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1.  Mortality and Morbidity of VLBW Infants With Trisomy 13 or Trisomy 18 
Pediatrics  2014;133(2):226-235.
Little is known about how very low birth weight (VLBW) affects survival and morbidities among infants with trisomy 13 (T13) or trisomy 18 (T18). We examined the care plans for VLBW infants with T13 or T18 and compared their risks of mortality and neonatal morbidities with VLBW infants with trisomy 21 and VLBW infants without birth defects.
Infants with birth weight 401 to 1500 g born or cared for at a participating center of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network during the period 1994–2009 were studied. Poisson regression models were used to examine risk of death and neonatal morbidities among infants with T13 or T18.
Of 52 262 VLBW infants, 38 (0.07%) had T13 and 128 (0.24%) had T18. Intensity of care in the delivery room varied depending on whether the trisomy was diagnosed before or after birth. The plan for subsequent care for the majority of the infants was to withdraw care or to provide comfort care. Eleven percent of infants with T13 and 9% of infants with T18 survived to hospital discharge. Survivors with T13 or T18 had significantly increased risk of patent ductus arteriosus and respiratory distress syndrome compared with infants without birth defects. No infant with T13 or T18 developed necrotizing enterocolitis.
In this cohort of liveborn VLBW infants with T13 or T18, the timing of trisomy diagnosis affected the plan for care, survival was poor, and death usually occurred early.
PMCID: PMC3904274  PMID: 24446439
trisomy 13; trisomy 18; trisomy 21; very low birth weight; preterm infants
2.  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
3.  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
4.  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
5.  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
6.  Retinopathy of Prematurity among Very-Low-Birth-Weight Infants in Korea: Incidence, Treatment, and Risk Factors 
Journal of Korean Medical Science  2015;30(Suppl 1):S88-S94.
This study was conducted to describe the incidence, risk factors, and current treatment status of retinopathy of prematurity (ROP) in very-low-birth-weight (VLBW) infants registered in the Korean Neonatal Network database. Medical records of 2,009 VLBW infants born between January 2013 and June 2014 who underwent examination by an ophthalmologist were reviewed. The total incidence of ROP was 34.1%. Of the patients, 11.6% showed ROP stage ≥ 3 and 11.5% received treatment of VLBW. Among all infants who received treatment of ROP, 63.6% underwent operation only; 16.9%, anti-vascular endothelial growth factor (anti-VEGF) treatment only; and 19.5%, both operation and anti-VEGF treatment. The mean gestational age (GA) and birth weight (BW) were significantly lower and the prevalence rates of respiratory distress syndrome, patent ductus arteriosus (PDA), invasive ventilator duration, and sepsis were significantly higher in the VLBW infants with ROP than in those without ROP. In the multivariable logistic regression analysis, PDA (odd ratio [OR], 2.1; 95% confidence interval [CI], 1.11-3.79) and invasive ventilator duration (OR, 1.0; 95% CI, 1.00-1.02) were significant risk factors of ROP and ROP stage ≥ 3. In conclusion, the high incidence of ROP is associated with low GA and BW, and attempt to reduce the aforementioned risk factors could reduce the incidence of ROP stage ≥ 3 in VLBW infants.
PMCID: PMC4641069  PMID: 26566363
Retinopathy of Prematurity; Infant; Very-Low-Birth-Weight
7.  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
8.  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
9.  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
10.  Beyond Building Better Brains: Bridging the Docosahexaenoic acid (DHA) Gap of Prematurity 
Long chain polyunsaturated fatty acids (LCPUFA) including docosahexaenoic acid (DHA), are essential for normal vision and neurodevelopment. DHA accretion in utero occurs primarily in the last trimester of pregnancy to support rapid growth and brain development. Premature infants, born before this process is complete, are relatively deficient in this essential fatty acid. Very low birth weight (VLBW) infants remain deficient for a long period of time due to ineffective conversion from precursor fatty acids, lower fat stores, and a limited nutritional provision of DHA after birth. In addition to long- term visual and neurodevelopmental risks, VLBW infants have significant morbidity and mortality from diseases specific to premature birth, including bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP). There is increasing evidence that DHA has protective benefits against these disease states. The aim of this article is to identify the unique needs of premature infants, review the current recommendations for LCPUFA provision in infants, and discuss the caveats and innovative new ways to overcome the DHA deficiency through postnatal supplementation, with the long term goal of improving morbidity and mortality in this at risk population.
PMCID: PMC4281288  PMID: 25357095
Docosahexaenoic Acid; DHA; Long Chain Polyunsaturated Acids; LCPUFA; Prematurity; Neonatal Nutrition; Bronchopulmonary Dysplasia; BPD; Necrotizing Enterocolitis; NEC; Retinopathy of Prematurity; ROP
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  Preterm Prelabor Rupture of Membranes and Outcome of Very-Low-Birth-Weight Infants in the German Neonatal Network 
PLoS ONE  2015;10(4):e0122564.
It was the aim of our study to evaluate the independent effect of preterm prelabor rupture of membranes (PPROM) as a cause of preterm delivery on mortality during primary hospital stay and significant morbidities in very-low-birth-weight (VLBW) infants < 32 weeks of gestation.
Observational, epidemiological study design.
Population-based cohort, German Neonatal Network (GNN).
6102 VLBW infants were enrolled in GNN from 2009-2012, n=4120 fulfilled criteria for primary analysis (< 32 gestational weeks, no pre-eclampsia, HELLP (highly elevated liver enzymes and low platelets syndrome) or placental abruption as cause of preterm birth).
Multivariable logistic regression analyses included PPROM as potential risk factors for adverse outcomes and well established items such as gestational age in weeks, birth weight, antenatal steroids, center, inborn delivery, multiple birth, gender and being small-for-gestational-age.
PPROM as cause of preterm delivery had no independent effect on the risk of early-onset sepsis, clinical sepsis and blood-culture proven sepsis, while gestational age proved to be the most important contributor to sepsis risk. The diagnosis of PPROM was associated with an increased risk for bronchopulmonary dysplasia (BPD; OR: 1.25, 95% CI: 1.02-1.55, p=0.03) but not with other major outcomes.
The diagnosis of PPROM per se is not associated with adverse outcome in VLBW infants < 32 weeks apart from a moderately increased risk for BPD. Randomized controlled trials with primary neonatal outcomes are needed to determine which subgroup of VLBW infants benefit from expectant or intentional management of PPROM.
PMCID: PMC4391753  PMID: 25856083
21.  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
22.  Blood Culture Proven Early Onset Sepsis and Late Onset Sepsis in Very-Low-Birth-Weight Infants in Korea 
Journal of Korean Medical Science  2015;30(Suppl 1):S67-S74.
Neonatal sepsis remains one of the most important causes of death and co-morbidity in very-low-birth-weight (VLBW) infants. The aim of this study was to determine the current incidences of early-onset sepsis (EOS) and late-onset sepsis (LOS), the distribution of pathogens, and the impact of infection on co-morbidities in VLBW infants. We analyzed the data including sepsis episode from 2,386 VLBW infants enrolled in Korean Neonatal Network from January 2013 to June 2014. We defined EOS as a positive blood culture occurring between birth and 7 days of life and LOS after 7 days of life. Sepsis was found in 21.1% of VLBW infants. The risk of sepsis was inversely related to birth weight and gestational age. EOS was found in only 3.6% of VLBW infants, however the mortality rate was as high as 34.1%. EOS was associated with the increased odds for bronchopulmonary dysplasia and intraventricular hemorrhage. The vast majority of EOS was caused by Gram-positive organisms, particularly coagulase-negative staphylococci (30.6%). LOS developed in 19.4% of VLBW infants with a 16.1% mortality rate. Pathogens in LOS were dominated by coagulase-negative staphylococci (38.3%). Twenty-five percent and fifty percent of first LOS episode occurred after 12 days and 20 days from birth, respectively. Younger and smaller VLBW infants showed the earlier occurrence day for the 25% of first LOS episode. This study provides a recent nationwide epidemiology of sepsis in VLBW infants in Korea. Based on this study, successful strategies to reduce infections would improve survival and reduce morbidity.
Graphical Abstract
PMCID: PMC4641066  PMID: 26566360
Sepsis; Infant; Very-Low-Birth-Weight; Risk Factors; Korean Neonatal Network; South Korea
23.  Neonatal Morbidities Associated with Histologic Chorioamnionitis Defined Based on the Site and Extent of Inflammation in Very Low Birth Weight Infants 
Journal of Korean Medical Science  2015;30(10):1476-1482.
Conflicting results on the influences of histologic chorioamnionitis (HC) on neonatal morbidities might be partly originated from using different definition of HC. The aim of this study was to determine the relationship between HC and neonatal morbidities using definition of HC that reflects the site and extent of inflammation. This was a retrospective cohort study of 261 very low birth weight (VLBW) infants admitted at a tertiary academic center. Based on the site of inflammation, HC was categorized: any HC; amnionitis; funisitis; amnionitis+funisitis. The extent of inflammation in each site was reflected by sub-defining high grade (HG). The incidences of morbidities in infants with and without HC were compared. The bronchopulmonary dysplasia (BPD) rate was significantly higher in infants with amnionitis and the severe retinopathy of prematurity (ROP) rate was significantly higher in infants with any HC and funisitis. After adjustment for both gestational age and birth weight, the respiratory distress syndrome (RDS) rate was significantly lower in infants with all categories of HC except for HG amnionitis and HG funisitis, which are not associated with lower RDS rate. HG amnionitis was significantly associated with increased BPD rate but the association of HC with severe ROP disappeared. In conclusion, HC is significantly associated with decreased RDS and HG amnionitis with increased BPD while lacking association with other neonatal morbidities in VLBW infants. The association with HC and neonatal morbidities differs by the site and extent of chorioamnionitis.
Graphical Abstract
PMCID: PMC4575938  PMID: 26425046
Chorioamnionitis; Amnionitis; Morbidity; Infant, Very Low Birth Weight; Infant, Premature
24.  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
25.  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

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