Black preterm infants had the highest incidence (5.14 cases/1,000 live births) and case fatality (24.4%). Non-black term infants had the lowest incidence (0.40 cases/1,000 live births) and case fatality (1.6%). The estimated national annual burden of EOS was approximately 3,320 cases (95% CI: 3,060–3,580) including 390 deaths (95% CI: 300–490). Among preterm infants, 1,570 cases (95% CI: 1,400–1,770; 47.3% of the overall) and 360 deaths (95% CI: 280–460; 92.3% of the overall) occurred annually.
Conclusions
The burden of invasive early-onset sepsis remains substantial in the era of GBS prevention and disproportionately affects preterm and black infants. Identification of strategies to prevent preterm births is needed to reduce the neonatal sepsis burden.
doi:10.1097/INF.0b013e318223bad2
PMCID: PMC3193564  PMID: 21654548
early-onset; neonatal sepsis; group B Streptococcus; disease burden
9.  Early Onset Neonatal Sepsis: The Burden of Group B Streptococcal and E. coli Disease Continues 
Pediatrics  2011;127(5):817-826.
BACKGROUND:
Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen.
OBJECTIVE:
To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers.
METHODS:
Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence.
RESULTS:
Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%).
CONCLUSION:
In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
doi:10.1542/peds.2010-2217
PMCID: PMC3081183  PMID: 21518717
neonatal sepsis; group B streptococcal disease; Escherichia coli infection
10.  T cell cytokines and the risk of blood stream infection in extremely low birth weight infants 
Cytokine  2010;53(2):249-255.
Cytokines mediate the host immune response to infectious microorganisms. The objective of this study was to determine whether immune regulatory interleukins (IL-4, IL-5, IL-6 and IL-10) and inflammatory cytokines (Interferon- [INF- ], tumor necrosis factor- [TNF- ], IL-2, and IL-17) are associated with an increased risk of developing blood stream bacterial/fungal infection (BSI) in extremely low birth weight (ELBW) infants. ELBW infants from 17 NICHD Neonatal Research Network centers without early onset sepsis were studied. Cytokines were measured from blood on days 1, 3, 7, 14, and 21 after birth. 996 ELBW infants contributed a minimum of 4080 unique measurements for each cytokine during the 5 sampling periods. Infants with BSI had lower levels of the inflammatory cytokines IL-17 (P=0.01), and higher levels of the regulatory cytokines, IL-6 (P=0.01) and IL-10 (P<0.001). Higher levels of regulatory cytokines relative to pro-inflammatory cytokines were associated with increased risk of BSI even after adjusting for confounding variables. In ELBW infants, the ratio of immune regulatory cytokines to inflammatory cytokines was associated with development of BSI. Altered maturation of regulatory and inflammatory cytokines may increase the risk of serious infection in this population.
doi:10.1016/j.cyto.2010.11.003
PMCID: PMC3042892  PMID: 21145756
11.  Survival and Morbidity Outcomes of Very Low Birth Weight Infants with Down Syndrome 
Pediatrics  2010;126(6):1132-1140.
OBJECTIVE
Individuals with Down syndrome (DS) are at increased risk of several morbidities with lifelong health consequences. Little is known about mortality or morbidity risks in early infancy among very-low-birth-weight (VLBW) infants with DS. Our objective was to compare survival and neonatal morbidities between VLBW infants with DS and VLBW infants with other non-DS chromosomal anomalies, other non-chromosomal birth defects, and VLBW infants without major birth defects.
METHODS
Data were collected prospectively for infants weighing 401-1500 grams born and/or cared for at one of the study centers participating in the NICHD Neonatal Research Network from 1994 through 2008. Risk of death and morbidities including patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), late onset sepsis (LOS), retinopathy of prematurity (ROP), and bronchopulmonary dysplasia (BPD), were compared between VLBW infants with DS and infants in the other groups.
RESULTS
Infants with DS were at increased risk of death (adjusted relative risk [RR] 2.47, 95% confidence interval [CI] 2.00-3.07), PDA, NEC, LOS, and BPD relative to infants with no birth defects. Decreased risk of death (RR 0.40, 95% CI 0.31-0.52) and increased risks of NEC and LOS were observed when comparing infants with DS to infants with other non-DS chromosomal anomalies. Relative to infants with non-chromosomal birth defects, infants with DS were at increased risk of PDA and NEC.
CONCLUSION
The increased risk of morbidities among VLBW infants with DS provides useful information for counseling parents and for caretakers in anticipating the need for enhanced surveillance for prevention of these morbidities.
doi:10.1542/peds.2010-1824
PMCID: PMC3059605  PMID: 21098157
neonatal mortality; neonatal morbidity; preterm infants; Down syndrome; trisomy 21
12.  Impact of Timing of Birth and Resident Duty-Hour Restrictions on Outcome of Small Preterm Infants 
Pediatrics  2010;126(2):222-231.
OBJECTIVE
To examine the impact of birth at night, on the weekend, and during July or August – the first months of the academic year – and the impact of resident duty-hour restrictions on mortality and morbidity of VLBW infants.
METHODS
Outcomes were analyzed for 11,137 infants with birth weight 501–1250 grams enrolled in the NICHD Neonatal Research Network registry 2001–2005. Approximately half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessment at 18–22 months was completed for 4,508 infants. Mortality (7-day and 28-day), short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth: night vs day, weekend vs weekday, and July or August vs other months, and after vs before implementation of resident duty-hour restrictions.
RESULTS
There was no effect of hour, day, or month of birth on mortality and no impact on the risks of short-term morbidities except the risk of ROP requiring operative treatment was lower for infants born during the late night hours than during the day. There was no impact of timing of birth on neurodevelopmental outcome except the risk of hearing impairment or death was slightly lower among infants born in July or August compared with other months. The introduction of resident and fellow duty-hour restrictions had no impact on mortality or neurodevelopmental outcome. The only change in short-term morbidity after duty-hour restrictions were introduced was an increase in the risk of ROP (stage 2 or higher).
CONCLUSION
In this network of academic centers, the timing of birth and the introduction of duty-hour restrictions had little effect on the risks of mortality and morbidity of VLBW infants, suggesting that staffing patterns were adequate to provide consistent care.
doi:10.1542/peds.2010-0456
PMCID: PMC2924191  PMID: 20643715
Neonatal; preterm infants; morbidity/mortality; resident education/training; workforce
13.  Validation of the Functional Status II questionnaire in the assessment of extremely-low-birthweight infants 
AIM
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.
METHOD
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
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.
INTERPRETATION
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.
doi:10.1111/j.1469-8749.2009.03318.x
PMCID: PMC3031102  PMID: 19459909
14.  Neonatal Outcomes of Extremely Preterm Infants From the NICHD Neonatal Research Network 
Pediatrics  2010;126(3):443-456.
OBJECTIVE
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).
METHODS
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.
RESULTS
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.
CONCLUSION
Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
doi:10.1542/peds.2009-2959
PMCID: PMC2982806  PMID: 20732945
extremely low gestation; very low birth weight; morbidity; death
15.  Very Low Birth Weight Preterm Infants With Surgical Short Bowel Syndrome: Incidence, Morbidity and Mortality, and Growth Outcomes at 18 to 22 Months 
Pediatrics  2008;122(3):e573-e582.
OBJECTIVES
The objective of this study was to determine the (1) incidence of short bowel syndrome in very low birth weight (<1500 g) infants, (2) associated morbidity and mortality during initial hospitalization, and (3) impact on short-term growth and nutrition in extremely low birth weight (<1000 g) infants.
METHODS
Infants who were born from January 1, 2002, through June 30, 2005, and enrolled in the National Institute of Child Health and Human Development Neonatal Research Network were studied. Risk factors for developing short bowel syndrome as a result of partial bowel resection (surgical short bowel syndrome) and outcomes were evaluated for all neonates until hospital discharge, death, or 120 days. Extremely low birth weight survivors were further evaluated at 18 to 22 months’ corrected age for feeding methods and growth.
RESULTS
The incidence of surgical short bowel syndrome in this cohort of 12 316 very low birth weight infants was 0.7%. Necrotizing enterocolitis was the most common diagnosis associated with surgical short bowel syndrome. More very low birth weight infants with short bowel syndrome (20%) died during initial hospitalization than those without necrotizing enterocolitis or short bowel syndrome (12%) but fewer than the infants with surgical necrotizing enterocolitis without short bowel syndrome (53%). Among 5657 extremely low birth weight infants, the incidence of surgical short bowel syndrome was 1.1%. At 18 to 22 months, extremely low birth weight infants with short bowel syndrome were more likely to still require tube feeding (33%) and to have been rehospitalized (79%). Moreover, these infants had growth delay with shorter lengths and smaller head circumferences than infants without necrotizing enterocolitis or short bowel syndrome.
CONCLUSIONS
Short bowel syndrome is rare in neonates but has a high mortality rate. At 18 to 22 months’ corrected age, extremely low birth weight infants with short bowel syndrome were more likely to have growth failure than infants without short bowel syndrome.
doi:10.1542/peds.2007-3449
PMCID: PMC2848527  PMID: 18762491
short bowel syndrome; preterm; necrotizing enterocolitis; nutrition
16.  Neurodevelopmental Outcome of Extremely Low Birth Weight Infants With Posthemorrhagic Hydrocephalus Requiring Shunt Insertion 
Pediatrics  2008;121(5):e1167-e1177.
OBJECTIVE
We aimed to evaluate neurodevelopmental and growth outcomes among extremely low birth weight infants who had severe intraventricular hemorrhage that required shunt insertion compared with infants without shunt insertion.
METHODS
Infants who were born in 1993–2002 with birth weights of 401 to 1000 g were enrolled in a very low birth weight registry at medical centers that participate in the National Institute of Child Health and Human Development Neonatal Research Network, and returned for follow-up at 18 to 22 months’ corrected age were studied. Eighty-two percent of survivors completed follow-up, and 6161 children were classified into 5 groups: group 1, no intraventricular hemorrhage/no shunt (n = 5163); group 2, intraventricular hemorrhage grade 3/no shunt (n = 459); group 3, intraventricular hemorrhage grade 3/shunt (n = 103); group 4, intraventricular hemorrhage grade 4/no shunt (n = 311); and group 5, intraventricular hemorrhage grade 4/shunt (n = 125). Group comparisons were evaluated with χ2 and Wilcoxon tests, and regression models were used to compare outcomes after adjustment for covariates.
RESULTS
Children with severe intraventricular hemorrhage and shunts had significantly lower scores on the Bayley Scales of Infant Development IIR compared with children with no intraventricular hemorrhage and with children with intraventricular hemorrhage of the same grade and no shunt. Infants with shunts were at increased risk for cerebral palsy and head circumference at the <10th percentile at 18 months’ adjusted age. Greatest differences were observed between children with shunts and those with no intraventricular hemorrhage on these outcomes.
CONCLUSIONS
This large cohort study suggests that extremely low birth weight children with severe intraventricular hemorrhage that requires shunt insertion are at greatest risk for adverse neurodevelopmental and growth outcomes at 18 to 22 months compared with children with and without severe intraventricular hemorrhage and with no shunt. Long-term follow-up is needed to determine whether adverse outcomes persist or improve over time.
doi:10.1542/peds.2007-0423
PMCID: PMC2803352  PMID: 18390958
hydrocephalus; neuromotor outcome; prematurity
17.  Prolonged Duration of Initial Empirical Antibiotic Treatment Is Associated With Increased Rates of Necrotizing Enterocolitis and Death for Extremely Low Birth Weight Infants 
Pediatrics  2009;123(1):58-66.
OBJECTIVES
Our objectives were to identify factors associated with the duration of the first antibiotic course initiated in the first 3 postnatal days and to assess associations between the duration of the initial antibiotic course and subsequent necrotizing enterocolitis or death in extremely low birth weight infants with sterile initial postnatal culture results.
METHODS
We conducted a retrospective cohort analysis of extremely low birth weight infants admitted to tertiary centers in 1998–2001. We defined initial empirical antibiotic treatment duration as continuous days of antibiotic therapy started in the first 3 postnatal days with sterile culture results. We used descriptive statistics to characterize center practice, bivariate analyses to identify factors associated with prolonged empirical antibiotic therapy (≥5 days), and multivariate analyses to evaluate associations between therapy duration, prolonged empirical therapy, and subsequent necrotizing enterocolitis or death.
RESULTS
Of 5693 extremely low birth weight infants admitted to 19 centers, 4039 (71%) survived >5 days, received initial empirical antibiotic treatment, and had sterile initial culture results through the first 3 postnatal days. The median therapy duration was 5 days (range: 1–36 days); 2147 infants (53%) received prolonged empirical therapy (center range: 27%–85%). Infants who received prolonged therapy were less mature, had lower Apgar scores, and were more likely to be black. In multivariate analyses adjusted for these factors and center, prolonged therapy was associated with increased odds of necrotizing enterocolitis or death and of death. Each empirical treatment day was associated with increased odds of death, necrotizing enterocolitis, and the composite measure of necrotizing enterocolitis or death.
CONCLUSION
Prolonged initial empirical antibiotic therapy may be associated with increased risk of necrotizing entero-colitis or death and should be used with caution.
doi:10.1542/peds.2007-3423
PMCID: PMC2760222  PMID: 19117861
antibiotic use; bloodstream infection; extremely low birth weight infants; necrotizing enterocolitis; death

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