The Maternal Lifestyle Study: drug use by meconium toxicology and maternal self-report.

OBJECTIVE: The objective of this study was to describe drug use by pregnant women participating in the 4-site Maternal Lifestyle Study of in utero cocaine and/or opiate exposure. METHODS: Meconium specimens of 8527 newborns were analyzed by immunoassay with GC/MS confirmation for metabolites of cocaine, opiates, cannabinoids, amphetamines, and phencyclidine. Maternal self-report of drug use was determined by hospital interview. RESULTS: The prevalence of cocaine/opiate exposure in the 4 sites was 10.7% with the majority (9.5%) exposed to cocaine based on the combination of meconium analysis and maternal self-report. However, exposure status varied by site and was higher in low birth weight infants (18.6% for very low birth weight and 21.1% for low birth weight). Gas chromatography/mass spectrometry (GC/MS) confirmation of presumptive positive cocaine screens was 75.5%. In the cocaine/opiate-exposed group, 38% were cases in which the mother denied use but the meconium was positive. There was 66% agreement between positive meconium results and positive maternal report. Only 2% of mothers reported that they used only cocaine during pregnancy and mothers were 49 times more likely to use another drug if they used cocaine. CONCLUSION: Accurate identification of prenatal drug exposure is improved with GC/MS confirmation and when the meconium assay is coupled with a maternal hospital interview. However, the use of GC/MS may have different implications for research than for public policy. We caution against the use of quantitative analysis of drugs in meconium to estimate the degree of exposure. Our study also highlights the polydrug nature of what used to be thought of as a cocaine problem.

Very low birth weight outcomes of the National Institute of Child health and human development neonatal research network, January 1995 through December 1996. NICHD Neonatal Research Network.

OBJECTIVES: To determine the mortality and morbidity for infants weighing 401 to 1500 g (very low birth weight [VLBW]) at birth by gestational age, birth weight, and gender. STUDY DESIGN: Perinatal data were collected prospectively on an inborn cohort from January 1995 through December 1996 by 14 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated. RESULTS: Eighty four percent of 4438 infants weighing 501 to 1500 g at birth survived until discharge to home or to a long-term care facility (compared with 80% in 1991 and 74% in 1988). Survival to discharge was 54% for infants 501 to 750 g at birth, 86% for those 751 to 1000 g, 94% for those 1001 to 1250 g, and 97% for those 1251 to 1500g. The incidence of chronic lung disease (CLD; defined as receiving supplemental oxygen at 36 weeks' postmenstrual age; 23%), proven necrotizing enterocolitis (NEC; 7%), and severe intracranial hemorrhage (ICH; grade III or IV; 11%) remained unchanged between 1991 and 1996. Furthermore, 97% of all VLBW infants and 99% of infants weighing <1000 g at birth had weights less than the 10th percentile at 36 weeks' postmenstrual age. Mortality for 195 infants weighing 401 to 500 g was 89%, with nearly all survivors developing CLD. Mortality in infants weighing 501 to 600 g was 71%; among survivors, 62% had CLD, 35% had severe ICH, and 15% had proven NEC. CONCLUSIONS: Survival for infants between 501 and 1500 g at birth continued to improve, particularly for infants weighing <1000 g at birth. This improvement in survival was not associated with an increase in major morbidities, because the incidence of CLD, proven NEC, and severe ICH did not change. However, poor postnatal growth remains a major concern, occurring in 99% of infants weighing <1000 g at birth. Mortality and major morbidity (CLD, severe ICH, and NEC) remain high for the smallest infants, particularly those weighing <600 g at birth.

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.

Neurodevelopmental and functional outcomes of extremely low birth weight infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994.

OBJECTIVES: The purposes of this study were to report the neurodevelopmental, neurosensory, and functional outcomes of 1151 extremely low birth weight (401-1000 g) survivors cared for in the 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network, and to identify medical, social, and environmental factors associated with these outcomes. STUDY DESIGN: A multicenter cohort study in which surviving extremely low birth weight infants born in 1993 and 1994 underwent neurodevelopmental, neurosensory, and functional assessment at 18 to 22 months' corrected age. Data regarding pregnancy and neonatal outcome were collected prospectively. Socioeconomic status and a detailed interim medical history were obtained at the time of the assessment. Logistic regression models were used to identify maternal and neonatal risk factors for poor neurodevelopmental outcome. RESULTS: Of the 1480 infants alive at 18 months of age, 1151 (78%) were evaluated. Study characteristics included a mean birth weight of 796 +/- 135 g, mean gestation (best obstetric dates) 26 +/- 2 weeks, and 47% male. Birth weight distributions of infants included 15 infants at 401 to 500 g; 94 at 501 to 600 g; 208 at 601 to 700 g; 237 at 701 to 800 g; 290 at 801 to 900 g; and 307 at 901 to 1000 g. Twenty-five percent of the children had an abnormal neurologic examination, 37% had a Bayley II Mental Developmental Index <70, 29% had a Psychomotor Developmental Index <70, 9% had vision impairment, and 11% had hearing impairment. Neurologic, developmental, neurosensory, and functional morbidities increased with decreasing birth weight. Factors significantly associated with increased neurodevelopmental morbidity included chronic lung disease, grades 3 to 4 intraventricular hemorrhage/periventricular leukomalacia, steroids for chronic lung disease, necrotizing enterocolitis, and male gender. Factors significantly associated with decreased morbidity included increased birth weight, female gender, higher maternal education, and white race. CONCLUSION: ELBW infants are at significant risk of neurologic abnormalities, developmental delays, and functional delays at 18 to 22 months' corrected age.

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.

Dexamethasone therapy increases infection in very low birth weight infants.

BACKGROUND: Infection is a major complication of preterm infants, resulting in increased morbidity and mortality. We recently reported the results of a multicenter trial of dexamethasone initiated at 14 or 28 days in very low birth weight (VLBW) infants who were at risk for chronic lung disease; the results showed an increase in nosocomial bacteremia in the group receiving dexamethasone. This study is an in-depth analysis of bacteremia/sepsis and meningitis among infants enrolled in the trial. METHODS: Data on cultures performed and antibiotic therapy were collected prospectively. Infections were classified as definite or possible/clinical. RESULTS: A total of 371 infants were enrolled in the trial. There were no baseline differences in risk factors for infection. For the first 14 days of study, infants received either dexamethasone (group I, 182) or placebo (group II, 189). During this period, infants in group I were significantly more likely than those in group II to have a positive blood culture result (48% vs 30%) and definite bacteremia/sepsis/meningitis (22% vs 14%). Over the 6-week study period, 47% of those cultured had at least one positive blood culture result (53% in group I vs 41% in group II) and 25% of the infants had at least one episode of definite bacteremia/sepsis/meningitis (29% in group I vs 21% in group II). Among infants with definite infections, 46.8% were attributable to Gram-positive organisms, 26.6% to Gram-negative organisms and 26.6% to fungi. The factors present at randomization were evaluated for their association with infection. Group I assignment and H(2) blocker therapy (before study entry) were associated with increased risk of definite infection, whereas cesarean section delivery and increasing birth weight were associated with decreased risk. CONCLUSIONS: Infants who received a 14-day course of dexamethasone initiated at 2 weeks of age were more likely to develop a bloodstream or cerebrospinal fluid infection while on dexamethasone therapy than were those who received placebo. Physicians must consider this increased risk of infection when deciding whether to treat VLBW infants with dexamethasone.

Immunoassay and GC-MS procedures for the analysis of drugs of abuse in meconium.

The analysis of meconium specimens for metabolites of substances of abuse is a relatively accurate method for the detection of fetal exposure to drugs. Most of the methods reported in the literature before the early 1990s relied on radioimmunoassays. The purpose of this study was to develop and validate methods for meconium sample preparation for the screening and gas chromatography-mass spectrometry (GC-MS) confirmation of meconium extracts for cannabinoids, cocaine, opiates, amphetamines, and phencyclidine. EMIT and TDx immunoassays were evaluated as screening methods. The sample preparation method developed for screening included extraction and purification prior to analysis. Cutoff levels were administratively set at 20 ng/g for 11-nor-delta9-THC-9-COOH (THCCOOH) and phencyclidine and at 200 ng/g for benzoylecgonine, morphine, and amphetamines, although lower levels could be detected in meconium using the EMIT-ETS system. Ninety-five meconium specimens were subjected to the screening procedure with GC-MS confirmation of presumptive positives. In addition, 30 (40 for cocaine) meconium specimens were subjected to GC-MS analysis for all analytes regardless of the screening results to determine the false-negative rate, if any, of the immunoassay. Although there were no false negatives detected, the GC-MS confirmation rate for the immunoassay-positive specimens was generally low, ranging from 0% for amphetamines to 75% for opiates. The lowest rate of confirmed positives was found with the cannabinoids, suggesting that tetrahydrocannabinol (THC) metabolites other than free 11-nor-9-carboxy-delta9-THC may be major contributors to the immunoassay response in meconium.

Inaccuracy of Ballard scores before 28 weeks' gestation. National Institute of Child Health and Human Development Neonatal Research Network.

OBJECTIVE: Ballard scores are commonly used to estimate gestational age (GA). The purpose of this study was to determine the accuracy of the New Ballard Score (NBS) for infants <28 weeks GA by accurate menstrual history and to evaluate NBS as an outcome predictor. METHODS: Infants weighing 401 to 1500 g in 12 National Institute of Child Health and Human Development Neonatal Research Network centers had NBS performed before age 48 hours. Accuracy of NBS estimates of GA was assessed for infants with GA determined by accurate menstrual history. In a larger cohort of infants, NBS was included in regression models of the association of NBS and death, poor outcome, and duration of hospital stay. RESULTS: At each week from 22 to 28 weeks GA by accurate menstrual history, NBS estimates exceeded GA by dates by 1.3 to 3.3 weeks, and estimates varied widely (range of widths of 95% CIs for the observations, 6.8 to 11.9 weeks). NBS did not contribute significantly to regression models of death, poor outcome, or duration of hospital stay. CONCLUSIONS: Inaccuracies in GA determined by the NBS should be considered when treating extremely premature infants, particularly in decisions to forego or administer intensive care. Refinement of GA scoring systems is needed to optimize clinical benefit.

Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994.

OBJECTIVES: Our purpose was to determine the mortality and morbidity rates for infants weighing 501 to 1500 g according to gestational age, birth weight, and gender. STUDY DESIGN: Perinatal data were collected prospectively on an inborn cohort from January 1993 through December 1994 by 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated. RESULTS: Eighty-three percent of infants survived until discharge to home or to a long- term care facility (compared with 74% in 1988). Survival to discharge was 49% for infants weighing 501 to 750 g at birth, 85% for those 751 to 1000 g, 93% for those 1001 to 1250 g, and 96% for those 1251 to 1500 g. The majority of deaths occurred within the first 3 days of life. Mortality rates were greater for male than for female infants. Respiratory distress syndrome was the most frequent pulmonary disease (52%). Chronic lung disease (defined as an oxygen requirement at 36 weeks after conception) developed in 19%. Thirty-two percent of infants had evidence of intracranial hemorrhage. Periventricular leukomalacia was noted in 6% of infants who had ultrasonography after 2 weeks. The average duration of hospitalization for survivors was 68 days (122 days for surviving infants weighing 501 to 750 g, compared with an average of 43 days for surviving infants 1251 to 1500 g). Among infants who died, the average length of stay was 19 days. CONCLUSIONS: The mortality rate for infants weighing between 501 and 1500 g at birth continues to decline. This increase in survival is not accompanied by an increase in medical morbidity. There are interactions between birth weight, gestational age, sex, and survival rates.

Incidence, presenting features, risk factors and significance of late onset septicemia in very low birth weight infants. The National Institute of Child Health and Human Development Neonatal Research Network.

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.

Prevention of events with angiotensin-converting enzyme inhibition (the PEACE study design). Prevention of Events with Angiotensin-Converting Enzyme Inhibition.

The Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial is an 8,100 patient, randomized, double-blind, placebo-controlled trial designed to determine the usefulness of angiotensin-converting enzyme (ACE) inhibitors in treating coronary patients with preserved left ventricular ejection fraction. The hypothesis being tested in this trial is that patients with coronary disease and ejection fraction > or =40% who are treated with ACE inhibitors will experience a reduction in the incidence of cardiovascular death, nonfatal myocardial infarction, or a revascularization procedure compared with patients treated with conventional therapy. The design of the PEACE trial is described herein.

Central and autonomic nervous systems' signs associated with in utero exposure to cocaine/opiates.

In summary, we found that the prevalence of CNS/ANS signs was significantly higher in the infants exposed to cocaine and/or opiates than in nonexposed infants. However, the prevalence of a large number of these signs was less than 5%. The prevalence rates of these signs are lower when exposure involved cocaine only; thus, their assessment has limited clinical utility.

A multicenter trial of two dexamethasone regimens in ventilator-dependent premature infants.

BACKGROUND: Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown. METHODS: We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory index scores (mean airway pressure x the fraction of inspired oxygen) of 52.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of > or =2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered. RESULTS: The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone-placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo-dexamethasone group, and diminished weight gain and head growth (P< 0.001) in both groups. CONCLUSIONS: Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of ages.

Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network.

OBJECTIVE: Inconsistent effects of vitamin A supplementation on prevention of bronchopulmonary dysplasia have been reported. Meta-analysis of these reports resulted in a relative risk of 0.69-1.02 for death or bronchopulmonary dysplasia associated with vitamin A supplementation. Effective dosage regimens or serum retinol concentrations have not been determined in previous reports. The purpose of this pilot study was to define a vitamin A regimen that produces serum retinol concentrations of 25-55 micrograms/dl. STUDY DESIGN: In this three-phase study, 91 infants (mean birth weight 799-864 g) were enrolled. Vitamin A was administered three times/week for 4 weeks at an average daily dose of 986-2143 IU/day. Physical examinations were performed and serum retinol specimens were collected weekly to assess clinical signs of toxicity. RESULTS: The majority of serum retinol concentrations remained < 25 micrograms/dl until an intramuscular vitamin A dose of 5000 IU/dose three times/week was used. No clinical signs of toxicity were associated with the higher dosage and higher serum concentrations of vitamin A. CONCLUSION: A large clinical trial of vitamin A supplementation with 5000 IU/dose three times/week (25-114% more than the dose used in the three published clinical trials) is needed to assess whether vitamin A supplementation safely reduces the risk of bronchopulmonary dysplasia in very-low-birth-weight infants.

Serotype-specific immunoglobulin G antibody responses to pneumococcal polysaccharide vaccine in children with sickle cell anemia: effects of continued penicillin prophylaxis.

OBJECTIVES: (1) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and (2) to determine whether continued penicillin prophylaxis had any adverse effects on these responses. STUDY DESIGN: Children with sickle cell anemia, who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday, were randomly selected at age 5 years to continue penicillin prophylaxis or to receive placebo treatment. These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of randomization. RESULTS: Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor; the poorest response was to serotype 6B. The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment, and in subjects who received one or two pneumococcal vaccinations before reimmunization. The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype. CONCLUSIONS: Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies, regardless of previous pneumococcal vaccine history. Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization.

Viability, morbidity, and resource use among newborns of 501- to 800-g birth weight. National Institute of Child Health and Human Development Neonatal Research Network.

OBJECTIVES: To assess risk factors affecting viability and analyze the effects of mechanical ventilation (MV) on neonatal outcome and resource use among extremely premature infants. DESIGN: Inception cohort study. SETTING: Neonatal intensive care units of the 12-center National Institute of Child Health and Human Development Neonatal Research Network. PARTICIPANTS: A total of 1126 infants with a birth weight of 501 to 800 g born in network centers between January 1, 1994, and December 31, 1995. MAIN OUTCOME MEASURES: Observed survival; maximum estimated survival (assuming the same survival among infants who died without MV as among infants in the same risk category who received MV); observed and maximum estimated survival without severe brain injury (either interventricular echodensity with ventricular dilation or parenchymal echodensity); hospital stay; resource investment. RESULTS: Overall mortality was 43%; mortality in infants without MV was 93%. A total of 15% of all the infants died without MV. Females, small-for-gestational-age infants, and infants whose mothers received antenatal steroids had an advantage in survival with MV equivalent to an increase in birth weight of 90 g, 57 g, and 67 g, respectively. The corresponding advantage of these infants in survival without severe brain injury was 107 g, 97 g, and 64 g, respectively. Females in the lowest birth-weight group were more likely to die without MV than were larger males with a similar estimated likelihood of survival with MV. Mean hospital stay was 115 days for the survivors, values much greater than the 17.9-day standard for 501- to 800-g survivors under the diagnosis related group system. Resource investment was considerable (127 hospital days per survivor and 148 days per survivor without severe brain injury), but, like outcome, varied markedly between risk categories. Had MV been used for all infants who died, we estimate a substantial increase in resource use and a maximum of 8 additional survivors (no more than 6 without severe brain injury per 100 infants with a birth weight of 501 to 800 g. CONCLUSIONS: Although recommendations to initiate or forgo MV for extremely premature infants have often focused on 1 factor (birth weight or gestational age), multiple factors should be considered. Other factors being equal, our analyses support use of MV for females at a minimum birth weight approximately 100 g lower than that for males. The current diagnosis related group reimbursement system can be expected to compromise resources for 501- to 800-g infants who would benefit from MV. Such care entails considerable resource use, although the cost per life-year gained is likely to be considerably less than that for many adults given intensive care. Our findings can be used to facilitate more appropriate treatment decisions, determine adequate resources, and better inform the debate about the benefits and burdens of intensive care for extremely premature newborns.

Epidemiologic assessment of the role of blood pressure in stroke: the Framingham Study. 1970.

Control of hypertension, labile or fixed, systolic or diastolic, at any age, in either sex appears to be central to prevention of atherothrombotic brain infarction (ABI). Prospectively, hypertension proved the most common and potent precursor of ABI's. Its contribution was direct and could not be attributed to factors related both to stroke and hypertension. Asymptomatic, causal "hypertension" was associated with a risk of ABI about four times that of normotensives. The probability of occurrence of an ABI was predicted no better with both blood pressure measurements or the mean arterial pressure than with systolic alone. Since there was no diminishing impact of systolic pressure with advancing age, the concept that systolic elevations are, even in the aged, innocuous is premature. Comparing normotensives and hypertensives in each sex, women did not tolerate hypertension better than men.

Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network.

OBJECTIVE: Late-onset sepsis (occurring after 3 days of age) is an important problem in very low birth weight (VLBW) infants. To determine the current incidence of late-onset sepsis, risk factors for disease, and the impact of late-onset sepsis on subsequent hospital course, we evaluated a cohort of 7861 VLBW (401 to 1500 gm) neonates admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991 to 1993). METHODS: The NICHD Neonatal Research Network maintains a prospectively collected registry of all VLBW neonates cared for at participating centers. Data from this registry were analyzed retrospectively. RESULTS: Of 6911 infants who survived beyond 3 days, 1696 (25%) had one or more episodes of blood culture-proven sepsis. The vast majority of infection (73%) were caused by gram-positive organisms, with coagulase-negative staphylococci accounting for 55% of all infections. Rate of infection was inversely related to birth weight and gestational age. Complications of prematurity associated with an increased rate of infection included intubation, respiratory distress syndrome, prolonged ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, severe intraventricular hemorrhage, and necrotizing enterocolitis. Among infants with bronchopulmonary dysplasia, those with late-onset sepsis had a significantly longer duration of mechanical ventilation (45 vs 33 days; p <0.01). Late-onset sepsis prolonged hospital stay: the mean number of days in the hospital for VLBW neonates with and without late-onset sepsis was 86 and 61 days, respectively (p <0.001). Even after adjustment for other complications of prematurity, including intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia, infants with late-onset sepsis had a significantly longer hospitalization (p <0.001). Moreover, neonates in whom late-onset sepsis developed were significantly more likely to die than those who were uninfected (17% vs 7%; p <0.000 1), especially if they were infected with gram-negative organisms (40%) or fungi (28%). Deaths attributed to infection increased with increasing chronologic age. Whereas only 4% of deaths in the first 3 days of life were attributed to infection, 45% of deaths after 2 weeks were related to infection. CONCLUSIONS: Late-onset sepsis is a frequent and important problem among VLBW preterm infants. Successful strategies to decrease late-onset sepsis should decrease VLBW mortality rates, shorten hospital stay, and reduce costs.

Early-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network.

OBJECTIVE: Early-onset sepsis (occurring within 72 hours of birth) is included in the differential diagnosis of most very low birth weight (VLBW) neonates. To determine the current incidence of early-onset sepsis, risk factors for disease, and the impact of early-onset sepsis on subsequent hospital course, we studied a cohort of 7861 VLBW neonates (401 to 1500 gm) admitted to the 12 National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers during a 32-month period (1991-1993). METHODS: The NICHD Neonatal Research Network maintains a prospectively collected registry on all VLBW neonates born or cared for at participating centers. Data from this registry were analyzed retrospectively. RESULTS: Blood culture-proven early-onset sepsis was uncommon, occurring in only 1.9% of VLBW neonates. Group B streptococcus was the most frequent pathogen associated with early-onset sepsis (31%), followed by Escherichia coli (16%) and Haemophilus influenzae (12%). Decreasing gestational age was associated with increased rates of infection. Antibiotic therapy for suspected sepsis is frequently initiated at birth in VLBW neonates. Almost half of the infants in this cohort were considered to have clinical sepsis and continued to receive antibiotics for 5 or more days, despite a negative blood culture result in 98% of cases. These findings underscore the difficulty of ruling out sepsis in the symptomatic immature neonate and the special concern for culture-negative clinical sepsis in the face of maternal antibiotic use. Neonates with early-onset sepsis were significantly more likely to have subsequent comorbidities, including severe intraventricular hemorrhage, patent ductus arteriosus, and prolonged assisted ventilation. Although 26% of VLBW neonates with early-onset sepsis died, only 4% of the 950 deaths that occurred in the first 72 hours of life were attributed to infection. For those infants discharged alive, early-onset sepsis was associated with a significantly prolonged hospital stay (86 vs 69 days; p <0.02). CONCLUSIONS: Early-onset sepsis remains an important but uncommon problem among VLBW preterm infants. Improved diagnostic strategies are needed to enable the clinician to distinguish between the infected and the uninfected VLBW neonate with symptoms and to target continued antibiotic therapy to those who are truly infected.