Avroy A. Fanaroff

Outcomes of children of extremely low birthweight and gestational age in the 1990's

Advances in perinatal care have improved the chances for survival of extremely low birthweight (< 800 g) and gestational age (< 26 weeks) infants. A review of the world literature and our own experience reveals that at 23 weeks gestation survival ranges from 2% to 35%. At 24 weeks gestation the range is 17% to 58%, and at 25 weeks gestation 35% to 85%. Differences in population descriptors, in the initiation and withdrawal of treatment and the duration of survival considered may account for the wide variations in the reported ranges of survival. Major neonatal morbidity increases with decreasing gestational age and birthweight. The rates of severe cerebral ultrasound abnormality range at 23 weeks gestation from 10% to 83%, at 24 weeks from 17% to 64% and at 25 weeks gestation from 10% to 22%. At 23 weeks gestation, chronic lung disease occurs in 57% to 70% of survivors, at 24 weeks in 33% to 89%, and at 25 weeks gestation in 16% to 71% of survivors. When compared to children born prior to the 1990s, the rates of neurodevelopmental disability have, in general, remained unchanged. Of 30 survivors reported at 23 weeks gestation nine (30%) are severely disabled. At 24 weeks gestation the rates of severe neurodevelopmental disability (including subnormal cognitive function, cerebral palsy, blindness and deafness) range from 17% to 45%, and at 25 weeks gestation 12% to 35% are similarly affected. In Cleveland, Ohio, we compared the outcomes of 114 children with birthweight 500-749 g born 1990-1992 to 112 infants born 1993-1995. Twenty month survival was similar (43% vs 38%). The use of antenatal and postnatal steroids increased (10% vs 54% and 43% vs 84%, respectively, P< 0.001), however the rates of chronic lung disease increased from 41% to 63% (P = 0.06). There was a significant increase in the rate of subnormal cognitive function at 20 months corrected age (20% vs 48%, P < 0.02) and a trend to an increase in the rate of cerebral palsy (10% vs 16%) and neurodevelopmental impairment. We conclude that, with current methods of care, the limits of viability have been reached. The continuing toll of major neonatal morbidity and neurodevelopmental handicap are of serious concern.

Longitudinal growth of hospitalized very low birth weight infants

Background. The interpretation of growth rates for very low birth weight infants is obscured by limited data, recent changes in perinatal care, and the uncertain effects of multiple therapies. Objectives. To develop contemporary postnatal growth curves for very low birth weight preterm infants and to relate growth velocity to birth weight, nutritional practices, fetal growth status (small- or appropriate-for-gestational-age), and major neonatal morbidities (chronic lung disease, nosocomial infection or late-onset infection, severe intraventricular hemorrhage, and necrotizing enterocolitis). Design. Large, multicenter, prospective cohort study. Methods. Growth was prospectively assessed for 1660 infants with birth weights between 501 to 1500 g admitted by 24 hours of age to 1 of the 12 National Institute of Child Health and Human Development Neonatal Research Network centers between August 31, 1994 and August 9, 1995. Infants were included if they survived >7 days (168 hours) and were free of major congenital anomalies. Anthropometric measures (body weight, length, head circumference, and midarm circumference) were performed from birth until discharge, transfer, death, age 120 days, or a body weight of 2000 g. To obtain representative data, nutritional practices were not altered by the study protocol. Results. Postnatal growth curves suitable for clinical and research use were constructed for body weight, length, head circumference, and midarm circumference. Once birth weight was regained, weight gain (14.4–16.1 g/kg/d) approximated intrauterine rates. However, at hospital discharge, most infants born between 24 and 29 weeks of gestation had not achieved the median birth weight of the reference fetus at the same postmenstrual age. Gestational age, race, and gender had no effect on growth within 100-g birth weight strata. Appropriate-for-gestational age infants who survived to hospital discharge without developing chronic lung disease, severe intraventricular hemorrhage, necrotizing enterocolitis, or late onset-sepsis gained weight faster than comparable infants with those morbidities. More rapid weight gain was also associated with a shorter duration of parenteral nutrition providing at least 75% of the total daily fluid volume, an earlier age at the initiation of enteral feedings, and an earlier age at achievement of full enteral feedings. Conclusions. These growth curves may be used to better understand postnatal growth, to help identify infants developing illnesses affecting growth, and to aid in the design of future research. They should not be taken as optimal. Randomized clinical trials should be performed to evaluate whether different nutritional management practices will permit birth weight to be regained earlier and result in more rapid growth, more appropriate body composition, and improved short- and long-term outcomes.

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 ≥28 days but not at 36 weeks’ postmenstrual age (PMA) or discharge, moderate BPD as O2 for ≥28 days plus treatment with <30% O2 at 36 weeks’ PMA, and severe BPD as O2 for ≥28 days plus ≥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 ≤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.

Improved Survival Rates With Increased Neurodevelopmental Disability for Extremely Low Birth Weight Infants in the 1990s

Background. Advances in perinatal care have resulted in increased survival rates for extremely low birth weight children. We sought to examine the relative changes in rates of survival and neurodevelopmental impairment at 20 months of corrected age among 500- to 999-g birth weight infants born at our perinatal center during 2 periods, before and after the introduction of surfactant therapy in 1990. Methods. Four hundred ninety-six infants with birth weights of 500 to 999 g were born at our perinatal center during period I (1982–1989) (mean body weight: 762 g; mean gestational age: 25.8 weeks) and 682 during period II (1990–1998) (mean body weight: 756 g; mean gestational age: 25.5 weeks). Rates of death and survival with and without neurodevelopmental impairment at 20 months of corrected age for the 2 periods were compared with logistic regression analyses, with adjustment for gestational age. Results. Survival rates increased from 49% during period I to 67% during period II. Neonatal morbidity rates also increased during period II, including rates of sepsis (from 37% to 51%), periventricular leukomalacia (from 2% to 7%), and chronic lung disease, defined as oxygen dependence at 36 weeks of corrected age (from 32% to 43%). Rates of severe cranial ultrasound abnormalities were similar (22% vs 22%). Among children monitored, the rate of neurologic abnormalities, including cerebral palsy, increased from 16% during period I to 25% during period II and the rate of deafness increased from 3% to 7%. The overall rate of neurodevelopmental impairment (major neurosensory abnormality and/or Bayley Mental Developmental Index score of <70) increased from 26% to 36%. Compared with period I, in period II there were decreased rates of death (odds ratio [OR]: 0.3; 95% confidence interval [CI]: 0.2–0.4) and increased rates of survival with impairment (OR: 2.3; 95% CI: 1.7–3.3) but also increased rates of survival without impairment (OR: 1.7; 95% CI: 1.3–2.2). Compared with period I, for every 100 infants with birth weights of 500 to 999 g born in period II, 18 additional infants survived, of whom 7 were unimpaired and 11 were impaired. Conclusions. The improved survival rates in the 1990s occurred with an increased risk of significant neurodevelopmental impairment. Prospective parents of extremely low birth weight infants should be advised of this substantial risk, to facilitate decision-making in the delivery room.

Persistent Pulmonary Hypertension of the Newborn in the Era Before Nitric Oxide: Practice Variation and Outcomes

Objectives. In the era before widespread use of inhaled nitric oxide, to determine the prevalence of persistent pulmonary hypertension (PPHN) in a multicenter cohort, demographic descriptors of the population, treatments used, the outcomes of those treatments, and variation in practice among centers. Study Design. A total of 385 neonates who received ≥50% inspired oxygen and/or mechanical ventilation and had documented evidence of PPHN (2D echocardiogram or preductal or postductal oxygen difference) were tracked from admission at 12 Level III neonatal intensive care units. Demographics, treatments, and outcomes were documented. Results. The prevalence of PPHN was 1.9 per 1000 live births (based on 71 558 inborns) with a wide variation observed among centers (.43–6.82 per 1000 live births). Neonates with PPHN were admitted to the Level III neonatal intensive care units at a mean of 12 hours of age (standard deviation: 19 hours). Wide variations in the use of all treatments studied were found at the centers. Hyperventilation was used in 65% overall but centers ranged from 33% to 92%, and continuous infusion of alkali was used in 75% overall, with a range of 27% to 93% of neonates. Other frequently used treatments included sedation (94%; range: 77%–100%), paralysis (73%; range: 33%–98%), and inotrope administration (84%; range: 46%–100%). Vasodilator drugs, primarily tolazoline, were used in 39% (range: 13%–81%) of neonates. Despite the wide variation in practice, there was no significant difference in mortality among centers. Mortality was 11% (range: 4%–33%). No specific therapy was clearly associated with a reduction in mortality. To determine whether the therapies were equivalent, neonates treated with hyperventilation were compared with those treated with alkali infusion. Hyperventilation reduced the risk of extracorporeal membrane oxygenation without increasing the use of oxygen at 28 days of age. In contrast, the use of alkali infusion was associated with increased use of extracorporeal membrane oxygenation (odds ratio: 5.03, compared with those treated with hyperventilation) and an increased use of oxygen at 28 days of age. Conclusions. Hyperventilation and alkali infusion are not equivalent in their outcomes in neonates with PPHN. Randomized trials are needed to evaluate the role of these common therapies.

Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants

BACKGROUND Septicemia is a major antecedent of morbidity and mortality in very low birth weight (501- to 1500-g) infants. Our purpose was to determine prospectively the incidence, clinical presentation, laboratory features, risk factors, morbidity and mortality associated with late onset septicemia in infants 501 to 1500 g. METHODS Clinical data were prospectively collected for 2416 infants enrolled in a multicenter trial to determine the efficacy of intravenous immunoglobulin in preventing nosocomial infections. Septicemia was confirmed by positive blood culture in 395 symptomatic infants. Multivariate analyses of factors associated with septicemia were performed. RESULTS Sixteen percent of VLBW infants developed septicemia at a median age of 17 days. Factors associated with septicemia by logistic regression included male gender, lower gestational age and birth weight and decreased baseline serum IgG concentrations. Increasing apnea (55%), feeding intolerance, abdominal distension or guaiac-positive stools (43%), increased respiratory support (29%), lethargy and hypotonia (23%) were the dominant presenting features of septicemia. An abnormal white blood cell count (46%), unexplained metabolic acidosis (11%) and hyperglycemia (10%) were the most common laboratory indicators. Septicemic infants, compared with nonsepticemic infants, had significantly increased mortality (21% vs. 9%), longer hospital stay (98 vs. 58 days) and more serious morbidity, including severe intraventricular hemorrhage, bronchopulmonary dysplasia and increased ventilator days (P < 0.001). CONCLUSIONS Late onset septicemia is common in very low birth weight infants, and the rate is inversely proportional to gestational age and birth weight. Septicemia is more common in males and those with low initial serum IgG values. A set of clinical signs (apnea, bradycardia, etc.) and laboratory values (leukocytosis, immature white blood cells and neutropenia) increase the probability of late onset sepsis, but they have poor positive predictive value.

The NICHD Neonatal research network: Changes in practice and outcomes during the first 15 years

The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network was founded in 1986 to perform trials that, because of their size and complexity, were beyond the scope of a single center and required the expertise and resources of many collaborating centers. This report briefly documents changes in mortality, selected morbidities, and therapies amongst Network centers. The Network registry incorporating perinatal and neonatal data on all infants with a birth weight 501-1500 g cared for at participating centers served as the database. Mortality and selected morbidities were compared for 3 time periods, 1987/1988, (7 centers 1,765 infants, presurfactant); 1993/1994 (12 centers, 4,593 infants, postsurfactant and moderate antenatal corticosteroid utilization); and 1999/2000 (15 centers, 5,848 infants, postsurfactant and widespread corticosteroid use). Detailed outcomes for infants with birth weights between 501 and 800 g, and gestational ages of 23 to 25 weeks are also presented because they dramatically document the changes over time. Mortality for the entire cohort decreased from 23% in 1987/1988 to 17% in 1993/1994 and 14% in 1999/2000. Between 1987/1988 and 1999/2000 mortality prior to discharge, decreased from 66% to 45% for infants weighing 501-750 g; from 34% to 12% for birth weight between 751 to 1000 g, and from 13% to 7% for infants between 1001 and 1500 g. Mortality was higher in boys. Survival free of major morbidity (chronic lung disease/bronchopulmonary dysplasia, necrotizing enterocolitis or grade III/IV intraventricular hemorrhage) did not change significantly over time. Since the inception of the Network, multiple births have increased from 18% to 26%; deliveries by Cesarean section from 47% to 57%, and antenatal corticosteroid use increased from 16% to 79%. Surfactant, which was not used prior to 1990, is now given to 57% of the infants, including 87% with birth weights between 501 and 750 g. There have been significant decreases in the incidence of grade III-IV intraventricular hemorrhage from 18% in 1987/1988 to about 11% since 1993/1994, and periventricular leukomalacia from 8% to 3%. However, other morbidities, including necrotizing enterocolitis, patent ductus arteriosus, and late onset sepsis, have not changed substantially. Advances in perinatal care within NICHD Network centers have resulted in marked improvements in survival. Further advances are required to increase survival free of neonatal morbidity or neurodevelopmental impairment.

Necrotizing enterocolitis in very low birth weight infants: Biodemographic and clinical correlates

We studied the occurrence of necrotizing enterocolitis in 2681 very low birth weight infants during an 18-month period to characterize the biodemographic and clinical correlates. Proven necrotizing enterocolitis (Bell stage II and beyond) occurred in 10.1% of study infants; necrotizing enterocolitis was suspected in 17.2% of study infants. Positivity of blood cultures was related to necrotizing enterocolitis staging. The mortality rate increased only for stage III necrotizing enterocolitis (54% died). Logistic regression identified medical center of birth, race, gender, birth weight, maternal hemorrhage, duration of ruptured membranes, and cesarean section as significant risk factors. For one center the odds ratio was 3.7, whereas for another center it was only 0.3. For black boys, the odds ratio was 2.3 relative to nonblack boys; for girls, race did not affect prevalence of necrotizing enterocolitis. Age at onset was related to birth weight and gestational age. Intercenter differences in necrotizing enterocolitis prevalence were related to time required to regain birth weight and other indicators of fluid management. Gram-positive organisms predominated in positive blood cultures for stage I and II necrotizing enterocolitis; enteric bacteria were isolated more frequently in infants with stage III disease. We conclude that necrotizing enterocolitis prevalence varies greatly among centers; this may be related to early clinical practices of neonatal care.

Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage

OBJECTIVE To determine the differences in short term outcome of very low birthweight infants attributable to sex. METHODS Boys and girls weighing 501–1500 g admitted to the 12 centres of the National Institute of Child Health and Human Development Neonatal Research Network were compared. Maternal information and perinatal data were collected from hospital records. Infant outcome was recorded at discharge, at 120 days of age if the infant was still in hospital, or at death. Best obstetric estimate based on the last menstrual period, standard obstetric factors, and ultrasound were used to assign gestational age in completed weeks. Data were collected on a cohort that included 3356 boys and 3382 girls, representing all inborn births from 1 May 1991 to 31 December 1993. RESULTS Mortality for boys was 22% and that for girls 15%. The prenatal and perinatal data indicate few differences between the sex groups, except that boys were less likely to have been exposed to antenatal steroids (odds ratio (OR) = 0.80) and were less stable after birth, as reflected in a higher percentage with lower Apgar scores at one and five minutes and the need for physical and pharmacological assistance. In particular, boys were more likely to have been intubated (OR = 1.16) and to have received resuscitation medication (OR = 1.40). Boys had a higher risk (OR > 1.00) for most adverse neonatal outcomes. Although pulmonary morbidity predominated, intracranial haemorrhage and urinary tract infection were also more common. CONCLUSIONS Relative differences in short term morbidity and mortality persist between the sexes.

Very low birth weight preterm infants with early onset neonatal sepsis: The predominance of Gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002-2003

Background: Early onset neonatal sepsis (EOS, occurring in the first 72 hours of life) remains an important cause of illness and death among very low birth weight (VLBW) preterm infants. We previously reported a change in the distribution of pathogens associated with EOS from predominantly Gram-positive to primarily Gram-negative organisms. Objective: To compare rates of EOS and pathogens associated with infection among VLBW infants born at centers of the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network during 3 time periods: 1991–1993; 1998–2000; and 2002–2003. Study Design: Prospectively collected data from the NICHD Neonatal Research Network VLBW registry were retrospectively reviewed. Rates of blood culture confirmed EOS, selected maternal and infant variables and pathogens associated with infection were compared between 2002–2003 and 2 previously published cohorts. Results: During the past 13 years, overall rates of EOS have remained stable (15–19 per 1000 live births of infants 401–1500 g). More than one-half of early infections in the 2002–2003 cohort were caused by Gram-negative organisms (53%), with Escherichia coli the most common organism (41%). Rates of group B streptococcal infections remain low (1.8 per 1000 live births). Between 1991–1993 and 1998–2000, there was a significant increase in rates of E. coli infections; but in 2002–2003, there was no significant change (7.0 per 1000 live births). Infants with EOS continue to be at significantly increased risk for death compared with uninfected infants. Conclusion: EOS remains an uncommon but important cause of morbidity and mortality among VLBW infants. Gram-negative organisms continue to be the predominant pathogens associated with EOS.