Indomethacin Prophylaxis In Preterms Research Articles

Neuroprotection for Premature Infants?

APPROXIMATELY 85% OF INFANTS BORN WEIGHING LESS than 1500 g at birth (approximately 30 weeks’ gestational age) survive to hospital discharge. However, these surviving preterm infants, especially those at the threshold of viability (23 to 25 weeks’ gestational age) often have major developmental deficits or minor functional morbidities that interfere with daily living. One-third of children with birth weight less than 1000 g who had no neurosensory problems detected at hospital discharge had an IQ of less than 85, learning problems, or poor motor skills at 8 to 9 years of age, and two-thirds had behavioral problems; those with abnormalities identified in the newborn period had an even greater rate of adverse outcome. In the United States, preterm infants contribute more than half of all new cases of cerebral palsy and contribute disproportionately to cognitive impairment as well, although the extent is more difficult to evaluate. The resulting burden on family and societal resources is substantial. On average, a child with cerebral palsy born in 2000 incurs an estimated lifetime medical and nonmedical direct and indirect cost of nearly $1 million in 2003 dollars. The combined cost for all children with cerebral palsy, deafness, and blindness was estimated at $16 billion in 2003. Other costs that cannot easily be measured are reflected in the high rates of depression, anxiety, and behavioral problems of children with cerebral palsy and their families. An intervention that could reduce the effect of disability in preterm infants would be beneficial for the children, their families, and society as a whole. However, with the exception of antenatal corticosteroids and surfactant replacement therapy, the results of most clinical trials aimed at improving outcomes of prematurity have been disappointing. Promising short-term results are often not sustained through infancy or childhood. For example, in the Trial of Indomethacin Prophylaxis in Preterms, indomethacin administered to extremely low-birthweight infants significantly decreased the incidence of patent ductus arteriosus and periventricular and intraventricular hemorrhage. However, the rate of survival without neurosensory impairment at 18 months of age, the primary outcome of the trial, was similar in both groups. In another study that compared vitamin A supplementation with placebo, vitamin A supplementation reduced the rate of chronic lung disease in extremely low-birth-weight infants, but respiratory and neurodevelopmental outcomes were similar in both groups at 18 to 22 months of age. In this issue of JAMA, Schmidt and colleagues report the results of their 5-year follow-up of infants enrolled in the Caffeine for Apnea of Prematurity (CAP) trial. This publication is the third report from a large international trial to assess the long-term effects on neurodevelopment and growth of an agent widely used to treat apnea in preterm infants. In the CAP trial, infants with a birth weight of 500 to 1250 g whose clinicians considered treatment with a methylxanthine during the first 10 days of age were randomly assigned to receive caffeine or placebo. The indications for treatment were to prevent or treat apnea or to facilitate endotracheal extubation; treatment was continued until the clinicians thought it was no longer needed. The 18-month neurodevelopmental outcomes were measured using the Bayley Scales of Infant Development, Second Edition (BSID-II), which was the gold standard for neurodevelopmental assessment when the study was conducted. As reported previously, the primary outcome of the trial—a composite of death before 18 months and cerebral palsy, cognitive delay, severe hearing loss, or bilateral blindness at a corrected age of 18 to 21 months—occurred in 40.2% of the caffeine group compared with 46.2 percent of the placebo group (odds ratio adjusted for center, 0.77; 95% CI, 0.640.93, P=.008). Treatment with caffeine nearly halved the rate of cerebral palsy, and resulted in a modest decrease in cognitive delay. Among short-term outcomes, caffeine substantially reduced the rate of bronchopulmonary dysplasia but did not affect the rates of death, brain injury detected by ultrasonography, or necrotizing enterocolitis. In the current study, neurobehavioral, neuropsychological, and motor outcomes were comprehensively evaluated at 5 years of age. The Wechsler Preschool and Primary School Scale of Intelligence III, Child Behavior Checklist, and Move-

Patent ductus arteriosus and effects of low oxygen saturation limits

Patent ductus arteriosus and effects of low oxygen saturation limits

Using a Count of Neonatal Morbidities to Predict Poor Outcome in Extremely Low Birth Weight Infants: Added Role of Neonatal Infection

A count of 3 neonatal morbidities (bronchopulmonary dysplasia, brain injury, and severe retinopathy of prematurity) strongly predict the risk of death or neurosensory impairment in extremely low birth weight infants who survive to 36 weeks' postmenstrual age. Neonatal infection has also been linked with later impairment. We examined whether the addition of infection to the count of 3 neonatal morbidities further improves the prediction of poor outcome. We studied 944 infants who participated in the Trial of Indomethacin Prophylaxis in Preterms and survived to 36 weeks' postmenstrual age. Culture-proven sepsis, meningitis, and stage II or III necrotizing enterocolitis were recorded prospectively. We investigated the incremental prognostic importance of neonatal infection by adding terms for the different types of infection to a logistic model that already contained terms for the count of bronchopulmonary dysplasia, brain injury, and severe retinopathy. Poor outcome at 18 months of age was death or survival with 1 or more of the following: cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness. There were 414 (44%) infants with at least 1 episode of infection or necrotizing enterocolitis. Meningitis and the presence of any type of infection added independent prognostic information to the morbidity-count model. The odds ratio associated with infection or necrotizing enterocolitis in this model was 50% smaller than the odds ratio associated with each count of the other 3 neonatal morbidities. Meningitis was rare and occurred in 22 (2.3%) of 944 infants. In this cohort of extremely low birth weight infants who survived to 36 weeks' postmenstrual age, neonatal infection increased the risk of a late death or survival with neurosensory impairment. However, infection was a weaker predictor of poor outcome than bronchopulmonary dysplasia, brain injury, and severe retinopathy.

Prevention and 18-Month Outcomes of Serious Pulmonary Hemorrhage in Extremely Low Birth Weight Infants: Results From the Trial of Indomethacin Prophylaxis in Preterms

A patent ductus arteriosus is a risk factor for pulmonary hemorrhage; however, despite halving the incidence of patent ductus arteriosus, indomethacin prophylaxis did not reduce the rate of pulmonary hemorrhage in the Trial of Indomethacin Prophylaxis in Preterms. Inclusion of mild bleeds after trauma to the upper airways may have masked a beneficial drug effect. Using the Trial of Indomethacin Prophylaxis in Preterms database, we studied the effect of prophylactic indomethacin on the prevention of serious hemorrhages in extremely low birth weight infants. We also compared the 18-month outcomes of infants with and without a serious pulmonary bleed. Pulmonary hemorrhage was classified as serious when it was treated with increased ventilator support, a higher concentration of oxygen, or transfusion of blood products. The cumulative risk for serious pulmonary hemorrhage was estimated for the first week of life and for the entire NICU stay. Poor outcome at a corrected age of 18 months was death or survival with cerebral palsy, cognitive delay, blindness, and/or deafness. A total of 123 (10.2%) of 1202 infants developed a serious pulmonary hemorrhage. During week 1, prophylactic indomethacin reduced the risk for serious pulmonary hemorrhage by 35%; however, during the entire NICU stay, the risk for such hemorrhages was decreased by only 23%. A reduced risk for patent ductus arteriosus explained 80% of the beneficial effect of prophylactic indomethacin on serious pulmonary bleeds. The risks for death or for survival with neurosensory impairment were doubled after a serious pulmonary hemorrhage. Extremely low birth weight infants with serious pulmonary hemorrhage have an increased risk for poor long-term outcome. Prophylactic indomethacin reduces the rate of early serious pulmonary hemorrhage, mainly through its action on patent ductus arteriosus. Prophylactic indomethacin is less effective in preventing serious pulmonary hemorrhages that occur after the first week of life.

Neurosensory Impairment after Surgical Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms

Neurosensory Impairment after Surgical Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms

Neurosensory Impairment after Surgical Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms

To determine whether surgical closure of a patent ductus arteriosus (PDA) is a risk factor for bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (ROP), and neurosensory impairment in extremely low birth weight (ELBW) infants. We studied 426 infants with a symptomatic PDA, 110 of whom underwent PDA ligation and 316 of whom received medical therapy only. All infants participated in the multicenter Trial of Indomethacin Prophylaxis in Preterms (TIPP) and were observed to a corrected age of 18 months. Of the 95 infants who survived after PDA ligation, 50 (53%) had neurosensory impairment, compared with 84 of the 245 infants (34%) who survived after receiving only medical therapy (adjusted odds ratio, 1.98; 95% CI, 1.18-3.30; P = .0093). BPD (adjusted odds ratio, 1.81; 95% CI, 1.09-3.03; P = .023) and severe ROP (adjusted odds ratio, 2.20; 95% CI, 1.19-4.07; P = .012) were also more common after surgical PDA closure. PDA ligation may be associated with increased risks of BPD, severe ROP, and neurosensory impairment in ELBW infants.

Microarray Analysis and Tumor Classification

for the Caffeine for Apnea of Prematurity Trial Investigators Bauer J, Maier K, Linderkamp O, Hentschel R. Effect of caffeine on oxygen consumption and metabolic rate in very low birth weight infants with idiopathic apnea. Pediatrics 2001;107: 660-3. Davis PG, Thorpe K, Roberts R, Schmidt B, Doyle LW, Kirpalani H. Evaluating “old” definitions for the “new” bronchopulmonary dysplasia. J Pediatr 2002;140:555-60. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA 2003; 289:1124-9. 1.

Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: Further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

To determine the risk of bronchopulmonary dysplasia (BPD) in subgroups of infants with and without patent ductus arteriosus (PDA) who were randomized to indomethacin prophylaxis or placebo, and to examine whether adverse drug effects on edema formation and oxygenation may explain why indomethacin prophylaxis does not reduce BPD. We studied 999 extremely low birth weight infants who participated in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) and who survived to a postmenstrual age of 36 weeks. The incidence of BPD in the 2 subgroups of infants with PDA was 52% (55/105) after indomethacin prophylaxis and 56% (137/246) after placebo. In contrast, rates of BPD in the 2 subgroups without a PDA were 43% (170/391) after indomethacin prophylaxis and 30% (78/257) after placebo (P [interaction] = .015). Logistic regression analysis with adjustment for prognostic baseline factors showed that adverse and independent effects of indomethacin prophylaxis on the need for supplemental oxygen and on weight loss by the end of the first week of life may increase the risk of BPD in infants without PDA. Harmful side effects on oxygenation and edema formation may explain why indomethacin prophylaxis does not prevent BPD even though it reduces PDA.

Indomethicin and BPD

The outcome of bronchopulmonary dysplasia (BPD) in very low birth weight infants (VLBW) has many clinical associations. However, treatments to avoid or decrease adverse effects of those associations have not consistently decreased BPD. For example, antenatal corticosteroids or surfactant treatments to decrease RDS have not decreased the incidence of BPD, although each therapy has decreased mortality and has decreased the severity of BPD. The presumed explanation for the lack of effect on incidence of BPD is that increased survival has put more marginal infants at risk of developing BPD. Similarly, different ventilation strategies have not consistently decreased BPD. BPD is thought to result from injury resulting in lung inflammation, and anti-inflammatory corticosteroids have been used to treat BPD. A patent ductus arteriosis (PDA) also is linked to BPD. However, the cyclo-oxygenase inhibitors, which close the PDA and are anti-inflammatory, have not decreased PDA.Schmidt et al have revisited the Trial of Indomethacin Prophylaxis in Preterms (TIPP) database to demonstrate that randomization of infants to indomethacin may increase BPD because of decreased weight loss and increased supplemental oxygen need. In a very thoughtful editorial, Carl Bose reflects on what other mechanisms might explain why indomethacin does not decrease (and may increase) BPD. The clinical associations with BPD may primarily indicate the immaturity of the infant at risk, and BPD seems to result from interference in the development of the immature lung.Effective therapies to decrease BPD may need to be directed at the abnormal development rather than other associations with immaturity. The outcome of bronchopulmonary dysplasia (BPD) in very low birth weight infants (VLBW) has many clinical associations. However, treatments to avoid or decrease adverse effects of those associations have not consistently decreased BPD. For example, antenatal corticosteroids or surfactant treatments to decrease RDS have not decreased the incidence of BPD, although each therapy has decreased mortality and has decreased the severity of BPD. The presumed explanation for the lack of effect on incidence of BPD is that increased survival has put more marginal infants at risk of developing BPD. Similarly, different ventilation strategies have not consistently decreased BPD. BPD is thought to result from injury resulting in lung inflammation, and anti-inflammatory corticosteroids have been used to treat BPD. A patent ductus arteriosis (PDA) also is linked to BPD. However, the cyclo-oxygenase inhibitors, which close the PDA and are anti-inflammatory, have not decreased PDA. Schmidt et al have revisited the Trial of Indomethacin Prophylaxis in Preterms (TIPP) database to demonstrate that randomization of infants to indomethacin may increase BPD because of decreased weight loss and increased supplemental oxygen need. In a very thoughtful editorial, Carl Bose reflects on what other mechanisms might explain why indomethacin does not decrease (and may increase) BPD. The clinical associations with BPD may primarily indicate the immaturity of the infant at risk, and BPD seems to result from interference in the development of the immature lung. Effective therapies to decrease BPD may need to be directed at the abnormal development rather than other associations with immaturity.

Early prediction of poor outcome in extremely low birth weight infants by classification tree analysis

To predict death or neurodevelopmental impairment (NDI) in extremely low birth weight infants by classification trees with recursive partitioning and automatic selection of optimal cut points of variables. Data from the Trial of Indomethacin Prophylaxis in Preterms were randomly divided into development (n=784) and validation sets (n=262). Three models were developed for the combined outcome of death (8 days to 18 months) or NDI (cerebral palsy, cognitive delay, deafness, or blindness at 18 months corrected age): antenatal: antenatal data; early neonatal: antenatal+first 3 days data; and first week: antenatal, first 3 days, and 4th to 8th days data. Decision trees were tested on the validation set. Variables associated with death/NDI in each model were: Antenatal: Gestation<or=25.5 weeks and antenatal steroids<7 days. Early neonatal: Birth weight<or=787 g and fluid intake>01 mL/kg/d. First week: Birth weight<or=787 g: transfusion>3 mL/kg/d. Birth weight>787 g: cranial echodense intraparenchymal lesion and transfusion>1 mL/kg/d. Correct classification rates were 61% to 62% for all models. The ability to predict long-term morbidity/death in extremely low birth weight infants does not improve significantly over the first week of life. Effects of different variables depend on age.

Retrospective economic evaluation of a controlled trial of indomethacin prophylaxis for patent ductus arteriosus in premature infants

Objective To determine the incremental cost-effectiveness of indomethacin prophylaxis in extremely low birth weight infants enrolled in the Trial of Indomethacin Prophylaxis in Preterms (TIPP). Study design Participants in this economic evaluation were 428 infants enrolled at 9 Canadian TIPP centres. The study took a third-party payer perspective. Prior to the analysis of clinical trial data, direct medical costs were derived from chart review of 89 items of resource utilization, for each day from admission to hospital discharge. Unit costs for each resource were obtained from a provincially standardized cost-accounting system. Incremental cost-effectiveness analysis was performed, with estimation of cost-effectiveness acceptability curves through non-parametric bootstrapping. Results The mean (SD) cost was $68 279 (40 317) for the placebo group and $69 629 (37 989) for the indomethacin group. Indomethacin prophylaxis cost an additional $67 500 per death or impairment averted. However, the precision of this estimate was low, such that the probability that the estimate was lower than $300 000 per death or impairment averted was only 61%. The results were similar when surgical costs were assumed to be 500% of those measured in the trial. Conclusions This study does not provide an economic rationale for the use of indomethacin prophylaxis in ELBW infants.

234 Surgical Closure of A Patient Ductus Arteriosus (PDA) is Associated with Increased Neuro-Sensory Impairment in Extremely Low Birth Weight (ELBW) Infants: Results from The Trial of Indomethacin Prophylaxis in Preterms

Background: The Victorian Infant Collaborative Study Group has reported that surgery with general anesthesia during the initial hospitalization increases the risk of adverse sensorineural outcome in ELBW infants. PDA ligation was the single most frequent type of surgery in this study. Objective: To determine whether surgical PDA closure was a risk factor for neurosensory impairment in ELBW infants who participated in the international Trial of Indomethacin Prophylaxis in Preterms (TIPP). Methods: Using the TIPP database, we studied 1180 children who survived their first day of birth. Infants were divided into 3 groups according to their PDA status in the NICU: ‘No PDA', ‘Non-surgical PDA', and ‘Surgical PDA'. As in TIPP, the primary outcome was a composite of death or neurosensory impairment at a corrected age of 18 months (cerebral palsy, cognitive delay, deafness, and blindness). Deaths and impairments were also examined separately. Odds ratios and 95% confidence intervals were calculated to estimate the differences in prognostic risk for the ‘No PDA' and the ‘Surgical PDA' groups in comparison with the ‘Non-surgical PDA' group. The analysis was adjusted for gestational age, gender, multiple birth, antenatal steroids, mother's education, and moderate to severe pulmonary hemorrhage. We also examined the relationship between the rate of surgical PDA closure in individual study centres and the 18-month outcome. Results: The results are summarized in the table. There was a significant direct correlation between the rates of surgical PDA closure in individual study centres and the prevalence of neurosensory impairments in survivors (p=0.032). Conclusion: Surgical PDA closure was associated with reduced mortality but increased neurosensory impairment in ELBW infants. It remains uncertain whether PDA ligation is a cause or a marker of adverse long-term outcome in this population.

5 Prevention and 18-Month Outcome of Serious Pulmonary Hemorrhage in Extremely-Low-Birth-Weight (ELBW) Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

5 Prevention and 18-Month Outcome of Serious Pulmonary Hemorrhage in Extremely-Low-Birth-Weight (ELBW) Infants: Results from the Trial of Indomethacin Prophylaxis in Preterms (TIPP)

Impact of Bronchopulmonary Dysplasia, Brain Injury, and Severe Retinopathy on the Outcome of Extremely Low-Birth-Weight Infants at 18 Months: Results From the Trial of Indomethacin Prophylaxis in Preterms

Research on outcomes in extremely low-birth-weight (ELBW) infants has to date failed to demonstrate to what degree neonatal disorders predict long-term outcomes. This cohort study, enrolling 910 infants weighing 500 to 999 g at birth, attempted to learn the prognostic influence of bronchopulmonary dysplasia (BPD), ultrasound signs of brain injury, and severe retinopathy of prematurity (ROP) separately and together. The infants were admitted to 32 neonatal intensive-care units in Canada, the United States, Australia, New Zealand, and Hong Kong from 1996 through 1998. All of them lived to a postmenstrual age of 36 weeks and were followed up prospectively for 18 months. BPD developed in 45% of the cohort, ultrasonographic signs of brain injury in 21%, and severe ROP in 10%. Each of these conditions, but particularly severe ROP, was strongly associated with a poor outcome at 18 months of age. BPD was somewhat less predictive of the long-term outcome than the other morbidities. All 3 conditions appeared to have independent prognostic value, and the odds ratios associated with each of them were of similar magnitude. The risk of a poor long-term outcome (death, cerebral palsy, cognitive delay, severe hearing loss, bilateral blindness) in infants lacking all 3 neonatal morbidities was 18%. The figure was 42% when any one of these morbidities was present, 62% with 2 of them, and 88% when all 3 were present. Nearly the same predictive accuracy was achieved using a model based on a simple morbidity count. This remained the case when considering birth weight, gestational age, race (white or nonwhite), and maternal educational level. This study showed that, in ELBW infants who live to 36 weeks' postmenstrual age, a simple count of 3 common neonatal morbid conditions greatly improves the prediction of death or survival with neurosensory impairment by age 18 months. This should be very helpful in counseling parents and foreseeing specific needs.

Evaluating “old” definitions for the “new” bronchopulmonary dysplasia

Objectives: To examine the accuracy of different criteria for the diagnosis of bronchopulmonary dysplasia (BPD), based on the final age at which oxygen therapy was stopped, in predicting pulmonary and neurologic outcomes at 18-month corrected age. Study design: Data were collected prospectively on infants with birth weights between 500 and 999 g enrolled in the Trial of Indomethacin Prophylaxis in Preterms (TIPP) who survived to discharge home. Differing postnatal ages and postmenstrual ages at which supplemental oxygen therapy was no longer required formed the criteria for defining BPD. Diagnostic accuracy of each criterion for defining BPD was calculated for both poor pulmonary and poor neurosensory outcomes. Results: The prevalence of poor pulmonary outcome was 54% and of poor neurosensory outcome was 34% in the 956 infants who were eligible for this analysis. Accuracy of different definitions of BPD was limited but greatest when using supplemental oxygen requirement at 36 weeks' postmenstrual age to predict long-term pulmonary outcome (63%) and 40 weeks to predict long-term neurosensory outcome (68%). Conclusions: Poor pulmonary outcome and poor neurosensory outcome are common late adverse outcomes in this population. BPD as defined by duration of oxygen therapy is a less accurate surrogate currently than in previous eras. (J Pediatr 2002;140:555-60)