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PubMed2004

The EPIBEL study: outcomes to discharge from hospital for extremely preterm infants in Belgium.

OBJECTIVE: To determine mortality and morbidity at discharge from the hospital of a large population-based cohort of infants who were born at <or=26 weeks' gestation. METHODS: Perinatal data were collected on extremely preterm infants who were alive at the onset of labor and born between January 1, 1999, and December 31, 2000, in all 19 Belgian perinatal centers. RESULTS: A total of 525 infants were recorded. Life-supporting care was provided to 322 liveborn infants, 303 of whom were admitted for intensive care. The overall survival rate of liveborn infants was 54%. Of the infants who were alive at the age of 7 days, 82% survived to discharge. Vaginal delivery, shorter gestation, air leak, longer ventilator dependence, and higher initial oxygen need all were independently associated with death; gender, plurality, and surfactant therapy were not. Among the 175 survivors, 63% had 1 or more of the 3 major adverse outcome variables at the time of discharge (serious neuromorbidity, chronic lung disease at 36 weeks' postmenstrual age, or treated retinopathy of prematurity). The chance of survival free from serious neonatal morbidity at the time of hospital discharge was <15% (21 of 158) for the admitted infants with a gestation <26 weeks. CONCLUSIONS: If for the time being prolongation of pregnancy is unsuccessful, then outcome perspectives should be discussed and treatment options including nonintervention explicitly be made available to parents of infants of <26 weeks' gestation within the limits of medical feasibility and appropriateness.

Belgium↗

PubMed2005

Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis.

OBJECTIVES: Necrotizing enterocolitis (NEC) is a significant complication for the premature infant. However, subsequent neurodevelopmental and growth outcomes of extremely low birth weight (ELBW) infants with NEC have not been well described. We hypothesized that ELBW infants with surgically managed (SurgNEC) are at greater risk for poor neurodevelopmental and growth outcomes than infants with medically managed NEC (MedNEC) compared with infants without a history of NEC (NoNEC). The objective of this study was to compare growth, neurologic, and cognitive outcomes among ELBW survivors of SurgNEC and MedNEC with NoNEC at 18 to 22 months' corrected age. METHODS: Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight <1000 g in the National Institute of Child Health and Human Development Neonatal Research Network Registry. Neurodevelopment and growth were assessed at 18 to 22 months' postmenstrual age. chi2, t test, and logistic regression analyses were used. RESULTS: A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference <10 percentile at 18 to 22 months were significantly more likely among SurgNEC but not MedNEC compared with NoNEC infants. After correction for anthropometric measures at birth and adjusted age at follow-up, all growth parameters at 18 to 22 months for SurgNEC but not MedNEC infants were significantly less than for NoNEC infants. SurgNEC but not MedNEC was a significant independent risk factor for Mental Developmental Index <70 (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.05-2.50), Psychomotor Developmental Index <70 (OR: 1.95; 95% CI: 1.25-3.04), and neurodevelopmental impairment (OR: 1.78; 95% CI: 1.17-2.73) compared with NoNEC. CONCLUSIONS: Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease.

Cerebral Palsy↗

PubMed2004

Growth, efficacy, and safety of feeding an iron-fortified human milk fortifier.

OBJECTIVE: Survival rates for preterm infants who weigh between 501 and 1500 g at birth have continued to improve over time. In response to this continuing decrease in birth weight of surviving preterm infants, Enfamil Human Milk Fortifier has recently been reformulated to meet the nutritional requirements of these smaller, more rapidly growing infants. It now provides an increased protein level of 1.1 g/58 kJ, a decreased carbohydrate level of 0.2 g/58 kJ, and a combined linoleic and alpha-linolenic fatty acid content of 157 mg/58 kJ. As these very small preterm infants have an increased requirement for dietary iron, the fortifier has been supplemented with 1.44 mg/58 kJ of iron, an amount of iron similar to that provided in a typical iron-fortified term infant formula. An iron-fortified product obviates the need for administration of an iron supplement, a hyperosmolar-inducing intervention. The purpose of this prospective, double-blind, randomized, controlled study was to evaluate growth, safety, and efficacy in a population of very low birth weight (VLBW) preterm infants who received human milk fortified with either the reformulated iron-fortified powdered human milk fortifier test product (HMF-T) or a powdered commercially available human milk fortifier control product (HMF-C). METHODS: Infants who weighed < or =1500 g, had a gestational age < or =33 weeks postmenstrual age, and had an enteral intake of at least 100 mL/kg per day of unfortified human milk were stratified by gender and birth weight and randomized to receive HMF-T or HMF-C product from study day 1 to study day 28, hospital discharge, or the termination of human milk feedings, whichever came first. Unless medically indicated, investigators were not to administer iron supplements from study days 1 to 14. Infants were assessed serially for growth; enteral and parenteral intake; serum chemistry and hematologic values; clinical histories, including the administration of blood transfusions; feeding tolerance; respiratory outcomes; and morbidities, including adverse events. RESULTS: Of the 181 participating infants in this study, 96 received HMF-T and 85 received HMF-C. At randomization, there were no significant differences in infant characteristics between the fortifier groups. The percentage of participants who remained in the study for 28 days was similar between fortifier groups (57% HMF-T, 46% HMF-C). For both fortifier groups, the most frequent reasons for discontinuing the study before study day 28 were unavailability of human milk and hospital discharge. Rate of weight gain was similar between the fortifier groups (17.5 +/- 0.53 g/kg per day for HMF-T and 17.3 +/- 0.59 g/kg per day for HMF-C). Mean achieved weight, length, and head circumference were comparable between groups across the 28-day study period. Total protein intake from enteral and parenteral nutrition was significantly greater for the HMF-T fortifier group; however, this difference did not result in any difference in growth between the 2 fortifier groups. An analysis of the growth and energy intake data of a subset of the intent-to-treat population who adhered more strictly to the study feeding protocol yielded results similar to those seen for the intent-to-treat population. There were no clinically significant differences in the results of laboratory studies between the groups at study days 0, 14, and 28. Anemia of prematurity was prevalent in both study groups; by study day 28, median hematocrit levels were 27.0% (interquartile range [IQR]: 24.0%-29.6%) for the HMF-T group and 26.0% (IQR: 24.0%-31.0%) for the HMF-C group. Median ferritin levels were 77.0 ng/mL (IQR: 37-155 ng/ml) for HMF-T and 92.0 ng/mL (IQR: 33-110 ng/mL) for HMF-C. There were no significant differences between the study fortifier groups in regard to the receipt of medically indicated iron supplements on or before study day 14 or in the administration of blood transfusions before study day 0 or from study days 0 through 14. However, from study day 15 to study day 28, fewer HMF-T infants (n = 12) required a blood transfusion than did HMF-C infants (n = 20). Although the higher levels of iron in the HMF-T fortifier (1.44 mg vs 0.35 mg for HMF-C per 4 packets of powdered fortifier) did not prevent anemia per se, it did reduce the frequency of one of the most serious outcomes of anemia: the need for a blood transfusion. There was no statistically significant difference between fortifier groups in regard to feeding tolerance. Rates of suspected sepsis (26% HMF-T vs 31% HMF-C) and confirmed sepsis (5% HMF-T, 7% HMF-C) were low as were the rates of suspected necrotizing enterocolitis (NEC; 6% HMF-T and 5% HMF-C) and confirmed Bell's stage 2 or more NEC (1% HMF-T and 1% HMF-C). There were no statistically significant differences between the study fortifier groups in regard to the incidence of confirmed and suspected sepsis and NEC. CONCLUSION: Both human milk fortifiers studied are safe, are well tolerated, and facilitate comparable good growth; however, using the iron-fortified product may reduce the need for blood transfusions in VLBW infants. The similar low rates of suspected and confirmed NEC and sepsis seen in both fortifier groups in this study refutes the premise that the inclusion of iron in fortifiers will increase the incidence of sepsis and NEC. Indeed, the incidence for NEC and sepsis for both groups in this study was lower than is reported for VLBW infants and similar to that seen for infants who are fed human milk.

Blood Transfusion↗

PubMed2005

Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: the INNOVO multicentre randomised controlled trial (ISRCTN 17821339).

BACKGROUND: Although inhaled nitric oxide (iNO) may be a promising treatment for newborn infants with severe respiratory failure, the results from 3 previous small trials were inconclusive. METHODS: Infants of <34 weeks' gestation, <28 days old, and with severe respiratory failure requiring ventilatory support were randomized to receive or not receive iNO. The study was not blinded. FINDINGS: Recruited were 108 infants (55 allocated to receive iNO and 53 not allocated to receive iNO) from 15 neonatal units in the United Kingdom and Republic of Ireland. Fifty-nine percent (64 of 108) died, and 84% of the survivors (37 of 44) had signs of some impairment or disability, 9 (20%) of them classified as severely disabled. There was no evidence of an effect of iNO on the primary outcomes: death or severe disability at 1 year corrected age (relative risk [RR]: 0.99; 95% confidence interval [CI]: 0.76 to 1.29); death or supplemental oxygen on expected date of delivery (RR: 0.84; 95% CI: 0.68 to 1.02); or death or supplemental oxygen at 36 weeks' postmenstrual age (RR: 0.98; 95% CI: 0.87 to 1.12). There was a trend for infants allocated to the iNO group to spend more time on the ventilator (log rank: 3.6), on supplemental oxygen (log rank: 1.4), and in hospital (log rank: 3.5) than those allocated to receive no iNO. This pattern predominantly reflected the infants who died. Mean total costs at 1 year corrected age were significantly higher in the iNO group, partly because of the costs of the gas but mainly because of the difference in initial hospitalization costs. INTERPRETATION: Evidence of prolongation of intensive care and increased costs of such care, without clear beneficial effects, implies that iNO cannot be recommended for preterm infants with severe hypoxic respiratory failure.

Administration, Inhalation↗

PubMed2005

Prenatal risk factors for severe retinopathy of prematurity among very preterm infants of the Australian and New Zealand Neonatal Network.

OBJECTIVE: To identify prenatal and perinatal risk factors for clinically severe (stage 3 or 4) retinopathy of prematurity (ROP). METHODS: Data were collected prospectively as part of the ongoing Australian and New Zealand Neonatal Network audit of high-risk infants (birth weight of <1500 g or gestational age [GA] of <32 weeks) admitted to a level III neonatal unit in Australia or New Zealand. Prenatal and perinatal factors to 1 minute of age were examined for the subset of infants with GA of <29 weeks who survived to 36 weeks' postmenstrual age and were examined for ROP (n = 2105). The factors significantly associated with stage 3 or 4 ROP were entered into a multivariate logistic regression model. RESULTS: Two-hundred three infants (9.6%) had stage 3 or more ROP. Prematurity was the dominant risk factor, with infants with GA of <25 weeks having 20 times greater odds of severe ROP than infants with GA of 28 weeks. Birth weight for GA also had a "dose-response" effect; the more growth-restricted infants had greater risk, with infants below the 3rd percentile of weight for GA having 4 times greater odds of severe ROP than those between the 25th and 75th percentiles. Male gender was also a significant risk factor (odds ratio: 1.73; 95% confidence interval: 1.25-2.40). CONCLUSIONS: These data, for a large, essentially population-based cohort, suggest that factors related to the degree of immaturity, intrauterine growth restriction, and male gender contribute to severe ROP.

Australia↗

PubMed2005

Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months.

BACKGROUND: A National Institute of Child Health and Human Development Neonatal Research Network randomized trial showed that vitamin A supplementation reduced bronchopulmonary dysplasia (O2 at 36 weeks' postmenstrual age) or death in extremely low birth weight (ELBW) neonates (relative risk [RR]: 0.89). As with postnatal steroids or other interventions, it is important to ensure that there are no longer-term adverse effects that outweigh neonatal benefits. PRIMARY OBJECTIVE: To determine if vitamin A supplementation in ELBW infants during the first month after birth affects survival without neurodevelopmental impairment at a corrected age of 18 to 22 months. DESIGN/METHODS: Infants enrolled in the National Institute of Child Health and Human Development vitamin A trial were evaluated at 18 to 22 months by carefully standardized assessments: Bayley Mental Index (MDI) and Psychomotor Index (PDI), visual and hearing screens, and physical examination for cerebral palsy (CP). The medical history was also obtained. Neurodevelopmental impairment (NDI) was predefined as > or =1 of MDI <70, PDI <70, CP, blind in both eyes, or hearing aids in both ears. RESULTS: Of 807 enrolled infants, 133 died before and 16 died after discharge. Five hundred seventy-nine (88%) of the 658 remaining infants were followed up. The primary outcome of NDI or death could be determined for 687 of 807 randomized infants (85%). Baseline characteristics and predischarge and postdischarge mortality were comparable in both study groups. NDI or death by 18 to 22 months occurred in 190 of 345 (55%) infants in the vitamin A group and in 204 of 342 (60%) of the control group (RR: 0.94; 95% confidence interval: 0.80-1.07). RRs for low MDI, low PDI, and CP were also <1.0. We found no evidence that neonatal vitamin A supplementation reduces hospitalizations or pulmonary problems after discharge. CONCLUSION: Vitamin A supplementation for ELBW infants reduces bronchopulmonary dysplasia without increasing mortality or neurodevelopmental impairment at 18 to 22 months. However, this study was not powered to evaluate small magnitudes of change in long-term outcomes.

Bronchopulmonary Dysplasia↗

PubMed2004

Age terminology during the perinatal period.

Consistent definitions to describe the length of gestation and age in neonates are needed to compare neurodevelopmental, medical, and growth outcomes. The purposes of this policy statement are to review conventional definitions of age during the perinatal period and to recommend use of standard terminology including gestational age, postmenstrual age, chronological age, corrected age, adjusted age, and estimated date of delivery.

Gestational Age↗

PubMed2005

A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory distress syndrome.

BACKGROUND: Available therapeutic surfactants are either animal-derived or non-protein-containing synthetic products. Animal-derived surfactants contain variable amounts of surfactant apoproteins, whereas the older-generation synthetic products contain only phospholipids and lack surfactant proteins (SPs). Both decrease morbidity and mortality rates associated with respiratory distress syndrome (RDS) among preterm infants, compared with placebo. However, excess mortality rates have been observed with non-protein-containing synthetic surfactants, compared with the animal-derived products. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved with the addition of peptides that are functional analogs of SPs. Lucinactant is a new synthetic peptide-containing surfactant that contains sinapultide, a novel, 21-amino acid peptide (leucine and lysine repeating units, KL4 peptide) designed to mimic human SP-B. It is completely devoid of animal-derived components. OBJECTIVE: We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority. METHODS: A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial. RESULTS: The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: -7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, -7.3%, being greater than the prespecified noninferiority margin of -14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1-46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8-41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0-17.6%] vs 16.1% [95% CI: 9.7-22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%). CONCLUSIONS: Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.

Biological Products↗

PubMed2005

Oxygen delivery through nasal cannulae to preterm infants: can practice be improved?

OBJECTIVE: Oxygen delivery through nasal cannulae to convalescent preterm infants is a common but largely unstudied practice. To learn more about current nasal cannula oxygen delivery practices, we examined the variations in oxygen delivery through nasal cannulae among the centers of the Neonatal Research Network, the frequency of prescription of low levels of oxygen, and the success of weaning to room air. We hypothesized that some infants treated with oxygen through nasal cannulae were receiving oxygen levels equivalent to those of room air. METHODS: This was a descriptive, nested, cohort study of nasal cannula oxygen prescription among 187 infants with birth weights of <1250 g. All infants were studied at a postmenstrual age of 36 weeks, with a timed oxygen reduction challenge to establish their ability to be weaned to room air. The results of this challenge were compared with the fraction of inspired oxygen (FIO2) delivered, calculated as effective FIO2. Infants who maintained oxygen saturation values of > or =90% during oxygen weaning and during a 30-minute period in room air were defined as passing the challenge. RESULTS: Fifty-two infants (27.8%) were receiving oxygen concentrations and flow rates through nasal cannulae that delivered an effective FIO2 of <0.23, of whom 16 were receiving oxygen concentrations and flow rates that delivered an effective FIO2 of 0.21. In addition, 22 infants (11.8%) were prescribed room air through nasal cannulae intentionally. Seventy-two percent of those prescribed an effective FIO2 of <0.23 passed the room air challenge. CONCLUSIONS: Prescription of oxygen with combinations of flow rates and oxygen concentrations that delivered a low effective FIO2 was common. We speculate that some of this, including the inadvertent prescription of an effective FIO2 equivalent to that of room air, is related to lack of knowledge of the effective FIO2. Routine calculation of effective FIO2 values may prompt earlier trials of room air and thus reduce unnecessary days of oxygen therapy.

Humans↗

PubMed2005

Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.

OBJECTIVE: A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants <32 weeks' gestational age (GA). Mild BPD was defined as a need for supplemental oxygen (O2) for > or =28 days but not at 36 weeks' postmenstrual age (PMA) or discharge, moderate BPD as O2 for > or =28 days plus treatment with <30% O2 at 36 weeks' PMA, and severe BPD as O2 for > or =28 days plus > or =30% O2 and/or positive pressure at 36 weeks' PMA. The objective of this study was to determine the predictive validity of the severity-based, consensus definition of BPD. METHODS: Data from 4866 infants (birth weight < or =1000 g, GA <32 weeks, alive at 36 weeks' PMA) who were entered into the National Institute of Child Health and Human Development Neonatal Research Network Very Low Birth weight (VLBW) Infant Registry between January 1, 1995 and December 31, 1999, were linked to data from the Network Extremely Low Birth Weight (ELBW) Follow-up Program, in which surviving ELBW infants have a neurodevelopmental and health assessment at 18 to 22 months' corrected age. Linked VLBW Registry and Follow-up data were available for 3848 (79%) infants. Selected follow-up outcomes (use of pulmonary medications, rehospitalization for pulmonary causes, receipt of respiratory syncytial virus prophylaxis, and neurodevelopmental abnormalities) were compared among infants who were identified with BPD defined as O2 for 28 days (28 days definition), as O2 at 36 weeks' PMA (36 weeks' definition), and with the consensus definition of BPD. RESULTS: A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months' corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. CONCLUSION: The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions.

Bronchopulmonary Dysplasia↗

PubMed2006

Prolonged indomethacin exposure is associated with decreased white matter injury detected with magnetic resonance imaging in premature newborns at 24 to 28 weeks' gestation at birth.

OBJECTIVES: Newborns delivered before 28 weeks' gestation commonly have white matter lesions on MRI that are associated with adverse neurodevelopmental outcomes. Our objective was to determine the risk factors for MRI-detectable white matter injury in infants delivered before 28 weeks' gestation who were treated with prophylactic indomethacin. METHODS: This was a prospective cohort study conducted at the intensive care nursery at University of California San Francisco Children's Hospital. Patients included 57 premature newborns between 24 and 27 (+6 days) weeks' gestation at birth (October 1998 to October 2004). We identified perinatal and neonatal risk factors associated with moderate-severe "white matter injuries" (T1 signal abnormalities >2 mm or >3 areas of T1 abnormality) and moderate-severe "brain abnormality" (moderate-severe white matter injuries, any degree of ventriculomegaly, or severe intraventricular hemorrhage) on MRI. Infants were studied with MRI at 31.1 weeks' postmenstrual age (median). RESULTS: Moderate-severe white matter injuries were detected in 12 (21%) of 53 preterm newborns, and 20 (35%) of 57 had moderate-severe brain abnormality. Prolonged indomethacin exposure was the only risk factor independently associated with a lower risk of white matter injury or brain abnormality, even when adjusting for the presence of a hemodynamically significant PDA, gestational age at birth, prenatal betamethasone, systemic infection, and days of mechanical ventilation. CONCLUSIONS: In this observational study, a longer duration of indomethacin exposure was associated with less white matter injury in infants delivered before 28 weeks' gestation. A randomized trial of prolonged indomethacin treatment is needed to determine whether indomethacin can decrease white matter injury and neurodevelopmental abnormalities.

Brain↗

PubMed2006

Randomized, controlled trial comparing synchronized intermittent mandatory ventilation and synchronized intermittent mandatory ventilation plus pressure support in preterm infants.

BACKGROUND: Prolonged mechanical ventilation is associated with lung injury in preterm infants. In these infants, weaning from synchronized intermittent mandatory ventilation may be delayed by their inability to cope with increased respiratory loads. The addition of pressure support to synchronized intermittent mandatory ventilation can offset these loads and may facilitate weaning. OBJECTIVE: The purpose of this work was to compare synchronized intermittent mandatory ventilation and synchronized intermittent mandatory ventilation plus pressure support in weaning from mechanical ventilation and the duration of supplemental oxygen dependency in preterm infants with respiratory failure. METHODS: Preterm infants weighing 500 to 1000 g at birth who required mechanical ventilation during the first postnatal week were randomly assigned to synchronized intermittent mandatory ventilation or synchronized intermittent mandatory ventilation plus pressure support. In both groups, weaning followed a set protocol during the first 28 days. Outcomes were assessed during the first 28 days and until discharge or death. RESULTS: There were 107 infants enrolled (53 synchronized intermittent mandatory ventilation plus pressure support and 54 synchronized intermittent mandatory ventilation). Demographic and perinatal data, mortality, and morbidity did not differ between groups. During the first 28 days, infants in the synchronized intermittent mandatory ventilation plus pressure support group reached minimal ventilator settings and were extubated earlier than infants in the synchronized intermittent mandatory ventilation group. Total duration of mechanical ventilation, duration of oxygen dependency, and oxygen need at 36 weeks' postmenstrual age alone or combined with death did not differ between groups. However, infants in synchronized intermittent mandatory ventilation plus pressure support within the 700- to 1000-g birth weight strata had a shorter oxygen dependency. CONCLUSIONS: The results of this study suggest that the addition of pressure support as a supplement to synchronized intermittent mandatory ventilation during the first 28 days may play a role in reducing the duration of mechanical ventilation in extremely low birth-weight infants, and it may lead to a reduced oxygen dependency in the 700- to 1000-g birth weight strata.

Female↗

PubMed2006

Twenty-four-hour esophageal impedance-pH monitoring in healthy preterm neonates: rate and characteristics of acid, weakly acidic, and weakly alkaline gastroesophageal reflux.

OBJECTIVE: Gastroesophageal reflux is a physiologic process and is considered pathologic (gastroesophageal reflux disease) when it causes symptoms or results in complications. It is common in preterm infants and occurs in healthy neonates. Twenty-four-hour pH monitoring commonly is used in children for diagnosis of gastroesophageal reflux disease, and abnormal reflux is considered with detection of increased esophageal acid exposure. However, in neonates, relatively few gastroesophageal reflux episodes cause esophageal acidification to pH < 4. Premature infants receive frequent feeds, which can induce a weaker acid secretory response than that observed in older infants and adults. As a consequence, gastric pH may be > 4 for prolonged periods, and reflux of gastric contents might be less acidic or even alkaline. Esophageal impedance monitoring can detect weakly acidic and even alkaline gastroesophageal reflux. The role of weakly acidic reflux in the pathophysiology of gastroesophageal reflux disease in preterm infants is not clear. To date, studies that have used impedance-pH in neonates assessed the association between nonacid reflux and cardiorespiratory symptoms, but no impedance data from healthy preterm neonates have been available to determine whether those symptomatic neonates had an increased number of weakly acidic reflux episodes or increased reactivity to a physiologic number of reflux events. Our aim with this study was to provide impedance-pH values for acid, weakly acidic, and weakly alkaline reflux from healthy preterm neonates. METHODS: Esophageal impedance was recorded for 24 hours in 21 asymptomatic preterm neonates by replacing the conventional feeding tube with a specially designed feeding tube that included 9 impedance electrodes (8 French). All neonates were asymptomatic, with spontaneous breathing. Reflux monitoring was performed after comprehensive explanation and on receipt of written parental consent. Esophageal and gastric pH were monitored using a separate parallel pediatric catheter (6 French). According to the corresponding pH change, impedance-detected reflux was classified as acid, weakly acidic, and weakly alkaline. For each infant, the total number of reflux events, the acid exposure and bolus exposure times at 2 cm above the respiratory inversion point, and average proximal extent of reflux were calculated. RESULTS: Twenty-six preterm neonates were recruited into this study. A preliminary analysis was performed, and tracings were classified according to their quality and the presence of technical artifacts (spontaneous pH and impedance drifts, esophageal probe migration, and dysfunction of 1 or more impedance channels). Five studies were excluded because of 1 or more technical artifacts; a total of 21 neonates represent the final cohort included. At birth, the infants had a median postmenstrual age of 32 weeks, and the measurements were performed at a median age of 12 days. The total recording time was 23.7 +/- 2 hours. Gastric pH was higher than 4 during 69.3 +/- 20.4% of the recording time. The median number of reflux events in 24 hours was 71, 25.4% (range: 0%-53.1%) of which were acid, 72.9% (range: 45.3%-98.0%) were weakly acidic, and 0% (range: 0%-8.1%) were weakly alkaline. Compared with fasting periods, feeding periods tended to be associated with a higher number of total reflux events per hour. The acidity of reflux, however, was significantly different: during fasting, the number of acid reflux episodes per hour was higher, whereas during feeding, the number of weakly acidic reflux episodes was increased. Most reflux events were only liquid, whereas gas was present either mixed with liquid or pure only in 7.7% of all reflux episodes detected. The proximal esophageal segments were reached in 90% of reflux episodes. Reflux-related acid exposure (pH drops associated with impedance-detected reflux) was 1.66% (range: 0%-6.43%), whereas total acid exposure (associated and not associated with reflux detected by impedance) was 5.59% (range: 0.04%-20.69%). There was no relationship between the number or acidity of reflux events and anthropometric parameters such as weight and gestational age. CONCLUSIONS: We present the first study using 24-hour impedance-pH recordings in asymptomatic premature neonates. Previous studies that used pH-metry suggested that neonatal cardiorespiratory symptoms could be related to acid gastroesophageal reflux. However, pH-metry could not detect accurately weakly acidic or nonacid reflux. Our healthy premature neonates had approximately 70 reflux events in 24 hours, 25% of which were acid, 73% were weakly acidic, and 2% were weakly alkaline. The number of reflux events per hour (2-3 per hour) was slightly lower than that described in premature neonates with cardiorespiratory events (4 per hour). We confirmed that weakly acidic reflux is more prevalent than acid reflux, particularly so during the feeding periods. In contrast, similar to healthy adults, weakly alkaline reflux was very rare. We confirmed findings from previous studies in which most reflux events were pure liquid during both fasting and during postprandial periods and gas reflux was very rare. As in neonates with cardiorespiratory symptoms, the majority of reflux events in asymptomatic preterms reached the proximal esophagus or pharynx, and there were no differences between acid and weakly acidic reflux. The lack of differences between asymptomatic and diseased infants contravenes the hypothesis for macro- or microaspiration but does not exclude hypersensitivity to reflux as a cause for respiratory symptoms. The acid exposure that was related to reflux events and detected by impedance was significantly lower than the total acid exposure during 24 hours. Increased acid exposure could be attributable to pH-only reflux events or, less frequently, to slow drifts of pH from baselines at approximately 5 to values < 4. These changes were not accompanied by a typical impedance pattern of reflux but by slow drifts in impedance in 1 or 2 channels. Our findings confirm the need for the use of impedance together with pH-metry for diagnosis of all gastroesophageal reflux events. The relationship between gastroesophageal reflux and cardiorespiratory events in neonates and older infants has been studied extensively. The current evidence for such a relationship is controversial. This study provides values of impedance-pH monitoring for acid, weakly acidic, and weakly alkaline reflux from healthy preterm neonates that can be used for comparison when evaluating gastroesophageal reflux in preterm infants with a cardiorespiratory disease.

Buffers↗

PubMed2006

Erythropoietin concentrations and neurodevelopmental outcome in preterm infants.

OBJECTIVE: Erythropoietin therapy is effective in decreasing transfusions to varying degrees in preterm infants. Recent animal studies using erythropoietin doses to achieve serum concentrations > 1000 mU/mL report neuroprotective effects. We evaluated the relationship between erythropoietin concentrations and neurodevelopmental outcome in extremely low birth weight infants. METHODS: Preterm infants who weighed < or = 1000 g at birth were randomly assigned to erythropoietin (400 U/kg 3 times per week) or placebo/control. Therapy was initiated by 4 days after birth and continued through the 35th postmenstrual week. All infants received supplemental parenteral and enteral iron. Peak serum erythropoietin concentrations were obtained every 2 weeks. Follow-up evaluation included anthropometric measurements, Bayley scales of mental and psychomotor development, neurologic examination, and determination of overall neurodevelopmental impairment. Data were collected at 18 to 22 months' corrected age by certified examiners who were masked to the treatment group. Analyses were performed to identify correlations between erythropoietin concentrations and outcomes. RESULTS: Sixteen extremely low birth weight infants were enrolled; 1 infant died at 2 weeks (placebo/control), and 15 had erythropoietin concentrations measured (7 erythropoietin, 8 placebo/control). Peak erythropoietin concentrations were significantly different between groups during the study (erythropoietin: 2027 +/- 1464 mU/mL; placebo/control: 26 +/- 11 mU/mL). Before follow-up, 3 infants died (1 erythropoietin, 2 placebo/control), and 12 were available for follow-up (6 erythropoietin, 6 placebo/control). At 18 to 22 months' follow-up, none of the erythropoietin recipients and 2 of the placebo/control infants had Mental Development Index scores < 70. Erythropoietin recipients had Mental Development Index scores of 96 +/- 11, and placebo/control infants had Mental Development Index scores of 78 +/- 7. Psychomotor Development Index scores were similar between groups (87 +/- 13 vs 80 +/- 7). There were no differences between groups with respect to anthropometric measurements. Two of 6 infants in the erythropoietin group and 4 of 6 infants in the placebo/control group had some form of neurodevelopmental impairment. Posthoc analysis showed that infants with erythropoietin concentrations > or = 500 mU/mL had higher Mental Development Index scores than infants with erythropoietin concentrations < 500 mU/mL. CONCLUSIONS: Erythropoietin concentrations did not correlate with Psychomotor Development Index or overall incidence of neurodevelopmental impairment; however, infants with elevated erythropoietin concentrations had higher Mental Development Index scores than those with lower erythropoietin concentrations. Close follow-up of infants who are enrolled in large, multicenter, high-dose erythropoietin studies is required to determine whether a correlation exists between elevated erythropoietin concentrations and improved neurodevelopmental outcome.

Blood Transfusion↗

PubMed2006

Changes in the use of postnatal steroids for bronchopulmonary dysplasia in 3 large neonatal networks.

BACKGROUND: Postnatal corticosteroids were widely used in the 1990s in an attempt to reduce the incidence of bronchopulmonary dysplasia. However, high rates of short-term adverse effects and impaired neurodevelopmental outcomes were seen. In early 2002, a joint statement of the American Academy of Pediatrics and Canadian Paediatric Society called for limitation in the use of postnatal corticosteroids. The impact of this statement is not known. OBJECTIVES: The purpose of this work was to determine the frequency of postnatal corticosteroid use and mortality and morbidities over time, particularly before and after the joint statement. DESIGN/METHODS: We conducted a retrospective analysis of cohort data within 3 large network registries (the National Institute of Child Health and Development Neonatal Research Network [18 centers], the Vermont Oxford Network [444 centers], and the Canadian Neonatal Network [10 centers]) for the following 3 periods: prestatement (2001), statement (2002), and poststatement (2003) of very low birth-weight infants (501-1500 g). The National Institute of Child Health and Development Neonatal Research Network and the Vermont Oxford Network were also analyzed for longer-term trends from 1990 to 2003. Postnatal corticosteroid use, mortality at discharge, and neonatal morbidities (bronchopulmonary dysplasia at 36 weeks, late-onset infection >72 hours of age, necrotizing enterocolitis treated with surgery, and length of stay) between periods were compared. RESULTS: Mean birth weight (range: 1022-1060 g), postmenstrual age (28 weeks), and gender (51% male) were similar between the networks. Race differed with more black infants in the National Institute of Child Health and Development Neonatal Research Network than the Vermont Oxford Network (38% vs 24%). Antenatal steroid use was similar (range: 61%-75%). Postnatal corticosteroid use rose from 1990 (8%-16%), peaked in 1996-1998 (24%-28%), and began to decline in 1999. Use in 2003 was significantly less than in 2001. Mortality and major morbidities were similar. CONCLUSIONS: Postnatal corticosteroid use had decreased significantly in 3 large neonatal networks before the joint statement with further decreases after the statement with no apparent impact on mortality and short-term morbidity. Despite substantial decreases, approximately 8% of very low birth-weight infants continue to be treated with postnatal corticosteroid.

Adrenal Cortex Hormones↗

PubMed2006

Genetic susceptibility to retinopathy of prematurity.

OBJECTIVES: The goals were to isolate and to estimate the genetic susceptibility to retinopathy of prematurity. METHODS: A retrospective study (1994-2004) from 3 centers was performed with zygosity data for premature twins who were born at a gestational age of < or = 32 weeks and survived beyond a postmenstrual age of 36 weeks. Retinopathy of prematurity was diagnosed and staged by pediatric ophthalmologists at each center. Data analyses were performed with mixed-effects logistic regression analysis and latent variable probit modeling. RESULTS: A total of 63 monozygotic and 137 dizygotic twin pairs were identified and analyzed. Data on gestational age, birth weight, gender, respiratory distress syndrome, retinopathy of prematurity, bronchopulmonary dysplasia, duration of ventilation and supplemental oxygen use, and length of stay were comparable between monozygotic and dizygotic twins. In the mixed-effects logistic regression analysis for retinopathy of prematurity, gestational age and duration of supplemental oxygen use were significant covariates. After controlling for known and unknown nongenetic factors, genetic factors accounted for 70.1% of the variance in liability for retinopathy of prematurity. CONCLUSION: In addition to prematurity and environmental factors, there is a strong genetic predisposition to retinopathy of prematurity.

Female↗

PubMed1996

Vomeronasal organ growth and development in normal and cleft lip and palate human fetuses.

As part of an ongoing investigation of normal and cleft lip and palate (CLP) fetal midfacial development, the vomeronasal organ (VNO) was examined in 35 human fetuses (26 normal and 9 CLP) ranging in age from 8 to 30 weeks postmenstrual age. All specimens were examined histologically, and a computer reconstruction technique was used to quantify lengths and volumes of right and left VNOs and anterior paraseptal cartilages (PCs). Growth curves were generated for these data and were compared between normal and cleft samples. VNOs and PCs were present in all normal fetuses, whereas VNOs were found in only 5 of 9 CLP specimens and PCs were found in 8 CLP specimens. The side of the palatal cleft in specimens with unilateral CLP was associated with PC dysmorphologies but appeared to have no influence on VNO presence or absence. Septal dysmorphologies were observed in most CLP specimens with absent or abnormal VNOs. VNO length increased in a linear fashion across ages, and VNO volume was seen to change in a logarithmic fashion. Individual CLP specimens did not differ significantly from the mean of the normal sample for VNO length or volume. PC length was seen to change in a sigmoidal fashion, and PC volume changes were best described by a logarithmic curve. In contrast to findings on the VNO, CLP specimens exhibited significantly different growth rates (line slopes) for PC length and volume compared to the normal sample. Results on the normal sample suggested that the human fetal VNO exhibits volumetric increases between the 16th and 30th weeks of development, but this increase begins later and proceeds more slowly than that of the PCs. Examination of the CLP sample suggested that the VNOs were of "normal" size for age, but may be vulnerable to septal dysmorphologies that result in altered location or disruption.

Case-Control Studies↗

PubMed2000

Quantitative comparison of intrabrain diffusion in adults and preterm and term neonates and infants.

OBJECTIVE: Quantitative measurements of mean water diffusivity (D(av)) were made in human neonates, infants, and adults to assess changes in brain tissue that occur with maturation. SUBJECTS AND METHODS: Values of D(av) were obtained by calculating the average of the diffusion measurements made with diffusion-sensitizing gradients placed along three orthogonal directions. The mean diffusivity, a rotationally invariant determination of apparent diffusion coefficient, was measured in five healthy prematurely born neonates and infants, in 10 healthy term neonates and infants, and in five adults. RESULTS: Values of D(av) were found to decrease with maturation in most parts of the brain. In prematurely born neonates and infants with a postmenstrual age (postgestastional age + postnatal age) under 36 weeks, the average value of D(av) in frontal white matter was 1.90 x 10(-3) mm2 sec(-1). The corresponding value was measured as 1.62 x 10(-3) mm2 sec(-1) in neonates and infants born at term with a postnatal age of no more than 43 days and 0.79 x 10(-3) mm2 sec(-1) in the adult brain. CONCLUSION: Values of D(av) are known to decrease in neonates and young infants in the period immediately after ischemic insult. This decrease and the associated increase in signal intensity seen on diffusion-weighted imaging have been used to monitor ischemic brain injury in neonates and infants. Therefore, the decrease in D(av) that occurs with maturation, which we report in this study, must be considered if quantitative diffusion measurements are used to assess ischemic neonatal brain injury.

Adult↗