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1.  Analysis of the association between necrotizing enterocolitis and transfusion of red blood cell in very low birth weight preterm infants 
Korean Journal of Pediatrics  2013;56(3):112-115.
To investigate the association between necrotizing enterocolitis (NEC) and red blood cell transfusions in very low birth weight (VLBW) preterm infants.
We studied were 180 VLBW preterm infants who were admitted to the neonatal intensive care unit of CHA Gangnam Hospital from January of 2006 to December of 2009. The subjects were divided into 2 groups: an NEC group (greater than stage II on the modified Bell's criteria) and a control group (less than stage II on the modified Bell's critieria). We defined red blood cell transfusion before NEC diagnosis as the frequency of transfusion until NEC diagnosis (mean day at NEC diagnosis, day 18) in the NEC group and the frequency of transfusion until 18 days after birth in the control group.
Of the 180 subjects, 18 (10%) belonged to the NEC group, and 14 (78%) of these 18 patients had a history of transfusion before NEC diagnosis. The NEC group received 3.1±2.9 transfusions, and the control group received 1.0±1.1 transfusions before the NEC diagnosis (P=0.005). In a multivariate logistic regression corrected for gestational age, Apgar score at 1 minute, the presence of respiratory distress syndrome, patent ductus arteriosus, premature rupture of membrane, disseminated intravascular coagulopathy and death were confounding factors. The risk of NEC increased 1.63 times (95% confidence interval, 1.145 to 2.305; P=0.007) with transfusion before the NEC diagnosis.
The risk for NEC increased significantly with increased transfusion frequency before the NEC diagnosis.
PMCID: PMC3611044  PMID: 23559972
Necrotizing enterocolitis; Very low birth weight infants; Red blood cell transfusion
2.  Preeclampsia and the Risk of Bronchopulmonary Dysplasia in VLBW Infants: A Population Based Study 
PLoS ONE  2013;8(9):e75168.
Preeclampsia remains a leading cause of maternal mortality and preterm delivery. Both preeclampsia and bronchopulmonary dysplasia (BPD) of prematurity are associated with impaired angiogenesis. However, the relationship between maternal preeclampsia and BPD remains controversial. This study aims to test whether or not preeclampsia is associated with development of BPD in a cohort of premature infants.
Materials and Methods
We conducted a retrospective cohort study assessing the association between preeclampsia and the risk of developing BPD in very-low-birth-weight (VLBW) infants registered in the Premature Baby Foundation of Taiwan from 1997 through 2006. All 21 neonatal departments in Taiwan participated in the data collection. A total of 8,653 VLBW infants were registered in the database. The exclusion criteria included congenital anomalies, chromosome anomalies, infants that died before 36 weeks post-conceptual (PCA), and those whose BPD status were unavailable. BPD was defined as oxygen dependence at 36 weeks postmenstrual age. The association between maternal preeclampsia and BPD was assessed using a multivariate-adjusted logistic regression model.
In the end, a total of 5,753 cases were enrolled in this study. The incidence of preeclampsia was 14.7% (n=847) and the overall incidence of BPD was 34.9%. Infants with maternal preeclampsia had a higher gestational age, higher incidence of cesarean section and being small for their gestational age, lower incidence of respiratory distress syndrome, patent ductus arteriosus, and sepsis. BPD occurred significantly less frequently in the maternal preeclampsia group (24.1% vs. 36.7%; adjusted odds ratio: 0.78; 95% confidence interval, 0.62–0.98). Subgroup analysis showed that the association between preeclampsia and BPD was significant only in those VLBW infants with a gestational age between 31–34 weeks.
This data supports the association between fetal exposure to maternal preeclampsia and a reduced risk of BPD in relatively mature VLBW infants.
PMCID: PMC3779258  PMID: 24073247
3.  Short-Term Outcomes of Very Low Birth Weight Infants Born at a Tertiary Care Hospital, Istanbul, Turkey 
Iranian Journal of Pediatrics  2013;23(2):205-211.
To evaluate mortality and short-term outcomes in very low birth weight infants admitted to the tertiary neonatal intensive care unit, Istanbul, Turkey.
Study data were recorded prospectively from January 1, 2010, to December 31, 2010. The clinical findings in neonates with birth weights <1000g were compared with infants with birth weights of between 1000g and 1499g.
In the present study, survival rates were 40% and 86.2% for infants weighing <1000g and 1000g to 1499g, respectively. There was no difference between males and females with respect to mortality (P>0.05). The mean (±standard deviation) birth weight was 985.6±150.15 g and mean gestational age was 27.5±2.04 weeks. The antenatal steroid rate was 37.2%, and the Cesarean section rate was 73%. Respiratory distress syndrome was diagnosed in 89% of the infants, with a 69% surfactant administration rate. Severe intracranial hemorrhage (IVH) (grade >II) was 14%. Grade 4 periventricular leukomalacia was 10%. Twelve (24%) infants had evidence of bronchopulmonary dysplasia (BPD). Retinopathy of prematurity (stage >II) was 4%. The correlation between ROP rate and need for ventilation therapy was present (r=0.52). Proven necrotizing enterocolitis (stage >2) was not observed. Patent ductus arteriosus (PDA) was diagnosed in 67% of the neonates. BPD, IVH, and PDA were statistically higher in neonates with a birth weight <1000g.
Survival rate of VLBW infants increased with increasing BW. Sex was not a risk factor for mortality. The need for ventilatory therapy may be an important risk factor for ROP in infants <1500g.
PMCID: PMC3663314  PMID: 23724184
Mortality; Morbidity; Neonate; Very Low Birth Weight
4.  Ten-Year Review of Major Birth Defects in VLBW Infants 
Pediatrics  2013;132(1):49-61.
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.
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.
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).
Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants.
PMCID: PMC3691532  PMID: 23733791
birth defects; prematurity; Neonatal Research Network; low birth weight
5.  Population based trends in mortality, morbidity and treatment for very preterm- and very low birth weight infants over 12 years 
BMC Pediatrics  2012;12:17.
Over the last two decades, improvements in medical care have been associated with a significant increase and better outcome of very preterm (VP, < 32 completed gestational weeks) and very low birth weight (VLBW, < 1500 g) infants. Only a few publications analyse changes of their short-term outcome in a geographically defined area over more than 10 years. We therefore aimed to investigate the net change of VP- and VLBW infants leaving the hospital without major complications.
Our population-based observational cohort study used the Minimal Neonatal Data Set, a database maintained by the Swiss Society of Neonatology including information of all VP- and VLBW infants. Perinatal characteristics, mortality and morbidity rates and the survival free of major complications were analysed and their temporal trends evaluated.
In 1996, 2000, 2004, and 2008, a total number of 3090 infants were enrolled in the Network Database. At the same time the rate of VP- and VLBW neonates increased significantly from 0.87% in 1996 to 1.10% in 2008 (p < 0.001). The overall mortality remained stable by 13%, but the survival free of major complications increased from 66.9% to 71.7% (p < 0.01). The percentage of infants getting a full course of antenatal corticosteroids increased from 67.7% in 1996 to 91.4% in 2008 (p < 0.001). Surfactant was given more frequently (24.8% in 1996 compared to 40.1% in 2008, p < 0.001) and the frequency of mechanical ventilation remained stable by about 43%. However, the use of CPAP therapy increased considerably from 43% to 73.2% (p < 0.001). Some of the typical neonatal pathologies like bronchopulmonary dysplasia, necrotising enterocolitis and intraventricular haemorrhage decreased significantly (p ≤ 0.02) whereas others like patent ductus arteriosus and respiratory distress syndrome increased (p < 0.001).
Over the 12-year observation period, the number of VP- and VLBW infants increased significantly. An unchanged overall mortality rate and an increase of survivors free of major complication resulted in a considerable net gain in infants with potentially good outcome.
PMCID: PMC3311070  PMID: 22356724
6.  Red Blood Cell Transfusion-Related Necrotizing Enterocolitis in Very Low Birth Weight Infants: A Near-Infrared Spectroscopy Investigation 
Transfusion  2013;53(11):2650-2658.
Recent evidence suggests that antecedent packed red blood cell (PRBC) transfusions increase the risk for necrotizing enterocolitis (NEC), the most common gastrointestinal emergency encountered by very low birth weight (VLBW) infants. The underlying mechanism for this association is unknown. Altered oxygenation of the mesenteric vasculature during PRBC transfusion has been hypothesized to contribute to NEC development and was investigated in this study.
Study design and methods
Oxygenation patterns among four VLBW infants who developed transfusion-related NEC (TR-NEC) were compared to four VLBW infants with similar gestational age who were transfused but did not develop NEC (non-NEC). Cerebral and mesenteric patterns were recorded before, during and 48 hours subsequent to PRBC transfusion using near-infrared spectroscopy technology (NIRS). Percentage change from mean baseline regional saturation (rSO2) values and cerebro- splanchnic oxygenation ratio (CSOR) were analyzed.
All TR-NEC infants (24–29 weeks gestation; 705–1080 grams) demonstrated greater variation in mesenteric oxygenation patterns surrounding transfusions than non-NEC infants (27.6–30 weeks gestation; 980–1210 grams). TR-NEC infants received larger mean volumes of total blood (27.75 ml/kg ± 8.77) than non-NEC infants (15.25ml/kg ± 0.5).
Wide fluctuation and decreases in mesenteric oxygenation patterns are more pronounced in TR-NEC infants, especially prior to TR-NEC onset, as compared to non-NEC infants. Greater total volume of infused blood was associated with TR-NEC in preterm infants. Using NIRS, larger prospective studies are needed to further evaluate potential risk factors for NEC in this high risk population.
PMCID: PMC3686850  PMID: 23480548
Transfusion-related NEC; necrotizing enterocolitis; near-infrared spectroscopy
7.  Neonatal physiological correlates of near-term brain development on MRI and DTI in very-low-birth-weight preterm infants 
NeuroImage : Clinical  2014;5:169-177.
Structural brain abnormalities identified at near-term age have been recognized as potential predictors of neurodevelopment in children born preterm. The aim of this study was to examine the relationship between neonatal physiological risk factors and early brain structure in very-low-birth-weight (VLBW) preterm infants using structural MRI and diffusion tensor imaging (DTI) at near-term age.
Structural brain MRI, diffusion-weighted scans, and neonatal physiological risk factors were analyzed in a cross-sectional sample of 102 VLBW preterm infants (BW ≤ 1500 g, gestational age (GA) ≤ 32 weeks), who were admitted to the Lucile Packard Children's Hospital, Stanford NICU and recruited to participate prior to routine near-term brain MRI conducted at 36.6 ± 1.8 weeks postmenstrual age (PMA) from 2010 to 2011; 66/102 also underwent a diffusion-weighted scan. Brain abnormalities were assessed qualitatively on structural MRI, and white matter (WM) microstructure was analyzed quantitatively on DTI in six subcortical regions defined by DiffeoMap neonatal brain atlas. Specific regions of interest included the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, the thalamus, and the globus pallidus. Regional fractional anisotropy (FA) and mean diffusivity (MD) were calculated using DTI data and examined in relation to neonatal physiological risk factors including gestational age (GA), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), and sepsis, as well as serum levels of C-reactive protein (CRP), glucose, albumin, and total bilirubin.
Brain abnormalities were observed on structural MRI in 38/102 infants including 35% of females and 40% of males. Infants with brain abnormalities observed on MRI had higher incidence of BPD (42% vs. 25%) and sepsis (21% vs. 6%) and higher mean and peak serum CRP levels, respectively, (0.64 vs. 0.34 mg/dL, p = .008; 1.57 vs. 0.67 mg/dL, p= .006) compared to those without. The number of signal abnormalities observed on structural MRI correlated to mean and peak CRP (rho = .316, p = .002; rho = .318, p= .002). The number of signal abnormalities observed on MRI correlated with thalamus MD (left: r= .382, p= .002; right: r= .400, p= .001), controlling for PMA-at-scan. Thalamus WM microstructure demonstrated the strongest associations with neonatal risk factors. Higher thalamus MD on the left and right, respectively, was associated with lower GA (r = −.322, p = .009; r= −.381, p= .002), lower mean albumin (r = −.276, p= .029; r= −.385, p= .002), and lower mean bilirubin (r = −.293, p= .020; r= −.337 p= .007).
Results suggest that at near-term age, thalamus WM microstructure may be particularly vulnerable to certain neonatal risk factors. Interactions between albumin, bilirubin, phototherapy, and brain development warrant further investigation. Identification of physiological risk factors associated with selective vulnerability of certain brain regions at near-term age may clarify the etiology of neurodevelopmental impairment and inform neuroprotective treatment for VLBW preterm infants.
•Biomarkers of inflammation in preterm infants correlated with brain abnormalities detected on near-term structural MRI.•Biomarkers of inflammation in preterm infants correlated with near-term WM microstructure assessed on DTI.•Signal abnormalities observed on near-term structural MRI correlated with increased thalamus MD.
PMCID: PMC4110350  PMID: 25068107
MRI; Diffusion tensor imaging; White matter microstructure; Brain development; Risk factors; Preterm infants; VLBW, very-low-birth-weight; GA, gestational age; PMA, post-menstrual age; DTI, diffusion tensor imaging; FA, fractional anisotropy; MD, mean diffusivity; CC, corpus callosum; IC, internal capsule; ALIC, anterior limb of the internal capsule; PLIC, posterior limb of the internal capsule; GloP, globus pallidus
8.  Surgical Ligation on Significant Patent Ductus Arteriosus in Very Low Birth Weight Infants: Comparison between Early and Late Ligations 
We aimed to evaluate the efficacy and safety of early surgical ligation (within 15 days of age) over late surgical ligation (after 15 days of age) by a comparative analysis of very low birth weight (VLBW) infants undergoing surgical correction for symptomatic patent ductus arteriosus (PDA) over the course of 6 years in our hospital.
We retrospectively reviewed all the medical records in the neonatal intensive care unit at Hanyang University Seoul Hospital, from March 2007 to May 2013, to identify VLBW infants (< 1,500 g) who underwent surgical PDA ligation.
The gestational age (GA) in the late ligation (LL) group was significantly younger than in the early ligation (EL) group (p=0.010). The other baseline characteristics and preoperative conditions did not differ significantly between the two groups. The intubation period before surgery (p < 0.001) and the age at surgery (p < 0.001) were significantly different. The postoperative clinical outcomes of the study patients, including major morbidity and mortality, are summarized. There were no significant differences in bronchopulmonary dysplasia, sepsis, or mortality between the EL and the LL groups. However, the LL group was significantly associated with an increased risk of necrotizing enterocolitis (p=0.037) and with a prolonged duration of the total parenteral nutrition (p=0.046) after adjusting for GA.
Early surgical ligation for the treatment of PDA that failed to close after medical treatment or in cases contraindicated for medical treatment might be desirable to reduce the incidence of necrotizing enterocolitis and to alleviate feeding intolerance in preterm infants.
PMCID: PMC4207104  PMID: 25346899
Congenital heart disease (CHD); Infant; Outcomes
9.  Early enteral feeding and nosocomial sepsis in very low birthweight infants 
Background: The interrelations between early enteral feeding, necrotising enterocolitis (NEC), and nosocomial sepsis (NS) remain unclear.
Objective: To evaluate the effect of age at the introduction of enteral feeding on the incidence of NS and NEC in very low birthweight (VLBW< 1500 g) infants.
Methods: Data were collected on the pattern of enteral feeding and perinatal and neonatal morbidity on all VLBW infants born in one centre during 1995–2001. Enteral feeding was compared between infants with and without NS and/or NEC.
Results: The study sample included 385 infants. Of these, 163 (42%) developed NS and 35 (9%) developed NEC. Enteral feeding was started at a significantly earlier mean (SD) age in infants who did not develop nosocomial sepsis (2.8 (2.6) v 4.8 (3.7) days, p  =  0.0001). Enteral feeding was introduced at the same age in babies who did or did not develop NEC (3.1 (2) v 3.7 (3) days, p  =  0.28). Over the study period, the mean annual age at the start of enteral feeding fell consistently, and this correlated with the mean annual incidence of NS (r2  =  0.891, p  =  0.007). Multiple logistic regression analysis showed age at start of enteral feeding, respiratory distress syndrome, and birth weight to be the most significant predictors of risk of NS (p  =  0.0005, p  =  0.024, p  =  0.011).
Conclusions: Early enteral feeding was associated with a reduced risk of NS but no change in the risk of NEC in VLBW infants. These findings support the use of early enteral feeding in this high risk population, but this needs to be confirmed in a large randomised controlled trial.
PMCID: PMC1721698  PMID: 15210657
10.  Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study 
PLoS Medicine  2009;6(8):e1000135.
Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers.
Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood.
Methods and Findings
The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28–0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34–0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity.
Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies last 40 weeks but some babies arrive earlier than expected. Sadly, babies born before 37 weeks of pregnancy—premature babies—are more likely to die than full-term babies, although recent improvements in neonatal care have increased their chances of survival. Premature babies also often have serious long-term health problems, particularly those born before 32 weeks of pregnancy. Such extremely premature babies have poorly developed internal organs and are usually very small—babies whose birth weight is less than 1,500 g are called very-low-birth-weight (VLBW) babies; the average full-term birth weight is about 3,500 g. Furthermore, their bones are not as well developed as those of full-term babies. The human skeleton initially consists of a soft fibrous material called cartilage. This is gradually transformed into bone by a process called bone mineralization. The last third of pregnancy is a crucial period for bone mineralization although the process continues throughout infancy and childhood. Thus, VLBW babies often have subnormal skeletal mineralization and their accrual of bone mass during childhood is frequently compromised.
Why Was This Study Done?
It is not known whether the childhood bone deficits of VLBW babies persist into adulthood because the first generation of these infants not to die soon after birth is only just reaching adulthood. Peak bone mass is reached in early adulthood (bone mass begins to decrease from the age of 35 years onward) and is an important indicator of whether an individual will develop osteoporosis (thinning of the bones) and be susceptible to bone fractures later in life. If adults with VLBW (about 1% of live births in high-income countries are now VLBW births) do have a subnormal peak bone mass and reduced bone mineral density (BMD), they may be able reduce their risk of developing osteoporosis by eating a healthy diet and exercising regularly. In this study (part of the Helsinki Study of Very Low Birth Weight Adults), the researchers investigate the skeletal health of people who were born with VLBW in the Helsinki area between 1978 and 1985.
What Did the Researchers Do and Find?
The researchers compared the skeletal health of 144 young adults who were born prematurely with VLBW and subnormal BMD with that of 139 age- and sex-matched individuals who were born at term. They measured the BMD of the participants (average age 22.6 years) using “dual energy X-ray absorptiometry” and determined a “Z score” for the spine in the lower back (the lower lumbar spine) and the hip (two sites that are routinely examined in assessments of skeletal health). Z scores indicate whether an individual's BMD is significantly different from the average BMD of healthy age- and sex-matched people; in this study, reduced BMD was defined as a Z score of −1.0 or less. The researchers found that adults born with VLBW had an average Z score of −0.51 at the lower lumbar spine and −0.56 at the hip when compared with the adults born at term. Furthermore, 44% of the VLBW participants but only 26% of the term-born participants had a lumbar spine Z score of −1.0 or less. Adjustment for the shorter height of the VLBW participants slightly reduced these differences in BMD but the differences remained statistically significant.
What Do These Findings Mean?
These findings show that, when studied close to the age of peak bone mass, young adults born with VLBW have a significantly lower BMD than their term-born peers and a 2-fold greater risk of having a lumbar spine Z score of below −1.0; a unit decrease in Z score approximately doubles the risk of bone fractures. Because BMD measurements were only taken at one age, it remains possible, however, that the BMD of the VLBW adults might eventually match that of their full-term peers. Recently born VLBW babies still have a lower than average BMD during their childhood, note the researchers, even though their care has changed since the people included in this study were born. Thus, these findings suggest that people who were VLBW infants should be encouraged to eat food rich in vitamin D and calcium and to do regular weight-bearing exercise throughout their lives to improve their bone health and reduce their risk of developing osteoporosis.
Additional Information
Please access these Web sites via the online version of this summary at
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies and to information on osteoporosis (in English and Spanish)
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases and the UK National Health Service also provide detailed information on all aspects of osteoporosis
Further details about the Helsinki Study of Very Low Birth Weight Adults are available
PMCID: PMC2722726  PMID: 19707270
11.  Impact of Timing of Birth and Resident Duty-Hour Restrictions on Outcome of Small Preterm Infants 
Pediatrics  2010;126(2):222-231.
To examine the impact of birth at night, on the weekend, and during July or August – the first months of the academic year – and the impact of resident duty-hour restrictions on mortality and morbidity of VLBW infants.
Outcomes were analyzed for 11,137 infants with birth weight 501–1250 grams enrolled in the NICHD Neonatal Research Network registry 2001–2005. Approximately half were born before the introduction of resident duty-hour restrictions in 2003. Follow-up assessment at 18–22 months was completed for 4,508 infants. Mortality (7-day and 28-day), short-term morbidities, and neurodevelopmental outcome were examined with respect to the timing of birth: night vs day, weekend vs weekday, and July or August vs other months, and after vs before implementation of resident duty-hour restrictions.
There was no effect of hour, day, or month of birth on mortality and no impact on the risks of short-term morbidities except the risk of ROP requiring operative treatment was lower for infants born during the late night hours than during the day. There was no impact of timing of birth on neurodevelopmental outcome except the risk of hearing impairment or death was slightly lower among infants born in July or August compared with other months. The introduction of resident and fellow duty-hour restrictions had no impact on mortality or neurodevelopmental outcome. The only change in short-term morbidity after duty-hour restrictions were introduced was an increase in the risk of ROP (stage 2 or higher).
In this network of academic centers, the timing of birth and the introduction of duty-hour restrictions had little effect on the risks of mortality and morbidity of VLBW infants, suggesting that staffing patterns were adequate to provide consistent care.
PMCID: PMC2924191  PMID: 20643715
Neonatal; preterm infants; morbidity/mortality; resident education/training; workforce
12.  Trends in morbidity and mortality among very-low-birth-weight infants from 2003 to 2008 in Japan 
Pediatric Research  2012;72(5):531-538.
Although medical care for very-low-birth-weight (VLBW) infants has improved over time, it is unclear how this has affected mortality and morbidity. To characterize these trends, a network database was analyzed.
This is a cohort study of VLBW infants born from 2003 through 2008.
Over the 6-y period, 19,344 infants were registered and analyzed. Crude mortality rates among the infants at discharge decreased significantly (from 10.8 to 8.7%) during the study period. The greatest improvement in mortality was observed among infants with birth weights between 501 and 750 g (25.6–17.7 %). The odds ratio (OR) of mortality over year adjusted for potential confounders by a logistic regression model was 0.94 (95% confidence interval 0.92–0.97). Significant increases were observed in some morbidities, including symptomatic patent ductus arteriosus with an OR of 1.11 (1.09–1.13); late-onset adrenal insufficiency, 1.21 (1.17–1.26); and necrotizing enterocolitis/intestinal perforation, 1.10 (1.01–1.12). However, the severe form of intraventricular hemorrhage, with an OR of 0.98 (0.92–0.99), decreased significantly. Risk-adjusted trends in other morbidities showed no significant change.
Mortality of VLBW infants decreased significantly over the 6-y study period. Decreasing morbidity is essential for further improvement in the outcomes in VLBW infants.
PMCID: PMC3547175  PMID: 22922774
13.  Early neurodevelopment in very low birth weight infants with mild intraventricular hemorrhage or those without intraventricular hemorrhage 
Korean Journal of Pediatrics  2012;55(11):414-419.
This study aimed to assess early development in very low birth weight (VLBW) infants with mild intraventricular hemorrhage (IVH) or those without IVH and to identify the perinatal morbidities affecting early neurodevelopmental outcome.
Bayley Scales of Infant Development-II was used for assessing neurological development in 49 infants with a birth weight <1,500 g and with low grade IVH (≤grade II) or those without IVH at a corrected age of 12 months.
Among the 49 infants, 19 infants (38.8%) showed normal development and 14 (28.6%) showed abnormal mental and psychomotor development. Infants with abnormal mental development (n=14) were mostly male and had a longer hospitalization, a higher prevalence of patent ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD), and were under more frequent postnatal systemic steroid treatment compared with infants with normal mental development (n=35, P<0.05). Infants with abnormal psychomotor development (n=29) had a longer hospitalization and more associated PDA compared to infants with normal psychomotor development (n=20, P<0.05). Infants with abnormal mental and psychomotor development were mostly male and had a longer hospitalization and a higher prevalence of PDA and BPD compared to infants with normal mental and psychomotor development (n=19, P<0.05). Using multiple logistic regression analysis, a longer duration of hospitalization and male gender were found to be significant risk factors.
Approximately 62% of VLBW infants with low grade IVH or those without IVH had impaired early development.
PMCID: PMC3510270  PMID: 23227060
Infant premature; Intracranial hemorrhages; Growth & development
14.  Bloodstream infections in very low birth weight infants with intestinal failure 
The Journal of pediatrics  2011;160(1):54-9.e2.
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.
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).
Recurrent BSIs are common in VLBW infants with IF. Gram positive bacteria were most commonly identified in these infants.
PMCID: PMC3419271  PMID: 21840538
Short bowel syndrome; Bloodstream infections; Late onset sepsis; Very low birth weight; Nutrition; Intestinal failure
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.  Bedside Surgery to Treat Patent Ductus Arteriosus in Low-Birth-Weight Premature Infants 
Patent ductus arteriosus (PDA) is commonly seen in premature infants with low birth weights (LBW). It is a condition that has high mortality and morbidity rates. Early closure of the ductus arteriosus may require surgery or medical treatment. However, the decision of first medical approach for symptomatic PDA closure is still debated. In this study, we compared the surgical and medical treatments for the closure of PDA in premature LBW infants.
This study included 27 premature infants whose birth weights were lower than 1500 g, who were born in the period between 2011 and 2013 and had symptomatic PDA. Patients were separated into two groups: groups A and B. Group A included patients whose PDAs were closed with medical treatment (n = 16), and group B included patients who had undergone surgical operations for PDA closure (n = 11).
There were no statistically significant differences between groups A and B when the groups were compared in terms of birth weight, gestational age, respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), sepsis, intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and pneumothorax. Although the mortality rate was determined to be lower in group B (2 out of 11, 18.1%) than in group A (7 out of 16, 43.7%), no statistically significant difference was found between the two groups. A statistically significant increase was determined in the incidence of kidney function loss in patient group that received Ibuprofen, a medical treatment, in comparison to the patients who had surgery.
In conclusion, surgery is a safe method to repair PDA in premature LBW infants. Although there is no remarkable difference between surgery and medical treatment, we suggest that a surgical approach may be used as a first choice to repair PDA considering the lower rate of mortality and morbidity and higher rate of closure compared to medical treatment.
PMCID: PMC4251059  PMID: 25512700
patent ductus arteriosus; low birth weight; surgery
17.  Increased incidence of intraventricular hemorrhage and developmental delay in cocaine-exposed, very low birth weight infants 
The Journal of pediatrics  1994;124(5 0 1):765-771.
This study sought to determine whether very low birth weight (VLBW) infants (<1500 gm) with fetal cocaine exposure differed from non-cocaine-exposed VLBW infants in incidence of neonatal medical complications and in later developmental outcome. Forty-one cocaine-exposed, VLBW infants, followed in a longitudinal study, were compared with 41 non-cocaine-exposed, VLBW infants of comparable race, social class, age, and incidence of bronchopulmonary dysplasia. Cocaine-exposed infants were identified on the basis of combined findings of maternal and/or infant urine immunoassay and on the basis of maternal self-report. At birth, groups did not differ on medical risk factors except that cocaine-exposed infants had a higher incidence of mild (grades I to II) intraventricular hemorrhage. Cocaine-using women were also more likely to use other drugs, especially alcohol, marijuana, and tobacco. At follow-up, at mean corrected ages of 16.5 ± 8 months for 30 cocaine-exposed infants and 18.5 ± 7 months for 37 non-cocaine-exposed infants, standardized assessments of cognitive (Mental Development Index) and motor (Psychomotor Development Index) development were administered. Cocaine-exposed infants had lower mean cognitive (83 ± 27 vs 91 ± 19), and motor (85 ± 25 vs 96 ± 18) scores; the incidence of developmental delay was significantly higher even after control for the effects of intraventricular hemorrhage and chronologic age. Cocaine-exposed VLBW infants were also more likely to be living with relatives or in foster homes. We conclude that these VLBW, cocaine-exposed infants were at increased risk of intraventricular hemorrhage, were more likely to be placed outside maternal care, and had higher incidences of cognitive and motor delays at follow-up.
PMCID: PMC4181569  PMID: 7513757
18.  Evaluating the Effect of Hospital and Insurance Type on the Risk of 1-Year Mortality of Very Low Birth Weight Infants: Controlling for Selection Bias 
Medical Care  2012;50(4):353-360.
We examined the effect of hospital type and medical coverage on the risk of 1-year mortality of very low birth weight (VLBW) infants while adjusting for possible selection bias.
The study population was limited to singleton live birth infants having birth weight between 500 and 1,500 grams with no congenital anomalies who were born in Arkansas hospitals between 2001 and 2007. Propensity score (PS) matching and PS covariate adjustment were used to mitigate selection bias. Additionally, a conventional multivariable logistic regression model was used for comparison purposes.
Generally, all three analytical approaches provided consistent results in terms of the estimated relative risk, absolute risk reduction, and the number needed to treat (NNT). Using the PS matching method, VLBW infants delivered at a hospital with a neonatal intensive care unit (NICU) were associated with a 35% relative decrease (95% bootstrap CI: 18.5% – 48.9%) in the risk of 1-year mortality as compared to those infants delivered at non-NICU hospitals. Furthermore, our results showed that on average, 16 VLBW infants (95% bootstrap CI: 11 – 32), would need to be delivered at a hospital with an NICU to prevent one additional death at one year. However, there was not a difference in the risk of 1-year mortality between VLBW infants born to Medicaid-insured versus non-Medicaid-insured women.
Estimated relative risk of infant mortality was significantly lower for births that occurred in hospitals with an NICU; therefore, greater efforts should be made to deliver VLBW neonates in an NICU hospital.
PMCID: PMC3306601  PMID: 22422056
19.  Necrotising Enterocolitis in Preterm Infants: Epidemiology and Antibiotic Consumption in the Polish Neonatology Network Neonatal Intensive Care Units in 2009 
PLoS ONE  2014;9(3):e92865.
The aim of this study was to describe the epidemiology of necrotising enterocolitis (NEC), antibiotic consumption and the usefulness of microbiological tests in very low birth weight (VLBW) Polish newborns.
Prospective surveillance was performed in the year 2009 by local infection control teams. The study covered 910 infants hospitalized in six Polish neonatal intensive care units. Two kinds of indicators were used for the description of antibiotic usage: the duration of treatment (days of treatment, DOTs) and the defined daily dose (DDD).
NEC incidence was 8.7% and fatality rate was 19%. Chorioamnionitis, late gestational age and low birth weight were identified as risk factors for NEC. Catheterization, mechanical ventilation and other selected procedures were used considerably longer in newborns with NEC than in the remaining neonates. Total usage of antibiotics reached 2.9 DDDs or 1.437 days; the average use of drugs per case of NEC amounted to 0.47 DDD or 23.2 DOTs. The level of antibiotic usage was analysed with correlation to microbiological tests performed and it was non-significantly greater in the group of children with NEC in whom the tests were performed.
A high risk of developing NEC is closely associated with VLBW and with inflammation of the amnion during labour. We observed no relationship between the consumption of antibiotics in neonates with NEC and positive results of microbiological testing indicating sepsis accompanying NEC or gut colonization with pathogens.
PMCID: PMC3962467  PMID: 24658445
20.  Cerebral autoregulation in neonates with a hemodynamically significant patent ductus arteriosus 
The Journal of Pediatrics  2012;160(6):936-942.
Very low birth weight (VLBW) preterm infants are at risk for impaired cerebral autoregulation with pressure passive blood flow. Fluctuations in cerebral perfusion may occur in infants with a hemodynamically significant patent ductus arteriosus (hsPDA), especially during ductal closure. Our goal was to compare cerebral autoregulation using near-infrared spectroscopy (NIRS) in VLBW infants treated for a hsPDA.
Study design
This prospective observational study enrolled 28 VLBW infants with a hsPDA diagnosed by echocardiogram and 12 control VLBW infants without a hsPDA. NIRS cerebral monitoring was applied during conservative treatment, indomethacin, or surgical ligation. A cerebral pressure passivity index (PPI) was calculated and PPI differences were compared using a mixed effects regression model. Cranial ultrasound and MRI data were also assessed.
Infants with surgically ligated PDAs were more likely to have had a greater PPI within two hours following ligation compared with those treated with conservative management (p=0.04) or indomethacin (p=0.0007). These differences resolved six hours following treatment.
Cerebral autoregulation was better preserved after indomethacin treatment of a hsPDA compared with surgical ligation. Infants requiring surgical hsPDA ligation may be at increased risk for cerebral pressure passivity in the six hours following surgery.
PMCID: PMC3335982  PMID: 22226574
near-infrared spectroscopy; neonate; pressure passivity; cerebral oxygenation
21.  A Longitudinal Study of Developmental Outcome of Infants With Bronchopulmonary Dysplasia and Very Low Birth Weight 
Pediatrics  1997;100(6):987-993.
Bronchopulmonary dysplasia (BPD) is now the leading cause of lung disease in US infants. In a large regional cohort, we tested the hypothesis that despite innovations in neonatal care, very low birth weight (VLBW) infants (<1500 g) with BPD had poorer developmental outcomes than nonaffected infants during the first 3 years of life, and that BPD predicted poorer outcome beyond the effects of other risk factors.
Three groups of infants (122 with BPD, 84 VLBW without BPD, and 123 full-term) were followed longitudinally to 3 years of age with the Bayley Scales of Mental and Motor Development. Comparison groups of VLBW infants without BPD and full-term infants did not differ in sex, race, or socioeconomic status. Statistical analyses included hierarchical and stepwise multiple regression.
Infants with BPD performed more poorly at all ages. By 3 years, cognitive and/or motor development was in the range of retardation (<70 standard score) for 21% to 22% of infants with BPD. In multiple regression analyses controlling for socioeconomic and neonatal risk conditions, BPD had an independent negative effect on motor outcome at 3 years. Neurologic risk, a summary measure of neurologic problems other than intraventricular hemorrhage, and the presence of BPD independently predicted motor delay. By 3 years, social class, race, and neurologic risk predicted mental outcome, suggesting that the specific effects of BPD are primarily on the motor domain.
In VLBW infants, BPD predicts poorer motor outcome at 3 years, after control for other risks. Cohorts of infants with BPD also had higher rates of mental retardation, associated with greater neurologic and social risk. These findings underscore the need for intensive prevention and habilitation efforts for this growing group of VLBW survivors, as well as investigation into the potential role of BPD in the higher rates of learning disabilities in VLBW cohorts at school age.
PMCID: PMC4196670  PMID: 9374570
22.  Long term healthcare costs of infants who survived neonatal necrotizing enterocolitis: a retrospective longitudinal study among infants enrolled in Texas Medicaid 
BMC Pediatrics  2013;13:127.
Infants who survive advanced necrotizing enterocolitis (NEC) at the time of birth are at increased risk of having poor long term physiological and neurodevelopmental growth. The economic implications of the long term morbidity in these children have not been studied to date. This paper compares the long term healthcare costs beyond the initial hospitalization period incurred by medical and surgical NEC survivors with that of matched controls without a diagnosis of NEC during birth hospitalization.
The longitudinal healthcare utilization claim files of infants born between January 2002 and December 2003 and enrolled in the Texas Medicaid fee-for-service program were used for this research. Propensity scoring was used to match infants diagnosed with NEC during birth hospitalization to infants without a diagnosis of NEC on the basis of gender, race, prematurity, extremely low birth weight status and presence of any major birth defects. The Medicaid paid all-inclusive healthcare costs for the period from 6 months to 3 years of age among children in the medical NEC, surgical NEC and matched control groups were evaluated descriptively, and in a generalized linear regression framework in order to model the impact of NEC over time and by birth weight.
Two hundred fifty NEC survivors (73 with surgical NEC) and 2,909 matched controls were available for follow-up. Medical NEC infants incurred significantly higher healthcare costs than matched controls between 6–12 months of age (mean incremental cost = US$ 5,112 per infant). No significant difference in healthcare costs between medical NEC infants and matched controls was seen after 12 months. Surgical NEC survivors incurred healthcare costs that were consistently higher than that of matched controls through 36 months of age. The mean incremental healthcare costs of surgical NEC infants compared to matched controls between 6–12, 12–24 and 24–36 months of age were US$ 18,274, 14,067 (p < 0.01) and 8,501 (p = 0.06) per infant per six month period, respectively. These incremental costs were found to vary between sub-groups of infants born with birth weight < 1,000g versus ≥ 1,000g (p < 0.05).
The all-inclusive healthcare costs of surgical NEC survivors continued to be substantially higher than that of matched controls through the early childhood development period. These results can have important treatment and policy implications. Further research in this topic is needed.
PMCID: PMC3765805  PMID: 23962093
23.  Hospital and neurodevelopmental outcomes of extremely low-birth-weight infants with necrotizing enterocolitis and spontaneous intestinal perforation 
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.
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.
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.
PMCID: PMC3496418  PMID: 22157625
necrotizing enterocolitis; extremely low-birth-weight; neurodevelopmental outcome; Bayley scales of infant development
24.  Postnatal weight increase and growth velocity of very low birthweight infants 
Only a few studies have dealt with postnatal growth velocity of very low birthweight (VLBW) infants.
To analyse weight growth kinetics of VLBW infants from birth to over 2 years of age.
A total of 262 VLBW infants were selected; inaccurate estimate of gestational age, major congenital anomalies, necrotising enterocolitis, death, and loss to follow up within the first year were the exclusion criteria.
Body weight was recorded daily up to 28 days or up to discontinuation of parenteral nutrition, weekly up to discharge, then at 1, 3, 6, 9, 12, 18, and 24 months of corrected age. Individual growth profiles were fitted with a seven constant, exponential‐logistic function suitable for modelling weight loss and weight recovery, two peaks, and the subsequent slow decrease in growth velocity.
After a postnatal weight loss, all infants showed a late neonatal peak of growth velocity between the 7th and 21st weeks; most also experienced an early neonatal peak between the 2nd and 6th week. VLBW infants who were small for gestational age and those with major morbidities grew less than reference VLBW infants who were the appropriate size for gestational age without major morbidities: at 2 years of age, the difference in weight was about 860 g. The more severe growth impairment seen in VLBW infants with major morbidities is almost entirely due to the reduced height of the late neonatal peak of velocity.
The growth model presented here should be a useful tool for evaluating to what extent different pathological conditions or nutritional and medical care protocols affect growth kinetics.
PMCID: PMC2672838  PMID: 16638781
growth velocity; growth curves; very low birthweight; models
25.  New Concepts of Microbial Translocation in the Neonatal Intestine: Mechanisms and Prevention 
Clinics in perinatology  2010;37(3):565-579.
In very-low-birth weight (VLBW, <1500 gram) infants, late-onset neonatal sepsis and necrotizing enterocolitis prolong the hospital stay, increase the cost of care, and place the infant at greater risk for morbidity and mortality (1). Long-term follow-up studies have demonstrated that these infections significantly increase the risk of neurological disabilities (2). With incidences of ~20% and 5–10% respectively, late-onset sepsis [LOS] and necrotizing enterocolitis [NEC] in VLBW infants need new preventive approaches. A long-held belief is that LOS and NEC result from bacterial translocation [BT]. Bacterial translocation is defined as invasion of indigenous intestinal bacteria through the mucosa into normally sterile tissue (3). This definition has been extended to include bacterial toxins or antigens, which damage intestinal epithelia and enter the circulation resulting in a systemic inflammatory response (4). Local BT through the intestinal mucosa, or toxin-related injury of intestinal epithelia, is associated with NEC (5), while BT beyond the intestine causes sepsis and multi-organ failure (6,7). This chapter describes: 1) development of the intestinal microbiota, 2) how immaturity of the nascent epithelial lining of the gastrointestinal [GI] tract and its sub-mucosal tissues mediate BT, 3) strategies to accelerate barrier functions in the immature GI tract and 4) the effects of nutrition and colonization by commensal bacteria on the susceptibility of the immature intestine to BT.
PMCID: PMC2933426  PMID: 20813271
intestinal microbiota; gut epithelia; enterocytes; goblet cells; Paneth cells; human milk; lactoferrin; probiotics; prebiotics

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