Extremely low birth weight twins have a higher rate of death or neurodevelopmental impairment than singletons. Higher-order extremely low birth weight multiple births may have an even higher rate of death or neurodevelopmental impairment.
Extremely low birth weight (birth weight 401–1000 g) multiple births born in participating centers of the Neonatal Research Network between 1996 and 2005 were assessed for death or neurodevelopmental impairment at 18 to 22 months' corrected age. Neurodevelopmental impairment was defined by the presence of 1 or more of the following: moderate to severe cerebral palsy; mental developmental index score or psychomotor developmental index score less than 70; severe bilateral deafness; or blindness. Infants who died within 12 hours of birth were excluded. Maternal and infant demographic and clinical variables were compared among singleton, twin, and triplet or higher-order infants. Logistic regression analysis was performed to establish the association between singletons, twins, and triplet or higher-order multiples and death or neurodevelopmental impairment, controlling for confounding variables that may affect death or neurodevelopmental impairment.
Our cohort consisted of 8296 singleton, 2164 twin, and 521 triplet or higher-order infants. The risk of death or neurodevelopmental impairment was increased in triplets or higher-order multiples when compared with singletons (adjusted odds ratio: 1.7 [95% confidence interval: 1.29–2.24]), and there was a trend toward an increased risk when compared with twins (adjusted odds ratio: 1.27 [95% confidence: 0.95–1.71]).
Triplet or higher-order births are associated with an increased risk of death or neurodevelopmental impairment at 18 to 22 months' corrected age when compared with extremely low birth weight singleton infants, and there was a trend toward an increased risk when compared with twins.
extremely low birth weight; triplets; neurodevelopmental outcomes
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.
twins; neuro-developmental impairment; extremely low birth weight infants
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.)
We compared neurodevelopmental outcomes at 18 to 22 months' corrected age of infants born with extremely low birth weight at an estimated gestational age of <25 weeks during 2 periods: 1999–2001 (epoch 1) and 2002–2004 (epoch 2).
PATIENTS AND METHODS:
We conducted a multicenter, retrospective analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Perinatal and neonatal variables and outcomes were compared between epochs. Neurodevelopmental outcomes at 18 to 22 months' corrected age were evaluated with neurologic exams and Bayley Scales of Infant Development II. Logistic regression analyses determined the independent risk of epoch for adverse outcomes.
Infant survival was similar between epochs (epoch 1, 35.4%, vs epoch 2, 32.3%; P = .09). A total of 411 of 452 surviving infants in epoch 1 and 405 of 438 surviving infants in epoch 2 were evaluated at 18 to 22 months' corrected age. Cesarean delivery (P = .03), surgery for patent ductus arteriosus (P = .004), and late sepsis (P = .01) were more common in epoch 2, but postnatal steroid use was dramatically reduced (63.5% vs 32.8%; P < .0001). Adverse outcomes at 18 to 22 months' corrected age were common in both epochs. Moderate-to-severe cerebral palsy was diagnosed in 11.1% of surviving infants in epoch 1 and 14.9% in epoch 2 (adjusted odds ratio [OR]: 1.52 [95% confidence interval (CI): 0.86–2.71]; P = .15), the Mental Developmental Index was <70 in 44.9% in epoch 1 and 51% in epoch 2 (OR: 1.30 [95% CI: 0.91–1.87]; P = .15), and neurodevelopmental impairment was diagnosed in 50.1% of surviving infants in epoch 1 and 58.7% in epoch 2 (OR: 1.4 [95% CI: 0.98–2.04]; P = .07).
Early-childhood outcomes for infants born at <25 weeks' estimated gestational age were unchanged between the 2 periods.
extremely preterm; neurodevelopmental; outcome; cerebral palsy; Bayley Scales of Infant Development II
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.
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.
premature; sepsis; steroids; Bayley; cognitive; motor
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.
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.
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.
preterm; neurodevelopmental impairment; electroencephalography
Treatment regimens for hyperbilirubinemia vary for very low birth weight infants. The present study seeks to determine whether the initiation of conservative phototherapy is as effective as aggressive phototherapy in reducing peak bilirubin levels without increasing adverse effects.
The present randomized, controlled study included infants with birth weights between 500 g and 1500 g, stratified into two birth weight groups. In one group, aggressive phototherapy was commenced by 12 h of age, while in the other group, conservative phototherapy was commenced if serum bilirubin levels exceeded 150 μmol/L. The primary outcome variables were peak serum bilirubin levels and hours of phototherapy. Secondary outcomes were age at peak bilirubin levels, number of infants with rebound hyperbilirubinemia, and number of adverse short- and long-term outcomes.
Of 174 eligible infants, 95 consented to participate −49 in the conservative arm and 46 in the aggressive arm. Ninety-two infants completed the study. There was no significant difference in peak bilirubin levels except in infants who weighed less than 1000 g −171.2±26 μmol/L (conservative) versus 139.2±46 μmol/L (aggressive); P<0.02. There was no difference in duration of phototherapy or rebound hyperbilirubinemia. There were no differences in short-term adverse outcomes. Of the 87 infants who survived until hospital discharge, 82 (94%) had some follow-up and 75 (86%) attended follow-up until 18 months corrected age. The incidence of cerebral palsy, abnormal mental developmental index at 18 months corrected age, or combined outcome of cerebral palsy and death did not significantly differ between the two groups.
In infants weighing less than 1000 g, peak bilirubin levels were significantly higher using conservative phototherapy regimens and there was a tendency for poor neurodevelopmental outcome.
Hyperbilirubinemia; Paediatrics; Phototherapy; Population-based; Preterm
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.
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.
outcomes; neurodevelopmental impairment; death
Bilirubin-related neurotoxicity is an important clinical issue in very low birthweight (VLBW) infants, and the existing literature is inconsistent.
To analyze the relationship between maximal serum unconjugated bilirubin levels (SBL) and neurodevelopmental outcome at 2-year corrected age in VLBW infants.
Phototherapy was initiated in all infants born before 33 weeks of gestation, according to Maisels' recommendations. Neurodevelopmental assessment at 2-year corrected age was performed in all infants that survived. SBLs collected during the first week of life were used to define three tertiles of max-SBL. The first tertile corresponded to infants with the lowest max-SBL.
Results and Conclusions
A total of 724 infants were included in the study, and among them, 631 (87%) were evaluated at two years old. The infants of the first tertile were younger and smaller than the infants of the other two tertiles, in accordance with Maisels' recommendations for very small infants. No difference in the risk of impaired functional outcome among the three groups was observed. However, among infants weighing less than 1001 g, those in the third tertile had a poorer neurodevelopmental prognosis as compared to those in the second tertile (adjusted odds ratio = 6.8, 95% CI: 1.2–36.7, p = 0.03). Considering the results obtained, we propose 196 µmol/L (11.5 mg/dL) when birthweight varies between 1001 and 1500 g, and 170 µmol/L (9.9 mg/dL) when birthweight is less than 1001 g, as recommended max-SBLs (defined as maximal levels of 95th percentile curves of SBLs in infants with an optimal outcome). When Maisels' recommendations were applied, max SBLs were higher in 8% of infants weighing 1001–1500 g and in 15% of infants weighing less than 1001 g. Our data seems to validate Maisels' recommendations in the overall population of infants born before 33 weeks of gestation, but not in infants weighing less than 1001 g.
To determine the relative contribution of clinical data versus head ultrasound (HUS) in predicting neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants.
2103 ELBW infants (<1000g) admitted to a National Institute of Child Health and Human Development Neonatal Research Network center who had a HUS within the first 28 days, a repeat one around 36 weeks’ post-menstrual age, and neurodevelopmental assessment at 18–22 months corrected age were selected. Multivariate logistic regression models were developed using clinical and/or HUS variables. The primary outcome was the predictive abilities of the HUS done before 28 days after birth and closer to 36 weeks post-menstrual age, either alone or in combination with “Early” and “Late” clinical variables.
Models using clinical variables alone predicted NDI better than models with only HUS variables at both 28 days and 36 weeks (both p < 0.001), and addition of the HUS data did not improve prediction. NDI was absent in 30% and 28% of the infants with grade IV intracranial hemorrhage or periventricular leukomalacia, respectively, but was present in 39% of the infants with a normal head ultrasound.
Clinical models were better than head ultrasound models in predicting neurodevelopment.
Logistic models; Predictive value of tests; ROC curve; Infant; premature; Intracerebral hemorrhage; Leukomalacia; periventricular
Both excess and insufficient levels of glucocorticoid in extremely low birth weight (ELBW) infants have been associated with adverse hospital outcomes, whereas excess glucocorticoid exposure has been associated with long-term adverse neurodevelopment. Our objective was to evaluate the relationship between neonatal cortisol concentrations and long-term outcomes of growth and neurodevelopment.
As part of a multicenter randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency, cortisol concentrations were obtained at 12 to 48 h of postnatal age and at days 5 to 7 on 350 intubated ELBW infants, of whom 252 survived and returned for neurodevelopmental follow-up at 18 to 22 months corrected age. Cortisol values from each time point were divided into quartiles. Growth and neurodevelopmental outcome were compared for each quartile.
Median cortisol value was 16.0 μg per 100 ml at baseline for all infants, and 13.1 μg per 100 ml on days 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or at days 5 to 7 were not associated with impaired growth or neurodevelopment at 18 to 22 months corrected age. High cortisol values were associated with an increase in cerebral palsy, related to the increased incidence of severe intraventricular hemorrhage (IVH) and periventricular leukomalacia.
Low cortisol concentrations were not predictive of adverse long-term outcomes. High cortisol concentrations, although predictive of short-term adverse outcomes such as IVH and periventricular leukomalacia, did not additionally predict adverse outcome. Further analysis into identifying factors that modulate cortisol concentrations shortly after birth could improve our ability to identify those infants who are most likely to benefit from treatment with hydrocortisone.
bronchopulmonary dysplasia; extremely preterm infants; hydrocortisone; outcomes of high-risk infants
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.
Extremely low birth weight infant; Neurodevelopmental outcome; Severe disability; Vermont Oxford Network
The outcome of 143 live-born infants of very low birth weight (defined as less than 1500 g) who were born in 1980-81 to women resident in Newfoundland and Labrador is described. Sixty-one infants (43%) died during the first year of life. Of the 82 surviving infants 79 were followed for 18 months to 3 years. Eight (10%) were found to have evidence of severe neurodevelopmental abnormality, and nine (11%) were found to have various minor problems, including seizures, developmental delay and behavioural disorders. There was an inverse association between birth weight and mortality. Neonatal pneumothorax, seizures and clinical evidence of intraventricular hemorrhage were more commonly seen among infants who died; these factors also seemed to be predictive of an adverse long-term outcome. Continuous monitoring of the rates of death and disability among infants of very low birth weight born within a defined region should provide the basis for rational planning and delivery of neonatal intensive care.
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.
The effect of postnatal age on serum bilirubin binding measurements was studied prospectively in extremely premature infants of 25-28 weeks' gestation. Serum was obtained from 10 infants at birth, 2-4 days of age, 1 week, 2 weeks, 4 weeks, 8 weeks, and 10-13 weeks. Using peroxidase oxidation, the apparent unbound bilirubin concentration (AUBC) was measured and plotted versus the molar ratio of total bilirubin:albumin (R) using the empiric power curve AUBC = aRb. The apparent unbound bilirubin concentration at bilirubin:albumin ratio 0.6 was used to compare relative binding ability among specimens. This value, as well as the apparent association constants, showed dramatic deterioration after birth, which persisted without improvement until 8 weeks of age. This pattern of recovery correlated in general with the resolution of clinical problems. Binding values equivalent to adult serum were achieved by 10-13 weeks. This study emphasises that diminished bilirubin binding by the sera of premature infants can persist for a prolonged period.
Neonatal jaundice (hyperbilirubinemia), extremely common in neonates, can be associated with neurotoxicity. A safe level of bilirubin has not been defined in either premature or term infants. Emerging evidence suggest that the level of unbound (or “free”) bilirubin has a better sensitivity and specificity than total serum bilirubin for bilirubin-induced neurotoxicity. Although recent studies suggest the usefulness of free bilirubin measurements in managing high-risk neonates including premature infants, there currently exists no widely available method to assay the serum free bilirubin concentration. To keep pace with the growing demand, in addition to reevaluation of old methods, several promising new methods are being developed for sensitive, accurate, and rapid measurement of free bilirubin and bilirubin binding capacity. These innovative methods need to be validated before adopting for clinical use. We provide an overview of some promising methods for free bilirubin and binding capacity measurements with the goal to enhance research in this area of active interest and apparent need.
Free bilirubin; total binding capacity; reserve binding capacity; binding affinity
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.
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.
Monochorionic (MC) twins are at increased risk for perinatal mortality and serious morbidity due to the presence of placental vascular anastomoses. Cerebral injury can be secondary to haemodynamic and hematological disorders during pregnancy (especially twin-to-twin transfusion syndrome (TTTS) or intrauterine co-twin death) or from postnatal injury associated with prematurity and low birth weight, common complications in twin pregnancies. We investigated neurodevelopmental outcome in MC and dichorionic (DC) twins at the age of two years.
This was a prospective cohort study. Cerebral palsy (CP) was studied in 182 MC infants and 189 DC infants matched for weight and age at delivery, gender, ethnicity of the mother and study center. After losses to follow-up, 282 of the 366 infants without CP were available to be tested with the Griffiths Mental Developmental Scales at 22 months corrected age, all born between January 2005 and January 2006 in nine perinatal centers in The Netherlands. Due to phenotypic (un)alikeness in mono-or dizygosity, the principal investigator was not blinded to chorionic status; perinatal outcome, with exception of co-twin death, was not known to the examiner.
Four out of 182 MC infants had CP (2.2%) - two of the four CP-cases were due to complications specific to MC twin pregnancies (TTTS and co-twin death) and the other two cases of CP were the result of cystic PVL after preterm birth - compared to one sibling of a DC twin (0.5%; OR 4.2, 95% CI 0.5–38.2) of unknown origin. Follow-up rate of neurodevelopmental outcome by Griffith's test was 76%. The majority of 2-year-old twins had normal developmental status. There were no significant differences between MC and DC twins. One MC infant (0.7%) had a developmental delay compared to 6 DC infants (4.2%; OR 0.2, 95% 0.0–1.4). Birth weight discordancy did not influence long-term outcome, though the smaller twin had slightly lower developmental scores than its larger co-twin.
There were no significant differences in occurrence of cerebral palsy as well as neurodevelopmental outcome between MC and DC twins. Outcome of MC twins seems favourable in the absence of TTTS or co-twin death.
The purpose of this work was to evaluate therapy for patent ductus arteri-osus as a risk factor for death or neurodevelopmental impairment at 18 to 22 months, bronchopulmonary dysplasia, or necrotizing enterocolitis in extremely low birth weight infants.
We studied infants in the National Institute of Child Health and Human Development Neonatal Research Network Generic Data Base born between 2000 and 2004 at 23 to 28 weeks’ gestation and at <1000-g birth weight with patent ductus arteriosus. Patent ductus arteriosus therapy was evaluated as a risk factor for outcomes in bivariable and multivariable analyses.
Treatment for subjects with patent ductus arteriosus (n = 2838) included 403 receiving supportive treatment only, 1525 treated with indomethacin only, 775 with indomethacin followed by secondary surgical closure, and 135 treated with primary surgery. Patients who received supportive therapy for patent ductus arteriosus did not differ from subjects treated with indomethacin only for any of the outcomes of interest. Compared with indomethacin treatment only, patients undergoing primary or secondary surgery were smaller and more premature. When compared with indomethacin alone, primary surgery was associated with increased adjusted odds for neurodevelopmental impairment and bronchopulmonary dysplasia in multivariable logistic regression. Secondary surgical closure was associated with increased odds for neurodevelopmental impairment and increased adjusted odds for bronchopulmonary dysplasia but decreased adjusted odds for death. Risk of necrotizing enterocolitis did not differ among treatments. Indomethacin prophylaxis did not significantly modify these results.
Our results suggest that infants treated with primary or secondary surgery for patent ductus arteriosus may be at increased risk for poor short- and long-term outcomes compared with those treated with indomethacin. Prophylaxis with indomethacin in the first 24 hours of life did not modify the subsequent outcomes of patent ductus arteriosus therapy.
patent ductus arteriosus; bronchopulmonary dysplasia; necrotizing enterocolitis; neurodevelopmental impairment; therapy ductus arteriosus
Objective: To study neurodevelopmental outcome in a two year cohort of extremely low birthweight (ELBW) infants at 18 months corrected age, to compare the development of the ELBW infant subcohort with that of control children, and to find risk factors associated with unfavourable outcome.
Study design: All 211 surviving ELBW infants (birth weight < 1000 g) born in Finland in 1996–1997 were included in a national survey. The ELBW infants (n = 78) who were born and followed in Helsinki University Hospital belonged to a regional subcohort and were compared with a control group of 75 full term infants. A national follow up programme included neurological, speech, vision, and hearing assessments at 18 months of corrected age. Bayley infant scale assessment was performed on the subcohort and their controls at 24 months of age. Risk factors for unfavourable outcome were estimated using logistic and linear regression models.
Results: The prevalence of cerebral palsy was 11%, of all motor impairments 24%, of ophthalmic abnormalities 23%, and of speech delay 42%. No impairment was found in 42% of children, and 18% were classified as severely impaired. The prevalence of ophthalmic abnormalities decreased with increasing birth weight and gestational age, but the prevalence of other impairments did not. In the subcohort, a positive correlation was found between the date of birth and Bayley scores.
Conclusion: Ophthalmic abnormalities decreased with increasing birth weight and gestational age, but no other outcome differences were found between birthweight groups or in surviving ELBW infants born at 22–26 weeks gestation. The prognosis in the regional subcohort seemed to improve during the short study period, but this needs to be confirmed.
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.
Extremely low birth weight; outcomes; neurodevelopmental impairment
To evaluate the effect of ibuprofen on bilirubin-albumin binding affinity and unbound bilirubin in premature infants.
A prospective study with subjects serving as their own controls was performed on <30 weeks’ gestational age infants with unconjugated hyperbilirubinemia and who received ibuprofen for patent ductus arteriosus. Infants with congenital malformation, TORCH infections, and conjugated hyperbilirubinemia were excluded. Total serum bilirubin (TSB) and unbound bilirubin (modified peroxidase test) were measured prior to (baseline) and after (follow-up) initiation of ibuprofen. The bilirubin/albumin equilibrium association binding constant was calculated using albumin, TSB, and unbound bilirubin.
Ten infants were studied. The mean TSB between baseline (5.9±1.7 mg/dL) was higher than that at follow-up [4.9±1.7 mg/dL]. Mean unbound bilirubin at baseline (0.75±0.65 µg/dL) was similar to that at follow-up (0.63±0.46 µg/dL). No difference existed between mean baseline binding constant (49±50 L/µmol) and that at follow-up (44±36 L/µmol). The ratio of unbound bilirubin with and without ibuprofen, index of displacing effect, was 0.88 (95% CI 0.63–1.14).
Ibuprofen may not be associated with bilirubin displacing effect in relatively stable premature infants with mild to moderate unconjugated hyperbilirubinemia.
Bilirubin:albumin ratio; free bilirubin; hyperbilirubinemia; patent ductus arteriosus
Inflammation mediated by cytokines may be important in the pathogenesis of bronchopulmonary dysplasia and the competing outcome of death in extremely low birth weight infants.
To develop multi-variable logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at 36w post-menstrual age using clinical and cytokine data from the first 28 days.
1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development had 25 cytokines measured from blood collected within 4 h of birth and on days 3, 7, 14, and 21. Stepwise regression using peak values of the 25 cytokines and 15 clinical variables identified variables associated with BPD/death. Multi-variable logistic regression was done for bronchopulmonary dysplasia/death using variables selected by stepwise regression. Similar analyses were also done using average cytokine values from days 0–21, days 0–3, and from days 14–21.
Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. Combining results from all models, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukins-1β, -6, -8, -10, and interferon-γ and lower concentrations of interleukin-17, RANTES, and tumor necrosis factor-β. Compared to models with only clinical variables, addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude.
The overall pattern of cytokines suggests bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T-lymphocytes.
Logistic models; Infant; premature; Predictive value of tests