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1.  Twin Gestation and Neuro-developmental Outcome in Extremely Low Birth Weight Infants 
Pediatrics  2009;123(2):e220-e227.
To compare the risk-adjusted incidence of death or neuro-developmental impairment at 18–22 months corrected age, between twin and singleton extremely low birth weight infants.
Twin gestation is independently associated with increased risk of death or adverse neuro-developmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Retrospective study of inborn extremely low birth weight infants (BW 401– 1000g) admitted to NICHD Neonatal Research Network units between 1997 and 2005, who either died or had follow-up data available at 18–22 months corrected age. Neuro-developmental impairment (NDI), the primary outcome variable, was defined as the presence of any one of the following: moderate or severe cerebral palsy, severe bilateral hearing loss needing amplification, bilateral blindness, Bayley Mental Developmental Index or Psychomotor Developmental Index of less than 70. Death was included with NDI as a composite outcome since it is a competing variable. Results were compared for both twins, twin A, twin B, same sex twins, unlike sex twins and singleton infants. Logistic regression analysis was done to control for demographic and clinical factors that were different among the groups.
The cohort of infants who either died or were assessed for NDI consisted of 7,630 singleton infants and 1,376 twins. Logistic regression adjusting for clinical and socio-demographic risk factors showed an increased risk of death or NDI for twins as a group when compared with the singletons (OR-1.39, 95% CI- 1.19–1.63). On analyzing twin A and B separately as well, risk of death or NDI was increased in both twin A (OR-1.32, 95% CI- 1.09–1.59) and for twin B (OR-1.47, 95% CI- 1.21–1.78), when compared with singleton infants.
Twin gestation in ELBW infants is associated with an independent increased risk of death or NDI at 18–22 months corrected age, compared to ELBW singleton gestation infants. Both first and second born twins are at increased risk of death or NDI when compared to singleton ELBW infants.
PMCID: PMC2842087  PMID: 19139085
twins; neuro-developmental impairment; extremely low birth weight infants
2.  Outcome of Extremely Low Birth Weight Infants with Congenital Heart Defects in the Eunice Kennedy Shriver NICHD Neonatal Research Network 
Pediatric cardiology  2012;33(8):1415-1426.
Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401–1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998 and December 31, 2005. Neonatal morbidities and 18–22 months’ corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index < 70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small for gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18–22 months’ corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20% of infants survived without NDI.
PMCID: PMC3687358  PMID: 22644414
heart defects; congenital; follow-up studies
3.  Outcome of Extremely Low Birth Weight Infants Who Received Delivery Room Cardiopulmonary Resuscitation 
The Journal of Pediatrics  2011;160(2):239-244.e2.
To determine whether delivery room cardiopulmonary resuscitation (DR-CPR) independently predicts morbidities and neurodevelopmental impairment (NI) in extremely low birth weight (ELBW) infants.
Study design
Cohort study of infants born with birth weight (BW) 401-1000g and gestational age (GA) 23-30wks. DR-CPR was defined as chest compressions and/or drugs. Logistic regression was used to determine associations between DR-CPR and morbidities, mortality and NI at 18-24 months (Bayley II mental or psychomotor index < 70, cerebral palsy, blindness or deafness). Data are adjusted Odds Ratio (OR) with 95% confidence interval.
Of 8685 infants, 1333(15%) received DR-CPR. DR-CPR infants had lower BW (708±141vs 764±146g, p<0.0001) and GA (25±2 vs 26±2 wks, p<0.0001). DR-CPR infants had more pneumothoraces (OR 1.28, 1.48-2.99), Grade 3-4 intraventricular hemorrhage (OR 1.47, 1.23-1.74), bronchopulmonary dysplasia (OR 1.34, 1.13-1.59), death by 12 hours (OR 3.69, 2.98-4.57) and by 120 days after birth (OR 2.22, 1.93-2.57). NI among survivors (OR 1.23, 1.02-1.49), and death or NI (OR 1.70, 1.46-1.99) were higher for DR-CPR infants. Only 14% of DR-CPR recipients with 5-minute Apgar score<2 survived without NI.
DR-CPR is a prognostic marker for higher mortality and NI for ELBW survivors. New DR-CPR strategies are needed for this population.
PMCID: PMC3258355  PMID: 21930284
cardiac compressions; epinephrine; neurodevelopmental outcomes
4.  Influence of gestational age on death and neurodevelopmental outcome in premature infants with severe intracranial hemorrhage 
To determine whether death and/or neurodevelopmental impairment (NDI) after severe intracranial hemorrhage (ICH; grade 3 or 4) differs by gestational age (GA) at birth in extremely low birth weight (ELBW) infants.
Study Design
Demographic, perinatal and neonatal factors potentially contributing to NDI for ELBW infants (23 to 28 weeks gestation) were obtained retrospectively; outcome data came from the ELBW Follow-up Study. NDI was defined at 18 to 22 months corrected age as moderate/severe cerebral palsy, Bayley Scales of Infant Development II cognitive or motor score <70, and/or blindness or deafness. Characteristics of younger versus older infants with no versus severe ICH associated with death or NDI were compared. Generalized linear mixed models predicted death or NDI in each GA cohort.
Of the 6638 infants, 61.8% had no ICH and 13.6% had severe ICH; 39% of survivors had NDI. Risk-adjusted odds of death or NDI and death were higher in the lower GA group. Lower GA increased the odds of death before 30 days for infants with severe ICH. Necrotizing enterocolitis (particularly surgical NEC), late onset infection, cystic periventricular leukomalacia and post-natal steroids contributed to mortality risk. NDI differed by GA in infants without ICH and grade 3, but not grade 4 ICH. Contributors to NDI in infants with severe ICH included male gender, surgical NEC and post-hemorrhagic hydrocephalus requiring a shunt.
GA contributes to the risk of death in ELBW infants, but not NDI among survivors with severe ICH. Male gender, surgical NEC and need for a shunt add additional risk for NDI.
PMCID: PMC3777699  PMID: 22814942
infant; premature; extremely low birth weight; death; neurodevelopmental impairment
5.  Influence of Clinical Status on the Association Between Plasma Total and Unbound Bilirubin and Death or Adverse Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18–22 months corrected age in extremely low birth weight infants.
Total plasma biirubin and unbound biirubin were measured in 1,101 extremely low birth weight infants at 5±1 day of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18–22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors.
Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants.
In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma and unbound bilirubin and death or adverse neurodevelopmental outcomes at 18–22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.
PMCID: PMC2875328  PMID: 20105142
Plasma bilirubin; unbound bilirubin; Extremely low birth weight infants; Neurodevelopmental outcomes
6.  Grade and Laterality of Intraventricular Hemorrhage to Predict 18–22 Month Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
To determine whether extremely low birth weight (ELBW) infants with bilateral compared to unilateral intraventricular hemorrhage (IVH) have worse neurodevelopmental outcomes at 18–22 months.
166 ELBW infants (<1000 g) admitted to a Cincinnati NICU from 1998–2005 with a head ultrasound showing Grade I–IV IVH and neurodevelopmental assessment at 18–22 months corrected age were included. Multivariable linear and logistic regression models were developed to determine the impact of laterality and grade of IVH and other clinical variables to predict scores on the Bayley Scales of Infant Development, Second Edition, Mental Development Index (MDI) and Psychomotor Development Index (PDI) and the combined outcome of neurodevelopmental impairment (NDI).
Infants with bilateral grade IV IVH had lower adjusted mean Bayley scores compared with infants with unilateral grade IV IVH. For grades I, II, and III IVH, bilaterality of IVH was not associated with lower mean Bayley scores. Infants with grade IV IVH had the highest odds of NDI. The probability of NDI increased with sepsis and postnatal steroid use.
ELBW infants with bilateral compared to those with unilateral grade IV IVH had worse neurodevelopmental outcomes. Infants with grades I–III IVH had similar outcomes whether they had unilateral or bilateral IVH.
PMCID: PMC3475499  PMID: 22220735
premature; sepsis; steroids; Bayley; cognitive; motor
7.  Severe pre-eclampsia and infants of very low birth weight. 
Archives of Disease in Childhood  1987;62(7):712-716.
The effect of severe pre-eclampsia on the outcome of infants of very low birth weight was studied in a prospective case control study of 35 pairs of infants of comparable gestation. Significantly more infants were delivered before the onset of labour and by caesarean section in the group with pre-eclampsia. These babies tended to be smaller and had a higher incidence of hyaline membrane disease, patent ductus arteriosus, pulmonary air leak, and hypotension. They also required more intensive treatment with oxygen and mechanical ventilation. The significant difference in birth weight was still apparent at 2 years of age. Although the mean psychomotor developmental index and the incidence of specific neurodevelopmental impairments were not significantly different between the two groups, survivors in the group born to pre-eclamptic mothers had a significantly lower mean mental developmental index, and significantly more of these children had one or more impairments compared with the control group at 2 years of age.
PMCID: PMC1779252  PMID: 3632019
8.  Neurodevelopmental Outcomes of Extremely Low Birth Weight Infants Ventilated With Continuous Positive Airway Pressure vs. Mechanical Ventilation 
Indian journal of pediatrics  2011;79(2):218-223.
To compare continuous positive airway pressure (CPAP) vs. traditional mechanical ventilation (MV) at 24 h of age as predictors of neurodevelopmental (ND) outcomes in extremely low birth weight (ELBW) infants at 18-22 mo corrected gestational age (CGA).
Infants ≤ 1000g birth weight born from January 2000 through December 2006 at two hospitals at the Cincinnati site of the National Institute of Child Health and Human Development Neonatal Research Network were evaluated comparing CPAP (N = 198) vs. MV (N = 109). Primary outcomes included the Bayley Score of Infant Development Version II (BSID-II), presence of deafness, blindness, cerebral palsy, bronchopulmonary dysplasia and death.
Ventilatory groups were similar in gender, rates of preterm prolonged rupture of membranes, antepartum hemorrhage, use of antenatal antibiotics, steroids, and tocolytics. Infants receiving CPAP weighed more, were older, were more likely to be non-Caucasian and from a singleton pregnancy. Infants receiving CPAP had better BSID-II scores, and lower rates of BPD and death.
After adjusting for acuity differences, ventilatory strategy at 24 h of age independently predicts long-term neurodevelopmental outcome in ELBW infants.
PMCID: PMC3498084  PMID: 21853318
9.  Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990–2000: a retrospective cohort study 
BMC Pediatrics  2007;7:20.
It is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23–27 weeks gestation) are changing over time.
Study infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness.
Survival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2.
The probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990's in this regionally based sample of ELGANs.
PMCID: PMC1876228  PMID: 17477872
10.  Role of Diffusion Tensor Imaging as an Independent Predictor of Cognitive and Language Development in Extremely Low-Birth-Weight Infants 
Diffusion tensor imaging at term can predict later development of cerebral palsy. Less is known about its ability to independently predict cognitive and language development in extremely preterm infants. The goals of the study were to investigate the following: 1) whether regional DTI measures at term-equivalent age in extremely low-birth-weight infants (birth weight, ≤1000 g) are predictive of Bayley III developmental scores at 18- to 22-months’ corrected age, and 2) to compare white matter microstructural development at term and neurodevelopmental outcomes of extremely low-birth-weight infants with healthy term controls.
Fractional anisotropy and mean diffusivity in 7 vulnerable cerebral regions were measured in 42 extremely low-birth-weight and 16 term infants with high-quality DTI scans. The Bayley mental scale score (average of cognitive and language scale scores) was the primary outcome of interest with individual scores serving as secondary outcomes. Multiple linear regression modeling was used to identify the incremental ability of DTI measures to predict Bayley scores over known predictors.
Compared with healthy term infants, extremely low-birth-weight infants exhibited significantly higher mean diffusivity and lower fractional anisotropy in 6 of 7 regions. At 18- to 22-months’ corrected age, 39 extremely low-birth-weight infants (93%) and 14 term infants (88%) had undergone neurodevelopmental assessments. Although not statistically significant, extremely low-birth-weight infants averaged 7–9 points lower on Bayley subtests than term controls. In multivariable analyses, centrum semiovale mean diffusivity was a significant predictor of mental and language scale scores, and subventricular zone fractional anisotropy was a significant predictor of cognitive scale scores. A 10% increase in centrum semiovale mean diffusivity was associated with a 4.6 (95% CI, 1.6–7.6) point lower mental scale score (adjusted R2 = 0.341, P = .001).
In our extremely low-birth-weight cohort, DTI was an independent predictor of later cognitive and language development.
PMCID: PMC3960368  PMID: 24052505
11.  Neurodevelopmental Outcome of Extremely Low Birth Weight Infants from the Vermont Oxford Network: 1998–2003 
Neonatology  2009;97(4):329-338.
Physicians and parents face significant uncertainties when making care decisions for extremely low birth weight (ELBW) infants. Many published estimates of death and developmental outcome are from well-funded university programs and may not reflect outcomes of infants from a variety of settings. The best estimates of the probabilities of death and severe disability combine local experience and published data. Objective: To describe the neurodevelopmental outcome of ELBW infants from centers of the ELBW Infant Follow-Up Group of the Vermont Oxford Network (VON) and to identify characteristics associated with severe disability.
Predefined measures of living situation, health and developmental outcome were collected at 18–24 months’ corrected age for infants born from July 1, 1998 to December 31, 2003 with birth weights of 401–1,000 g at 33 North American VON centers. Logistic regression was used to identify characteristics associated with severe disability.
6,198 ELBW infants were born and survived until hospital discharge; by the time of follow-up, 88 infants (1.4%) had died. Of the remaining 6,110 infants, 3,567 (58.4%) were evaluated. Severe disability occurred in 34% of the assessed infants. Multivariate logistic regression suggested cystic periventricular leukomalacia, congenital malformation and severe intraventricular hemorrhage were the characteristics most highly associated with severe disability. There were marked variations among the follow-up clinics in the attrition rate.
ELBW infants completing evaluation were at a high risk for severe disability. There are considerable differences among participating centers in attrition at follow-up. Further resources will be needed to study the effect of follow-up care for this group of infants.
PMCID: PMC2889257  PMID: 19940516
Extremely low birth weight infant; Neurodevelopmental outcome; Severe disability; Vermont Oxford Network
12.  Seizures in Extremely Low Birth Weight Infants Are Associated with Adverse Outcome 
The Journal of pediatrics  2010;157(5):720-725.e2.
To examine risk factors for neonatal clinical seizures and to determine the independent association with death or neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
Study design
A total of 6499 ELBW infants (401–1000 g) surviving to 36 weeks postmenstrual age (PMA) were included in this retrospective study. Unadjusted comparisons were performed between infants with (n=414) and without (n=6085) clinical seizures during the initial hospitalization. Multivariate logistic regression modeling examined the independent association of seizures with late death (after 36 weeks PMA) or NDI after controlling for multiple demographic, perinatal, and neonatal variables.
Infants with clinical seizures had a greater proportion of neonatal morbidities associated with poor outcome, including severe intraventricular hemorrhage, sepsis, meningitis, and cystic periventricular leukomalacia (all P < .01). Survivors were more likely to have NDI or moderate-severe cerebral palsy at 18 to 22 months corrected age (both P < .01). After adjusting for multiple confounders, clinical seizures remained significantly associated with late death or NDI (odds ratio 3.15 [95% confidence interval 2.37–4.19]).
ELBW infants with clinical seizures are at increased risk for adverse neurodevelopmental outcome, independent of multiple confounding factors.
PMCID: PMC2939969  PMID: 20542294
preterm; neurodevelopmental impairment; electroencephalography
13.  Cerebral palsy and multiple births. 
AIM: To compare the birthweight specific prevalence of cerebral palsy in singleton and multiple births. METHODS: Registered births of babies with cerebral palsy born to mothers resident in the counties of Merseyside and Cheshire during the period 1982 to 1989 were ascertained. RESULTS: The crude prevalence of cerebral palsy was 2.3 per 1000 infant survivors in singletons, 12.6 in twins, and 44.8 in triplets. The prevalence of cerebral palsy rose with decreasing birthweight. The birthweight specific prevalence among those of low birthweight < 2500 g was not significantly different in singleton than in multiple births. Among infants weighing > or = 2500 g, there was a significantly higher risk in multiple than in singleton births. The higher crude cerebral palsy prevalence in multiple births is partly due to the lower birthweight distribution and partly due to the higher risk among normal birthweight infants. CONCLUSIONS: Multiple birth babies are at increased risk of cerebral palsy. There is also an increased risk of cerebral palsy within a twin pregnancy if the co-twin has died in utero.
PMCID: PMC1061194  PMID: 8976682
14.  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
15.  A population-based study of effect of multiple birth on infant mortality in Nigeria 
Multi-foetal pregnancies and multiple births including twins and higher order multiples births such as triplets and quadruplets are high-risk pregnancy and birth. These high-risk groups contribute to the higher rate of childhood mortality especially during early period of life.
We examined the relationship between multiple births and infant mortality using univariable and multivariable survival regression procedure with Weibull hazard function, controlling for child's sex, birth order, prenatal care, delivery assistance; mother's age at child birth, nutritional status, education level; household living conditions and several other risk factors.
Children born multiple births were more than twice as likely to die during infancy as infants born singleton (hazard ratio = 2.19; 95% confidence interval: 1.50, 3.19) holding other factors constant. Maternal education and household asset index were associated with lower risk of infant mortality.
Multiple births are strongly negatively associated with infant survival in Nigeria independent of other risk factors. Mother's education played a protective role against infant death. This evidence suggests that improving maternal education may be key to improving child survival in Nigeria. A well-educated mother has a better chance of satisfying important factors that can improve infant survival: the quality of infant feeding, general care, household sanitation, and adequate use of preventive and curative health services.
PMCID: PMC2551580  PMID: 18783603
16.  Maternal Age, Multiple Birth and Extremely Low Birth Weight Infants 
The Journal of pediatrics  2008;154(4):498-503.e2.
To compare the rates of adverse neurodevelopmental outcome or death at 18 to 22 months among extremely low birth weight (ELBW) infants born to mothers ≥ 40 years to the corresponding rates among infants of younger mothers.
Study Design
Prospective evaluation of ELBW infants to quantify the relative risks of maternal age and multiple birth for death or adverse neurodevelopmental outcome.
The sample consisted of 14,671 live ELBW births divided into maternal age groups: <20; 20–29; 30–39; and ≥ 40 years. Of infants born to mothers ≥ 40 years, 20% were multiples. Mothers ≥ 40 years had high rates of obstetrical interventions and medical morbidities compared to mothers < 40 years. ELBW live births of mothers ≥ 40 years were 22 % more likely to survive and had a 13% decreased risk of neurodevelopmental impairment or death compared to mothers< 20. Multiple birth, however, was associated with a 10 % greater risk or neurodevelopmental impairment or death.
Although mothers ≥ 40 years had high pregnancy related morbidities, we found no overall increased risk of the composite outcome of death or NDI. Multiple birth, however, was a predictor of all adverse outcomes examined, regardless of maternal age.
PMCID: PMC2834530  PMID: 19111322
outcomes; neurodevelopmental impairment; death
17.  Unimpaired Outcome in Extremely Low Birth Weight Infants at 18–22 Months 
Pediatrics  2009;124(1):112-121.
To identify among extremely low birth weight (≤ 1000 grams) live births, the percent of infants who are unimpaired at 18–22 months corrected age.
Unimpaired outcome was defined as both Bayley-II MDI and PDI Scores ≥ 85, a normal neurological exam, normal vision, normal hearing and normal swallowing and ambulating. Outcomes at 18–22 months were determined for 5250 (86%) of 6090 ELBW inborn infants. Group comparisons were made and regression models were developed to identify factors associated with unimpaired outcome.
Of the 5250 infants whose outcome was known at 18 months, 850 (16%) were unimpaired, 1153 (22%) had mild impairments, 1147 (22%) had moderate to severe neurodevelopmental impairments and 2100 (40%) had died. Unimpaired survival rates varied by birth weight from <1% for infants ≤ 500 grams to 24% for infants 901–1000 grams for all live births. The regression model to predict unimpaired survival versus death or impairment for live births ( n=5250) identified that 25.3% of the variance was derived from infant factors present at birth including female gender, higher birth weight, singleton, and small for gestation, and less than 2% was explained either by maternal demographic factors or selected obstetric interventions. For the 3232 infants discharged from the NICU, the unimpaired survival rate was 26%. The regression model to predict unimpaired survival for discharged infants identified that most of the variance was derived from combined effects of major neonatal morbidities, neonatal interventions, and maternal demographics (15.7%) and only 8.5% was derived from infant factors present at birth.
Although <1% of ELBW live births ≤ 500 grams survive free of impairment at 18 months this increases to almost 24% for infants 901–1000 grams. Female gender, singleton, higher birth weight, absence of neonatal morbidities, private health insurance and White race increase the likelihood of unimpaired status.
PMCID: PMC2856069  PMID: 19564290
Extremely low birth weight; outcomes; neurodevelopmental impairment
18.  Neurodevelopmental outcome in babies weighing less than 2001 g at birth. 
From 1976 to 1980, 1034 infants with birth weights of 500-2000 g were cared for in the neonatal medical unit; 724 were discharged. Twenty (2.8%) subsequently died and 654 (90.3%) were followed up at a median age of 3 years 3 months. Fifty five (7.6%) survivors had major neurodevelopmental handicaps not attributable to congenital anomalies. Increasing prevalence of major handicap was found with decreasing birth weight and gestation. Children with birth weights of less than 1251 g had a higher incidence of all major disabilities. Handicapped children with a birth weight less than 1251 g were more likely to have blindness, deafness, multiple disabilities, and more severe cerebral palsy. There were 146 (20.2%) children with minor disabilities: neurological impairments (n = 11), borderline results on psychometric testing (n = 18), visual impairments (n = 52), hearing impairments (n = 40), and speech impairments (n = 71). Children weighing less than 1251 g at birth had a higher incidence of minor visual and hearing impairments. In 389 children the mean Griffiths quotient was 101.6 (SD 17.2) (range 50-147), and 158 children had a mean Wechsler preschool and primary intelligence quotient of 101.8 (13.2) (range 56-127): these quotients did not vary with birth weight or gestation but did vary with socioeconomic group, schooling, and family structure. During the study period an improving prognosis in terms of both survival and handicap was observed in children weighing less than 1251 g at birth.
PMCID: PMC1246729  PMID: 2441792
19.  Are Outcomes of Extremely Preterm Infants Improving? Impact of Bayley Assessment on Outcomes 
The Journal of pediatrics  2012;161(2):222-8.e3.
To compare 18- to 22-month cognitive scores and neurodevelopmental impairment (NDI) in 2 time periods using the National Institute of Child Health and Human Development’s Neonatal Research Network assessment of extremely low birth weight infants with the Bayley Scales of Infant Development, Second Edition (Bayley II) in 2006–2007 (period 1) and using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), with separate cognitive and language scores, in 2008–2011 (period 2).
Study design
Scores were compared with bivariate analysis, and regression analyses were run to identify differences in NDI rates.
Mean Bayley III cognitive scores were 11 points higher than mean Bayley II cognitive scores. The NDI rate was reduced by 70% (from 43% in period 1 to 13% in period 2; P < .0001). Multivariate analyses revealed that Bayley III contributed to a decreased risk of NDI by 5 definitions: cognitive score <70 and <85, cognitive or language score <70; cognitive or motor score <70, and cognitive, language, or motor score <70 (P < .001).
Whether the Bayley III is overestimating cognitive performance or whether it is a more valid assessment of emerging cognitive skills than the Bayley II is uncertain. Because the Bayley III identifies significantly fewer children with disability, it is recommended that all extremely low birth weight infants be offered early intervention services at the time of discharge from the neonatal intensive care unit, and that Bayley scores be interpreted with caution.
PMCID: PMC3796892  PMID: 22421261
20.  Twins, triplets, and cerebral palsy in births in Western Australia in the 1980s. 
BMJ : British Medical Journal  1993;307(6914):1239-1243.
OBJECTIVES--To examine the rate of cerebral palsy in twins and triplets in births from 1980 to 1989 in Western Australia and to identify factors associated with increase in risk. DESIGN--Pluralities for all births in Western Australia were identified through the standardised midwives' notification system, and cases of cerebral palsy were identified from the Western Australian cerebral palsy register. MAIN OUTCOME MEASURES--Multiple births, cerebral palsy, excluding postneonatal cause. RESULTS--The prevalence of cerebral palsy in triplets, of 28 per 1000 survivors to 1 year (95% confidence interval 11 to 63) exceeded that in twins (7.3; 5.2 to 10) and singletons (1.6; 1.4 to 1.8). Although twins and triples were more likely than singletons to be low in birth weight, their risks of cerebral palsy if low in birth weight were similar. In contrast, in normal birthweight categories twins had a higher rate of cerebral palsy (4.2; 2.2 to 7.7) than singletons (1.1; 1.0 to 1.3). The prevalence of cerebral palsy was similar in twins of unlike sex pairs, all of whom are dizygotic, and in like sex pairs. A twin pair in which one member died in utero was at higher risk of cerebral palsy: 96 per 1000 twin pairs (36 to 218) compared with 12 (8.2 to 17) for twin pregnancies in which both survived. There was a similar but non-significant trend for death of one triplet to be associated with increased risk of cerebral palsy in the survivors of the set. CONCLUSION--Triplet pregnancies produced a child with cerebral palsy 47 times more often than singleton pregnancies did and twin pregnancies eight times more often. Eighty six per cent of cerebral palsy in multiple births was in twins. As multiple births are increasing mainly because of personal and medical decisions the increased risk of cerebral palsy in multiple births is of concern.
PMCID: PMC1679356  PMID: 8281055
21.  Outcomes Following Candiduria in Extremely Low Birth Weight Infants 
Extremely low birth weight (ELBW) infants with candiduria are at substantial risk for death or neurodevelopmental impairment. Therefore, identification of candiduria should prompt a systemic evaluation for disseminated Candida infection and initiation of treatment in all ELBW infants.
Background. Candidiasis carries a significant risk of death or neurodevelopmental impairment (NDI) in extremely low birth weight infants (ELBW; <1000 g). We sought to determine the impact of candiduria in ELBW preterm infants.
Methods. Our study was a secondary analysis of the Neonatal Research Network study Early Diagnosis of Nosocomial Candidiasis. Follow-up assessments included Bayley Scales of Infant Development examinations at 18–22 months of corrected age. Risk factors were compared between groups using exact tests and general linear modeling. Death, NDI, and death or NDI were compared using generalized linear mixed modeling.
Results. Of 1515 infants enrolled, 34 (2.2%) had candiduria only. Candida was isolated from blood only (69 of 1515 [4.6%]), cerebrospinal fluid (CSF) only (2 of 1515 [0.1%]), other sterile site only (not urine, blood, or CSF; 4 of 1515 [0.3%]), or multiple sources (28 of 1515 [2%]). Eleven infants had the same Candida species isolated in blood and urine within 3 days; 3 (27%) had a positive urine culture result first. Most urine isolates were Candida albicans (21 of 34 [62%]) or Candida parapsilosis (7 of 34 [29%]). Rate of death or NDI was greater among those with candiduria (50%) than among those with suspected but not proven infection (32%; odds ratio, 2.5 [95% confidence interval, 1.2–5.3]) after adjustment. No difference in death and death or NDI was noted between infants with candiduria and those with candidemia.
Conclusions. These findings provide compelling evidence that ELBW infants with candiduria are at substantial risk of death or NDI. Candiduria in ELBW preterm infants should prompt a systemic evaluation (blood, CSF, and abdominal ultrasound) for disseminated Candida infection and warrants treatment.
PMCID: PMC3258271  PMID: 22144537
22.  Cerebral palsy in the surviving twin associated with infant death of the co-twin 
BACKGROUND—Monozygotic twins are at greater risk of dying and of serious morbidity than dizygotic twins, and both are at greater risk than singletons. This is only partly explained by the higher proportion of low birthweight infants among twins.
AIM—To compare, in same sex and different sex twins, birth weight specific neonatal death rates and cerebral palsy prevalence rates in the surviving twin when the co-twin has died in infancy.
METHODS—Analysis of birth and death registration data for same sex and different sex twins for England and Wales 1993-1995 where both were live births. Death certificates of all liveborn twins who died were obtained from the Office for National Statistics. A questionnaire was sent to the general practitioners of all surviving co-twins to determine if the child had any disability.
RESULTS—The neonatal death rate in same sex twins was 25.4 and in different sex twins 18.0 per 1000 live births (death rate difference 7.4; 95% confidence interval 4.7 to 10.1; p < 0.001). The higher neonatal death rate in same sex compared with different sex twins is attributable to the higher proportion of same sex twins with low birth weight. Prevalence of cerebral palsy in the low birthweight group (< 1000 g) was marginally higher in same sex (224 per 1000) than different sex (200 per 1000) twin survivors. In the birth weight group 1000-1999 g, same sex twin survivors were at a significantly higher risk of cerebral palsy than those of different sex: 167v 21 per 1000; difference 145 (95% confidence interval 44 to 231; p < 0.01) per 1000 infant survivors.
CONCLUSION—There are two components to the cause of cerebral palsy in twins. Immaturity per se predisposes to cerebral damage. Also, same sex twins may sustain cerebral damage that is in excess of that due to immaturity.

PMCID: PMC1721231  PMID: 11207227
23.  Cytokines and Neurodevelopmental Outcomes in Extremely Low Birth Weight Infants 
The Journal of pediatrics  2011;159(6):919-925.e3.
To determine if selected pro-inflammatory and anti-inflammatory cytokines/mediators of inflammation reported to be related to development of cerebral palsy predict neurodevelopmental outcome in extremely low birth weight infants.
Study design
Infants with birth weights ≤ 1000 g (n=1067) had blood samples collected at birth and on days 3±1, 7±1, 14±3, and 21±3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on five cytokines (IL-1β, IL-8, TNF-α, RANTES, and IL-2) reported to be most predictive of CP in term and late preterm infants.
IL-8 was higher on days 0–4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, TNF-β, SIL-rα, MIP-1β) were found to be altered on days 0–4 in infants who developed CP.
CP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
PMCID: PMC3215787  PMID: 21798559
24.  Is phototherapy exposure associated with better or worse outcomes in 501–1000 gram birth weight infants? 
To compare risk-adjusted outcomes at 18–22 months corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.
Outcomes at 18–22 months corrected age included death, neurodevelopmental impairment (NDI), and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for center and other potentially confounding variables.
Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501–1000 g BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI 0.60 –1.20), death, or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).
Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded due to bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501–750g BW NoPTx group is concerning, and consistent with NRN Trial results.
PMCID: PMC3505994  PMID: 21272067
25.  Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight 
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
PMCID: PMC2821221  PMID: 18971491

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