Epidemiology of Neonatal Chronic Lung Disease in Japan

A nationwide survey on the epidemiology of chronic lung disease (CLD) of the newborn was conducted. Questionnaires were sent to 391 level II and III neonatal centers in Japan and the registration of infants born in 1990 with chronic lung disease was requested. CLD was defined as an oxygen requirement greater than that obtainable in room air at 28 days after birth, with symptoms of persistent respiratory distress and a hazy or emphysematous and fibrous appearance on chest X-ray. A total of 301 neonatal centers (77.0%) responded and 50,290 infants at these centers were registered. Of these, 97% survived the first month and 1,135 of 48,762 neonatal survivors developed CLD. The mortality of infants with CLD was 6.2%. Survival rates at 28 days of age increased consistently with birthweight. Survival at 28 days of age in infants below 1,000 g at birth was 73.7%, but the rate was 93.9% in infants weighing 1,000–1,499 g. The incidence of CLD was inversely proportional to birthweight. Approximately one quarter of neonatal survivors with a birthweight below 1,500 g and approximately half of extremely small infants (<1,000 g) developed CLD. The analysis of CLD infants showed that 28.2% of them had a history of respiratory distress syndrome (RDS) and a typical fibrous appearance on chest X-ray (Type I), while 29.3% also had a history of RDS but had an atypical X-ray appearance (Type II). Approximately 13% of CLD infants showed evidence of intra-uterine infection and typical X-ray findings (Type III), 11.8% showed a typical X-ray appearance but no preceding diseases (Type IV), and another 11.5% showed atypical chest X-ray appearance and no preceding diseases (Type V). Only 5.8% of CLD infants could not be classified into any of these five types, and were grouped as Type VI. Ninety-two per cent of CLD infants were discharged, 6.2% died in hospital and 1.8% were still in hospital at the time of the survey.     

The Danish national study in infants with extremely low gestational age and birthweight (the ETFOL study): respiratory morbidity and outcome

AIM: To describe and analyse neonatal care, short and long-term morbidity with special reference to ventilatory support and chronic lung disease (CLD) in a population-based study. METHODS: During 1994 and 1995 a prospective, nation-wide, multicentre study was conducted, comprising 477 liveborn infants with gestational age (GA) < 28 wk and/or birthweight < 1000 g. Of these, 407 infants received active treatment. The ventilatory treatment was based on the principle of permissive hypercapnia and early nasal continuous positive airway pressure (NCPAP) supplemented with surfactant and ventilator therapy in case of CPAP failure. RESULTS: Among actively treated infants 85% received CPAP and 23% mechanical ventilation from the first day of life. A total of 269 infants (56%) survived to discharge. Of these, 195 had a GA < 28 wk. One-hundred and five survivors with GA < 28 wk survived with NCPAP as sole respiratory support. In surviving infants, periventricular leucomalacia/intraventricular haemorrhage grade 3-4 was found in 10%, retinopathy of prematurity grade > 2 in 4%, and oxygen requirement at 36 and 40 wk of postmenstrual age (CLD) in 16 and 5%, respectively. Three infants either died of CLD (n = 1) or required oxygen therapy beyond 43 wk of postmenstrual age. Logistic regression analysis showed significant associations between oxygen requirement at 40 wk and GA, septicaemia, mechanical ventilation, symptomatic patent ductus arteriosus and Clinical Risk Index for Babies score. Only the two last-mentioned factors proved significant in infants with GA < 28 wk. No infant died after discharge and 253 (94%) were followed up at 2 y of corrected age; one or more moderate to severe impairments were found in 66 (26%) of the examined children. CONCLUSION: Ventilatory treatment in extremely premature and extremely low-birthweight infants based on early NCPAP and permissive hypercapnia may result in comparable survival rates and sensorineural outcome; however, the incidence of CLD seems lower than that reported on conventional treatment.     

Looking back in time: outcome of a national cohort of very preterm infants born in The Netherlands in 1983

In 1983, Dutch pediatricians collaborated on a national level and collected perinatal data on 1338 liveborn infants with a gestational age <32 weeks and/or a birthweight <1500 g (project on preterm and small for gestational age infants, POPS). Their outcome was assessed at 2 years of age by their pediatricians, at 5 years by a team of investigators, and at 9-14 years by questionnaires completed by parents, teachers, and children themselves. The overall picture that emerges from this 14-year follow-up is that a low percentage of these very preterm infants (10%) has a severe disability or handicap at school age. Although 90% of the children are without severe disabilities at school age, many of them meet serious difficulties in everyday life and the burden of mild developmental abnormalities, behavioral and learning disorders increases with age. In adolescents, it is likely that as many as 40% of the survivors will not be able to become fully independent adults. Abnormalities found during early, standardized clinical neurological examination are highly predictive for these later problems.     

Perinatal factors and the development of chronic lung disease in preterm infants: a case control study

A case control study of neonates was performed to determine those factors contributing to the development of chronic lung disease (CLD). During the 5 years 1981-84 there were 487 neonatal survivors at gestations of 25-32 weeks; 391 of these developed respiratory failure (oxygen therapy required for more than 6 h). Fifty-six of the latter developed CLD (oxygen therapy required for more than 28 days and a coarse reticular pattern on chest X-ray). These neonates were predominantly of the shortest gestational ages, regardless of the initial chest X-ray diagnosis. Forty-three of these infants with CLD were matched for gestation and initial chest X-ray appearance (respiratory distress syndrome, n = 20; normal, n = 15; non-specific, n = 8) with 42 control infants. The mean duration of oxygen therapy (P less than 0.001), maximum FiO2 (P less than 0.001), incidence (P less than 0.01) and duration of intermittent positive pressure respiration (IPPR; P less than 0.05) and peak IPPR (P less than 0.05) were significantly greater in the CLD group. Mean birthweight (P less than 0.001), arterial cord pH (P less than 0.05) and base excess (P less than 0.05) were significantly lower in the CLD group. Factors that were not statistically significant in the development of CLD included antenatal fetal heart rate abnormality, hypertensive disease of pregnancy, acute intrauterine infection (chorioamnionitis or umbilical vasculitis), administration of antenatal steroids, sex, patent ductus arteriosus and pneumothorax. The association between CLD and ventilator/oxygen therapy is confirmed. Contrary to other reports, male sex, clinical patent ductus arteriosus and pneumothorax were not associated with CLD.     

Costs and outcomes in a regional neonatal intensive care unit.

At the Birmingham Maternity Hospital the mean cost of caring for surviving infants who require neonatal intensive care ranges from approximately pounds 2500 (for infants above 1500 g birthweight), to pounds 5500 (for infants 1000 to 1499 g birthweight), to pounds 10 000 (for infants less than 1000 g birthweight). The mean cost of caring for non-survivors is pounds 1000 or less, with little difference between the birthweight groups. These figures are based on the lengths of stay in three treatment regimens-intensive care, high dependency care, and special care-the average daily costs of which are estimated to be pounds 235, pounds 122, and pounds 43 respectively. The survival of very low birthweight infants (less than 1500 g) at this hospital has improved from 42% to 73% since the introduction of regional funding for neonatal intensive care. This increase in survival has been brought about without undue disability in the survivors.     

Outcome of intrauterine periventricular haemorrhage and leukomalacia

This case study reports five very low birthweight infants with ultrasound evidence of intrauterine insult to the brain. Intrauterine periventricular haemorrhage (PVH) accompanied by ventricular dilatation occurred in two preterm infants both of whom survived and were severely handicapped at follow-up. Three preterm infants had intrauterine periventricular leukomalacia (PVL); one survived and is severely handicapped at one year of age. Our experience and rare case reports in the literature indicate that intrauterine PVH and PVL carry a high risk of death in the neonatal period and severe neurological sequelae in survivors.     

Outcome of intrauterine periventricular haemorrhage and leukomalacia

This case study reports five very low birthweight infants with ultrasound evidence of intrauterine insult to the brain. Intrauterine periventricular haemorrhage (PVH) accompanied by ventricular dilation occurred in two preterm infants both of whom survived and were severely handicapped at follow-up. Three preterm infants had intrauterine periventricular leukomalacia (PVL); one survived and is severely handicapped at one year of age. Our experience and rare case reports in the literature indicate that intrauterine PVH and PVL carry a high risk of death in neonatal period and severe neurological sequelae in survivors.     

Cytokine imbalance in infants receiving extracorporeal membrane oxygenation for respiratory failure

BACKGROUND: It is likely that the imbalance between the pro- and anti-inflammatory cytokines will determine the outcome in infants with severe respiratory failure receiving extracorporeal membrane oxygenation (ECMO). AIMS: We determined if there was an imbalance between pro- and anti-inflammatory cytokines in serial bronchoalveolar lavage (BAL) fluid obtained from survivors and non-survivors of ECMO. METHODS: We therefore measured the cellular changes and the molar ratios of pro-inflammatory and anti-inflammatory cytokines in serial BAL fluid obtained from survivors and non-survivors of ECMO. Fifteen infants surviving ECMO (median age 1 day, range 1-120) and 7 who did not (28 days, range 1-402) were studied. RESULTS: In the lungs of survivors, the increased proportion of airway neutrophils at presentation decreased with time and was matched by a parallel increase in percent alveolar macrophages as the infants' condition improved. The pro- and anti-inflammatory pulmonary cytokine ratios were static in the survivors. In the non-survivors, the ratio of tumour necrosis factor-alpha (TNF-alpha) against soluble TNF-receptor 1 (sTNF-R1) and soluble TNF receptor 2 (sTNF-R2) was increased at days 2-3 when compared to the survivors, but the molar ratio interleukin-1beta (IL-1beta)/soluble IL-1 receptor antagonist (sIL-1RA) was largely undetectable due to undetectable IL-1beta. CONCLUSIONS: These data suggest that the infants who survive ECMO resolve their pulmonary inflammation and that in non-survivors the ratio of TNF-alpha against its receptor antagonists is increased and is associated with a poor outcome. Furthermore, this group of infants were unable to produce significant concentrations of IL-1beta.     

Hospital admissions in the first year of life in very preterm infants

OBJECTIVE: To analyse hospital readmissions to 1 year in infants < 33 weeks' gestation. STUDY DESIGN: Cohort of very preterm infants born in Western Australia. METHODS: Parental social class, history of asthma, race, gestational age, birthweight, sex, severity of respiratory disease and oxygen requirement at 28 days chronic lung disease (CLD), 36 weeks and term, maternal smoking, cohabitation with siblings, breast-feeding duration and hospital readmissions were recorded prospectively. RESULTS: Data were available for 538 of 560 (96%) infants discharged. Eight died in the first year. Two hundred and twenty-five infants (42%) had 443 readmissions, of which 370 were medical and 73 surgical. Risk factors for medical readmission were Aboriginal race, male sex and CLD. Breast-feeding was protective. Risk factors for surgical admission were male sex, lower gestation, severe hyaline membrane disease, severe CLD and birthweight < 10th centile. CONCLUSIONS: Readmission is common after very preterm birth. Risk factors for medical and surgical admission differ with CLD being the only perinatal factor associated with both medical and surgical admission.     

Randomised controlled trial of patient triggered and conventional fast rate ventilation in neonatal respiratory distress syndrome

AIM: To compare patient triggered, with conventional fast rate, ventilation in a randomised controlled trial using the incidence of chronic lung disease as the primary outcome measure. METHODS: Three hundred and eighty six preterm infants with birthweights from 1000 to 2000 g, and requiring ventilation for respiratory distress syndrome within 24 hours of birth, were randomised to receive either conventional or trigger ventilation with the SLE 2000 ventilator. RESULTS: There were no significant differences in the incidence of chronic lung disease (28 day and 36 week definitions), death, pneumothorax, intraventricular haemorrhage, number of ventilator days, or length of oxygen dependency between groups. CONCLUSIONS: Patient triggered ventilation in preterm infants with respiratory distress syndrome is feasible. No significant differences, when compared with conventional fast rate ventilation in important medium and longer term outcome measures, were evident.     

Randomised controlled trial of postnatal sodium supplementation on oxygen dependency and body weight in 25-30 week gestational age infants

AIM: To compare the effects of early against delayed sodium supplementation on oxygen dependency and body weight, in preterm infants of 25-30 weeks of gestational age. METHODS: Infants were stratified by gender and gestation and randomly assigned to receive a sodium intake of 4 mmol/kg/day starting on either the second day after birth or when weight loss of 6% of birthweight was achieved. Daily sodium intake, serum sodium concentration, total fluid intake, energy intake, clinical risk index for babies (CRIB) score and duration of ventilatory support and additional oxygen therapy were recorded. Infants were weighed daily. Weights at 36 weeks and six months of postmenstrual age were also recorded. RESULTS: Twenty four infants received early, and 22 delayed, sodium supplementation. There were no significant differences in total fluid and energy intake between the two groups. There was a significant difference in oxygen requirement at the end of the first week, with 9% of the early group in air in contrast to 35% of the delayed group (difference 26%, 95% confidence interval 2, 50). At 28 days after birth the proportions were 18% of the early group and 40% of the delayed group (difference 22%, 95% CI -5, 49). Proportional hazards modelling showed early sodium supplementation and lower birthweight to be significantly associated with increased risk of continuing oxygen requirement. The delayed sodium group had a greater maximum weight loss (delayed 16.1%; early 11.4%, p=0.02), but there were no significant differences in time to maximum weight loss, time to regain birthweight, and weight at 36 weeks and 6 months of postmenstrual age. CONCLUSION: In infants below 30 weeks of gestation, delaying sodium supplementation until at least 6% of birthweight is lost has a beneficial effect on the risk of continuing oxygen requirement and does not compromise growth.     

Neurodevelopmental sequelae of intraventricular haemorrhage at 8 years of age in a regional cohort of ELBW/very preterm infants

BACKGROUND: Major grades of intraventricular haemorrhage (IVH) are associated with adverse neurodevelopmental sequelae in early childhood but the extent of problems in specific cognitive areas, such as executive function, and the contribution of lesser grades of IVH to neurodevelopmental problems at school age are not well described. AIMS: To determine the neuromotor, cognitive and educational outcome of extremely low birthweight (ELBW, birthweight <1000 g) or very preterm (<28 weeks) infants at 8 years of age related to the severity of IVH diagnosed in the newborn period. DESIGN: Regional cohort study. PATIENTS: Consecutive surviving children of either birthweight <1000 g or gestational age <28 weeks born in the state of Victoria in 1991 or 1992. MAIN OUTCOME MEASURES: Neurological impairments and disabilities, cognitive function and academic progress. RESULTS: Of 298 consecutive ELBW/very preterm survivors 270 (90.6%) with cranial ultrasound data were assessed at 8 years of age. Cerebral palsy, poor motor performance and major neurosensory disability were more prevalent with increasing severity of IVH. Cognitive functioning across domains was worse with increasing severity of IVH. Most of the differences were attributable to the few (n=6) survivors who had grade 4 IVH; there were few substantial differences between survivors with lesser grades of IVH. CONCLUSIONS: Neurodevelopmental dysfunction at school age in ELBW/very preterm survivors varies little with increasing severity of IVH, with the exception of grade 4 IVH.     

Early pituitary-adrenal response and respiratory outcomes in preterm infants

OBJECTIVE: To assess the influence of circulating (basal) and stimulated plasma adrenocorticotrophin (ACTH) and serum cortisol on the duration of oxygen supplementation and development of chronic lung disease (CLD) in preterm, very low birthweight infants. METHODS: A total of 226 human corticotrophin releasing hormone stimulation tests were performed on 137 very low birthweight infants on days 7 and 14 in a tertiary neonatal centre. RESULTS: Multivariate regression analysis showed that the duration of oxygen supplementation was negatively associated with birth weight, but positively associated with alveolar-arterial oxygen gradient (A-aDO(2)) on the first day and with basal serum cortisol on day 14. In addition, the multivariate classification and regression trees model indicated that the two most useful indices for predicting CLD were clinical risk index for babies (CRIB) score (> 9) and peak serum cortisol (> 740 nmol/l) on day 14. The sensitivity, specificity, positive and negative predictive values of these factors for predicting CLD were 53%, 80%, 81%, and 70% respectively. CONCLUSIONS: The findings suggest that birth weight, severity of initial respiratory failure as reflected by the A-aDO(2) gradient, and continuing "stress" with persistent increase in serum cortisol on day 14 are significant risk factors associated with the duration of oxygen supplementation, whereas early pituitary-adrenal response (basal and peak plasma ACTH and serum cortisol on day 7) is not an independent risk factor. Although CRIB score in combination with peak serum cortisol on day 14 are useful predictors of CLD, the need to use a stimulation test and the relatively late timing of the forecast render these indices unattractive for routine clinical use.     

Systemic candidiasis and pneumonia in preterm infants

Twenty-two preterm infants with systemic candidiasis are reported, of which seven cases were presumed to be antenatally acquired and 15 postnatally acquired. All except one were of very low birthweight. Fifteen infants had positive cultures of blood, cerebrospinal fluid or urine and seven had candida pneumonia only. Clinical features included general instability, respiratory deterioration and a necrotizing enterocolitis-like presentation. The incidence of leukocytosis, shift to the left, eosinophilia and thrombocytopenia were not different from those with bacterial infection. The diagnosis was made after death in two infants. In the remaining 20 infants, treatment was initiated between 5 and 97 days of age, with a median delay of 4 days after the first positive cultures were taken. Complications of amphotericin and 5-flucytosine therapy which developed in five infants resolved on cessation of treatment. The mortality rate was 18% and impairment rate among the 17 very low birthweight survivors was 18%. A high index of suspicion is required for systemic candidiasis, especially in infants of less than 1000 g birthweight. If recognized early, effective and safe antifungal therapy is possible with favourable short- and long-term outcome.     

Retrolental fibroplasia--controlled study of 4 years' experience in a neonatal intensive care unit.

During the 4 years 1977-80, 14 infants developed retrolental fibroplasia (RLF) in the neonatal unit at this medical centre. All were very low birthweight (VLBW) infants who weighed 1500 g or less at birth. The incidence of RLF was 3.5% for all VLBW infants admitted for neonatal intensive care and 4.7% for VLBW survivors. The mean birthweight of the affected infants was 970 (range 730-1310) g and mean gestational age 26 (range 24-29) weeks. Seven of the affected infants (2.4% of VLBW survivors) had significant scarring with temporal dragging of the optic disc and retinal detachment. Each of the 14 infants was matched with 2 control infants in order to see whether any factors predisposing to the development of RLF, including those related to oxygen therapy and monitoring, could be identified. The only factor associated with RLF was a higher volume of blood given with replacement transfusions. The occurrence of RLF was unrelated to an increase in requirement for or duration of oxygen therapy, arterial oxygen tensions as determined by intermittent sampling, or the availability of transcutaneous oxygen monitoring. The care taken in oxygen therapy may have been responsible for failure to show a quantitative association between hyperoxaemia and RLF. Although the problem of oxygen therapy in preterm infants is far from being resolved, current neonatal intensive care methods have limited the occurrence of RLF to VLBW infants. This study demonstrated a lower incidence of RLF in VLBW infants despite an improved survival rate compared with that previously reported.     

Systemic candidiasis and pneumonia in preterm infants

Twenty-two preterm infants with systemic candidiasis are reported, of which seven cases were presumed to be antenatally acquired and 15 postnatally acquired. All except one were of very low birthweight. Fifteen infants had positive cultures of blood, cerebrospinal fluid or urine and seven had candida pneumonia only. Clinical features included general instability, respiratory deterioration and a necrotizing enterocolitis-like presentation. The incidence of leukocytosis, shift to the left, eosinophilia and thrombocytopenia were not different from those with bacterial infection. The diagnosis was made after death in two infants. In the remaining 20 infants, treatment was initiated between 5 and 97 days of age, with a median delay of 4 days after the first positive cultures were taken. Complications of amphotericin and 5-flucytosine therapy which developed in five infants resolved on cessation of treatment. The mortality rate was 18% and impairment rate among the 17 very low birthweight survivors was 18%. A high index of suspicion is required for systemic candidiasis, especially in infants of less than 1000 g birthweight. If recognized early, effective and safe antifungal therapy is possible with favourable short- and long-term outcome.     

Home oxygen therapy following neonatal intensive care

In a 12-month period 28 of 164 consecutive very low birthweight (VLBW) infants receiving intensive care within 48 h of birth at King's College Hospital developed chronic lung disease, (oxygen dependence beyond 28 days of age). Fifteen of the 28 infants were eligible for home oxygen therapy, but this was only practical, because of home circumstances, in 8 infants (4.9%). These 8 infants received home oxygen therapy. One further infant, born at term and suffering from pulmonary hypoplasia was also discharged home on oxygen therapy. Two infants subsequently required readmission due to a deterioration in their respiratory status and died. Three others required re-admissions (total duration 32 days) for respiratory problems. The median duration of home oxygen therapy was 17 weeks (range 4-486 days). We conclude that home oxygen therapy is needed by only a very small number of preterm infants and is appropriate for only a proportion of them. Parents need to be counselled carefully regarding the possibility that the need for oxygen might be protracted.     

Chronic respiratory morbidity after prolonged and premature rupture of the membranes.

Twenty one surviving infants of pregnancies complicated by rupture of the membranes during the second trimester that lasted at least one week have been followed up for a median of 15 months. Five infants (24%) had recurrent respiratory problems (episodes of wheezing and coughing occurring at least once a week) which related significantly to the use of neonatal ventilation and to very preterm delivery. Five of the 18 infants who were born preterm and with birth weights of less than 2500 g had recurrent respiratory symptoms (28%). This compares favourably with an incidence of symptoms of 67% among surviving low birthweight infants born at this hospital after pregnancies not complicated by premature rupture of the membranes. Neither recurrent respiratory symptoms nor admission to hospital for chest related disorders were associated with the timing of onset or duration of rupture of the membranes. We conclude that, among survivors of premature rupture of the membranes, chronic respiratory morbidity would best be prevented by avoiding very preterm delivery, regardless of the duration of the rupture.     

Retinopathy of prematurity: the relationship with intraventricular hemorrhage and bronchopulmonary dysplasia

We studied prospectively a cohort of 326 neonates weighing 500-1250 gm at birth. These babies were all born at Magee-Womens Hospital during 1986 and 1987. Sixty-five percent survived and were discharged from the hospital, and 197 of the survivors (93%) had at least one ophthalmological exam before their discharge. Of the patients who were examined, 34% had retinopathy of prematurity (ROP) and 12% had stage 3 or 4 ROP in at least one eye. There were six neonates with at least one blind eye, giving an estimated prevalence of blindness caused by ROP of 301 per million live births. By univariate analysis there was a strong association of ROP with birthweight, oxygen exposure, respirator treatment, and intraventricular hemorrhage (IVH). By multivariate analysis, only the respirator treatment was significantly associated with ROP. When birthweight, oxygen exposure, and IVH were controlled, a baby requiring more than 28 days of ventilator treatment was 4.07 times more likely to have stage 3 or 4 ROP than a baby with less ventilator exposure. These data confirm the strong association of ROP with bronchopulmonary dysplasia (BPD), low birth-weight, and IVH, and suggest that the key component among these interrelated variables may be time spent on a ventilator.     

Developmental patterns from 1 to 4 years of extremely preterm infants who required home oxygen therapy

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a common complication of prematurity, with those being discharged on home oxygen at particularly high risk of adverse developmental outcomes. AIMS: To compare the developmental patterns, from 1 to 4 years, of extremely preterm infants with BPD discharged from hospital on home oxygen, extremely preterm infants with BPD discharged breathing room air, and extremely preterm infants without BPD. SUBJECTS: Two hundred and seventy-six infants with a gestational age of <28 weeks or birthweight <1000 g, free from sensory and motor disabilities who were followed up longitudinally to 4 years corrected age. OUTCOME MEASURES: Children were assessed on the Griffiths Mental Development Scales at 1 and 2 years corrected age, and the McCarthy Scales of Children's Abilities at 4 years corrected age. RESULTS: The developmental trajectories of the three groups did not differ significantly, however at 1 year corrected age the non-BPD group had significantly higher developmental scores than both BPD groups. At 2 years corrected age the non-BPD group had significantly higher developmental scores than the BPD-home oxygen group, and at 4 years corrected age no differences between the groups were evident. CONCLUSIONS: Extremely preterm children with BPD exhibited an initial developmental lag compared to preterm peers. Children with BPD discharged breathing room air had developmental scores at 2 years corrected age that were comparable to the non-BPD group, but those discharged on home oxygen still had lower developmental scores. At 4 years, no differences between the groups were evident.