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School-age outcomes in children with birth weights under 750 g
CURRENT LITERATURE AND CLINICAL ISSUES
Abstracts from the literature Randomized trial of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania Alonso PL, Smith T, Armstrong Schellenberg JRM, et al. Lancet 1994;334:1175-81. Objective: To determine whether three doses of SPf66 malaria vaccine in African children living in an area of intense perennial malaria transmission protects children against malaria. Design: Randomized, double-blind, placebo-controlled trial. Setting: A village in the Kilombero valley of southern Tanzania. Patients: 586 children aged 1 to 5 years. Intervention: Three doses of SPf66 malaria vaccine or placebo given at baseline and at 4 and 26 weeks. Main outcome measures: Episodes of clinical malaria, incidence and density of parasitemia, anemia, and antibody levels to vaccine for the l-year period after vaccination. Results: The incidence of Clinical malaria was 0.25 in the vaccine group and 0.35 in the placebo group; the incidence and density of parasitemia were similar in the two groups. After three doses, all vaccine recipients had detectable antibody; the geometric mean index was 8.3 in the vaccine group and 0.7 in the control group. Six study participants died of malaria: one in the vaccine group and five in the placebo group. Mild side effects were seen in fewer than 6%, and there were no severe side effects. Conclusions: This study confirms that SPf66 is safe and immunogenic, and reduces the risk of clinical malaria among children exposed to intense P. falciparum transmission. Comment: Severe malaria (cerebral malaria, profound anemia) kills between one and three million African children each year. The journey toward an effective vaccine against malaria has been long, hard, and expensive, and it has been made more difficult by the lack of a good in vitro correlate of immunity. This trial of the SPf66 vaccine, discovered originally in Columbia, is the first outside South America. This was a difficult test for the vaccine because malaria transmission in the Kilombero valley in Tanzania is intense compared with that at the South American trial sites. Severe disease (mainly severe anemia) occurs in the first few years of life, but by adulthood immunity has gradually developed and nearly all malaria infections are symp-
The Journal of Pediatrics
tomless (premunition). The design and execution of this vaccine trial were good. The SPf66 vaccine was well tolerated and immunogenic, but the main outcome of the trial is tantalizing: a 31% protective efficacy with a 95% confidence interval that reaches zero is a borderline result. The lack of effect on anemia is disappointing because malaria is an important cause of anemia in malaria-endemic areas. A vaccine protective efficacy of 31% would be low for most infectious diseases, but a 31% reduction in malarial morbidity, especially if mortality rates were reduced as well, would certainly be worth achieving. In another year we will have the results of other ongoing trials with this vaccine and a clearer idea of the overall efficacy of SPf66. Will the vaccine select for resistant strains, or will it destabilize malaria and cause an increase in mortality rates in areas of intense stable transmission? Other, possibly improved, vaccines are also in development. We have not reached the end of the journey toward an ideal vaccine against falciparum malaria, but the SPf66 vaccine has held up well so far, and we are still on track. Nicholas J. White, BSc, MD, FRCP Director, Wellcome-Mahidol University, Oxford Tropical Medicine Research Programme Mahidol University Bangkok, Thailand
School-age outcomes in children with birth weights under 750 g Hack M, Taylor HG, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. N Engl J Med 1994;331:753-9. Objective: To determine the developmental outcomes of children with birth weights less than 750 gm. Design: Inception cohort with matched control subjects. Setting: Three regional tertiary care centers in Ohio. Patients: We matched a regional cohort of 68 surviving children born from 1982 through 1986 with birth weights less than 750 gm (mean, 670 gm; gestational age, 25.7 weeks) with 65 children weighing 750 to 1499 gm at birth and 61 children born at term. Main outcome measures: Growth, neurosensory status, and functioning at school age in the three groups were compared. Associations of biologic and social risk factors with major developmental outcomes were examined by means of logistic-regression analyses. Results: Children with birth weights less than 750 gm were
March 1995
499
500
Abstracts from the literature
inferior to both comparison groups in cognitive ability, psychomotor skills, and academic achievement. They had poorer social skills and adaptive behavior, and more behavioral and attention problems. The mean ( + S D ) Mental Processing Composite score for the cohort was 87 + 15, in comparison with 93 + 14 for children with birth weights of 750 to 1499 gm and 100 ___ 13 for children born at term (p <0.001). The rates of mental retardation (IQ <70) in the three groups were 21%, 8%, and 2%, respectively; the rates of cerebral palsy were 9%, 6%, and 0%; and the rates of severe visual disability were 25%, 5%, and 2%. Major cerebral ultrasonographic abnormalities were associated with mental retardation (odds ratio, 5.4; 95% confidence interval (CI), 1.8 to 15.8) and cerebral palsy (odds ratio, 15.2, 95% CI, 3.0 to 77.4). Oxygen dependence at 36 weeks of corrected age was associated with mental retardation (odds ratio, 4.5; 95% CI, 1.2 to 10.7) and severe visual disability (odds ratio, 4.3; 95% CI, 1.3 to 14.2). Social disadvantage, though associated with several adverse neuropsychologic outcomes, was not associated with major developmental impairment. Conclusions: Children with birth weights less than 750 gm who survive represent a subgroup of very low birth weight children who are at high risk of having neurobehavioral dysfunction and poor school performance. Comment: This report provides important information on the usefulness of applying our technologic expertise to neonates at the edge of extreme prematurity. The data may not be as sobering as a first glance might suggest. Many children with mild hearing or visual loss, or with specific language or visual-motor deficits, function relatively well if they are given appropriate support and educational interventions. The number of children enrolled in special education may reflect timely parental requests for services rather than specific adverse outcomes. Generalizability may be limited by time (given ongoing advances in neonatal intensive care) and place (the particular neonatal intensive care units where these data were collected). The authors matched their subjects with regard to age, sex, and race, and because race is so highly correlated with socioeconomic status, it may not be possible to detect an effect of the latter, independent of birth weight, on cognitive development. Although the details o f any report such as this can be criticized, the general conclusion that it would be better not to be born very prematurely is well supported here and in extensive earlier literature. We need more sophisticated, quantitative approaches to predict which babies will respond to our advancing techniques; we also need to commit ourselves to prevention of extreme prematurity, which will require that we address the issue of poverty and its connection to prematurity and poor outcomes. Until then, we must
The Journal of Pediatrics March 1995
continue to refine the approach in our neonatal intensive care units. Marie C. McCormick, MD, ScD Harvard Medical School Boston, M A 02115 Nebulized moderate Klassen TP, PC. N Engl
budesonide for children with mild-tocroup Feldman ME, Watters LK, Sutcliffe T, Rowe J Med 1994;331:285-9.
Objective: To compare a nebulized glucocorticoid, budesonide, with placebo in outpatients with mild-to-moderate croup. Design: Randomized, double-blind, placebo-controlled trial. Setting: Emergency department of a children's hospital. Patients: Children 3 months to 5 years of age were eligible for the study if their croup scores fell in the mild-to-moderate range (scores of 2 to 7 out of a possible 17). Intervention: The patients were randomly assigned to receive either 2 mg (4 ml) of nebulized budesonide (27 children) or 4 ml of nebulized isotonic saline solution (27 children). Main outcome measures: Subjects were assessed hourly for up to 4 hours for croup score, respiratory rate, heart rate, parental assessment of improvement, and other medical interventions by treating physicians not involved in the study. Results: The median croup score at entry into the study was 4 in both groups. At the final study assessment, the median score was significantly lower in the budesonide group than in the placebo group (1 vs 3; p = 0.005). The patients in the budesonide group were discharged from the emergency department significantly earlier than those in the placebo group (p = 0.002). One week after enrollment, 21 patients assigned to receive placebo had received dexamethasone, in comparison with 15 patients assigned to receive budesonide (p = 0.10), and 7 patients assigned to the placebo group had been admitted to the hospital, in comparison with 1 patient assigned to the budesonide group (p = 0.05). Conclusions: Nebulized budesonide leads to a prompt and significant clinical improvement in children with mild-tomoderate croup who come to the emergency department. Comment: There is now consistent evidence that corticosteroids can be beneficial in the treatment of children with croup. Kairys et al. 1 reported benefit from metaanalysis of studies up to 1989. Husby et al. 2 demonstrated a prompt symptom response to inhaled budesonide, and Klassen et al. 3 showed a more rapid clinical improvement with a shorter hospital stay and a reduced rate of subsequent admission in children with mild-to-moderate croup who come to the emergency department. Geelhoed and Macdonald 4
Abstracts from the literature Randomized trial of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania Alonso PL, Smith T, Armstrong Schellenberg JRM, et al. Lancet 1994;334:1175-81. Objective: To determine whether three doses of SPf66 malaria vaccine in African children living in an area of intense perennial malaria transmission protects children against malaria. Design: Randomized, double-blind, placebo-controlled trial. Setting: A village in the Kilombero valley of southern Tanzania. Patients: 586 children aged 1 to 5 years. Intervention: Three doses of SPf66 malaria vaccine or placebo given at baseline and at 4 and 26 weeks. Main outcome measures: Episodes of clinical malaria, incidence and density of parasitemia, anemia, and antibody levels to vaccine for the l-year period after vaccination. Results: The incidence of Clinical malaria was 0.25 in the vaccine group and 0.35 in the placebo group; the incidence and density of parasitemia were similar in the two groups. After three doses, all vaccine recipients had detectable antibody; the geometric mean index was 8.3 in the vaccine group and 0.7 in the control group. Six study participants died of malaria: one in the vaccine group and five in the placebo group. Mild side effects were seen in fewer than 6%, and there were no severe side effects. Conclusions: This study confirms that SPf66 is safe and immunogenic, and reduces the risk of clinical malaria among children exposed to intense P. falciparum transmission. Comment: Severe malaria (cerebral malaria, profound anemia) kills between one and three million African children each year. The journey toward an effective vaccine against malaria has been long, hard, and expensive, and it has been made more difficult by the lack of a good in vitro correlate of immunity. This trial of the SPf66 vaccine, discovered originally in Columbia, is the first outside South America. This was a difficult test for the vaccine because malaria transmission in the Kilombero valley in Tanzania is intense compared with that at the South American trial sites. Severe disease (mainly severe anemia) occurs in the first few years of life, but by adulthood immunity has gradually developed and nearly all malaria infections are symp-
The Journal of Pediatrics
tomless (premunition). The design and execution of this vaccine trial were good. The SPf66 vaccine was well tolerated and immunogenic, but the main outcome of the trial is tantalizing: a 31% protective efficacy with a 95% confidence interval that reaches zero is a borderline result. The lack of effect on anemia is disappointing because malaria is an important cause of anemia in malaria-endemic areas. A vaccine protective efficacy of 31% would be low for most infectious diseases, but a 31% reduction in malarial morbidity, especially if mortality rates were reduced as well, would certainly be worth achieving. In another year we will have the results of other ongoing trials with this vaccine and a clearer idea of the overall efficacy of SPf66. Will the vaccine select for resistant strains, or will it destabilize malaria and cause an increase in mortality rates in areas of intense stable transmission? Other, possibly improved, vaccines are also in development. We have not reached the end of the journey toward an ideal vaccine against falciparum malaria, but the SPf66 vaccine has held up well so far, and we are still on track. Nicholas J. White, BSc, MD, FRCP Director, Wellcome-Mahidol University, Oxford Tropical Medicine Research Programme Mahidol University Bangkok, Thailand
School-age outcomes in children with birth weights under 750 g Hack M, Taylor HG, Klein N, Eiben R, Schatschneider C, Mercuri-Minich N. N Engl J Med 1994;331:753-9. Objective: To determine the developmental outcomes of children with birth weights less than 750 gm. Design: Inception cohort with matched control subjects. Setting: Three regional tertiary care centers in Ohio. Patients: We matched a regional cohort of 68 surviving children born from 1982 through 1986 with birth weights less than 750 gm (mean, 670 gm; gestational age, 25.7 weeks) with 65 children weighing 750 to 1499 gm at birth and 61 children born at term. Main outcome measures: Growth, neurosensory status, and functioning at school age in the three groups were compared. Associations of biologic and social risk factors with major developmental outcomes were examined by means of logistic-regression analyses. Results: Children with birth weights less than 750 gm were
March 1995
499
500
Abstracts from the literature
inferior to both comparison groups in cognitive ability, psychomotor skills, and academic achievement. They had poorer social skills and adaptive behavior, and more behavioral and attention problems. The mean ( + S D ) Mental Processing Composite score for the cohort was 87 + 15, in comparison with 93 + 14 for children with birth weights of 750 to 1499 gm and 100 ___ 13 for children born at term (p <0.001). The rates of mental retardation (IQ <70) in the three groups were 21%, 8%, and 2%, respectively; the rates of cerebral palsy were 9%, 6%, and 0%; and the rates of severe visual disability were 25%, 5%, and 2%. Major cerebral ultrasonographic abnormalities were associated with mental retardation (odds ratio, 5.4; 95% confidence interval (CI), 1.8 to 15.8) and cerebral palsy (odds ratio, 15.2, 95% CI, 3.0 to 77.4). Oxygen dependence at 36 weeks of corrected age was associated with mental retardation (odds ratio, 4.5; 95% CI, 1.2 to 10.7) and severe visual disability (odds ratio, 4.3; 95% CI, 1.3 to 14.2). Social disadvantage, though associated with several adverse neuropsychologic outcomes, was not associated with major developmental impairment. Conclusions: Children with birth weights less than 750 gm who survive represent a subgroup of very low birth weight children who are at high risk of having neurobehavioral dysfunction and poor school performance. Comment: This report provides important information on the usefulness of applying our technologic expertise to neonates at the edge of extreme prematurity. The data may not be as sobering as a first glance might suggest. Many children with mild hearing or visual loss, or with specific language or visual-motor deficits, function relatively well if they are given appropriate support and educational interventions. The number of children enrolled in special education may reflect timely parental requests for services rather than specific adverse outcomes. Generalizability may be limited by time (given ongoing advances in neonatal intensive care) and place (the particular neonatal intensive care units where these data were collected). The authors matched their subjects with regard to age, sex, and race, and because race is so highly correlated with socioeconomic status, it may not be possible to detect an effect of the latter, independent of birth weight, on cognitive development. Although the details o f any report such as this can be criticized, the general conclusion that it would be better not to be born very prematurely is well supported here and in extensive earlier literature. We need more sophisticated, quantitative approaches to predict which babies will respond to our advancing techniques; we also need to commit ourselves to prevention of extreme prematurity, which will require that we address the issue of poverty and its connection to prematurity and poor outcomes. Until then, we must
The Journal of Pediatrics March 1995
continue to refine the approach in our neonatal intensive care units. Marie C. McCormick, MD, ScD Harvard Medical School Boston, M A 02115 Nebulized moderate Klassen TP, PC. N Engl
budesonide for children with mild-tocroup Feldman ME, Watters LK, Sutcliffe T, Rowe J Med 1994;331:285-9.
Objective: To compare a nebulized glucocorticoid, budesonide, with placebo in outpatients with mild-to-moderate croup. Design: Randomized, double-blind, placebo-controlled trial. Setting: Emergency department of a children's hospital. Patients: Children 3 months to 5 years of age were eligible for the study if their croup scores fell in the mild-to-moderate range (scores of 2 to 7 out of a possible 17). Intervention: The patients were randomly assigned to receive either 2 mg (4 ml) of nebulized budesonide (27 children) or 4 ml of nebulized isotonic saline solution (27 children). Main outcome measures: Subjects were assessed hourly for up to 4 hours for croup score, respiratory rate, heart rate, parental assessment of improvement, and other medical interventions by treating physicians not involved in the study. Results: The median croup score at entry into the study was 4 in both groups. At the final study assessment, the median score was significantly lower in the budesonide group than in the placebo group (1 vs 3; p = 0.005). The patients in the budesonide group were discharged from the emergency department significantly earlier than those in the placebo group (p = 0.002). One week after enrollment, 21 patients assigned to receive placebo had received dexamethasone, in comparison with 15 patients assigned to receive budesonide (p = 0.10), and 7 patients assigned to the placebo group had been admitted to the hospital, in comparison with 1 patient assigned to the budesonide group (p = 0.05). Conclusions: Nebulized budesonide leads to a prompt and significant clinical improvement in children with mild-tomoderate croup who come to the emergency department. Comment: There is now consistent evidence that corticosteroids can be beneficial in the treatment of children with croup. Kairys et al. 1 reported benefit from metaanalysis of studies up to 1989. Husby et al. 2 demonstrated a prompt symptom response to inhaled budesonide, and Klassen et al. 3 showed a more rapid clinical improvement with a shorter hospital stay and a reduced rate of subsequent admission in children with mild-to-moderate croup who come to the emergency department. Geelhoed and Macdonald 4