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PEDIATRICS Vol. 112 No. 6 December 2003, pp. 1283-1289

Ventilator-Associated Pneumonia in Extremely Preterm Neonates in a Neonatal Intensive Care Unit: Characteristics, Risk Factors, and Outcomes

Anucha Apisarnthanarak, MD*, Galit Holzmann-Pazgal, MD*, Aaron Hamvas, MD{ddagger}, Margaret A. Olsen, PhD, MPH* and Victoria J. Fraser, MD*

* Division of Infectious Diseases, Departments of Pediatrics and Internal Medicine
{ddagger} Division of Newborn Medicine, St Louis Children’s Hospital, Washington University School of Medicine, St Louis, Missouri


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Objective. To determine the rates, characteristics, risk factors, and outcomes of ventilator-associated pneumonia (VAP) in extremely preterm neonates in a neonatal intensive care unit (NICU).

Methods. A prospective cohort study was conducted at the St Louis Children’s Hospital on all patients who had birth weight ≤2000 g and were admitted to the NICU for ≥48 hours from October 2000 to July 2001. Extremely preterm neonates were defined as neonates with estimated gestational age (EGA) <28 weeks. The primary outcome was the development of VAP. Secondary outcomes were death and NICU length of stay (LOS). Multiple logistic regression was performed to determine independent predictors for VAP and mortality.

Results. A total of 229 patients were enrolled. Sixty-seven (29%) had EGA <28 weeks. Nineteen episodes of VAP occurred in 19 (28.3%) of 67 mechanically ventilated patients. VAP rates were 6.5 per 1000 ventilator days for patients with EGA <28 weeks and 4 per 1000 ventilator days for EGA ≥28 weeks. By multivariate analysis, bloodstream infection before VAP (adjusted odds ratio: 3.5; 95% confidence interval [CI]: 1.2–10.8) was an independent risk factor for VAP after adjustment for the duration of endotracheal intubation. Ventilator-associated pneumonia (adjusted odds ratio: 3.4; 95% CI: 1.2–12.3) was an independent predictor of mortality. A strong association between VAP and mortality was observed in neonates who stayed in the NICU >30 days (relative risk: 8.0; 95% CI: 1.9–35.0). Patients with VAP also had prolonged NICU LOS (median: 138 vs 82 days).

Conclusions. VAP occurred at high rates in extremely preterm neonates and was associated with increased mortality. Additional studies are needed to develop interventions to prevent VAP in NICU patients.

Key Words: ventilator-associated pneumonia • neonates • neonatal intensive care unit • risk factors • characteristics • nosocomial infections • outcomes

Abbreviations: VAP, ventilator-associated pneumonia • ICU, intensive care unit • LOS, length of stay • NICU, neonatal intensive care unit • EGA, estimated gestational age • SNAP-PE, Score of Neonatal Acute Physiology-Perinatal Extension • NNIS, National Nosocomial Infection Surveillance • BSI, bloodstream infection • CI, confidence interval

Ventilator-associated pneumonia (VAP) is a common and severe complication of critical illness. It is associated with increased hospital and intensive care unit (ICU) length of stay (LOS) and a high morbidity and mortality rate in adult ICU patients.1–5 With an estimated incidence of 10% to 65%, VAP is the most common nosocomial infection in adult ICU patients, accounting for up to 30% of nosocomial infections in this population.6,7

Recognized risk factors for VAP in adult ICU patients include prolonged duration of mechanical ventilation, exposure to antibiotics, prolonged ICU stay, the presence of invasive devices, treatment with antacids or histamine type 2 antagonists, and advanced age.7–9 Increased mortality in adult ICU patients with VAP has been associated with infection by Acinetobacter species and Pseudomonas aeruginosa, more severe underlying illness, and inappropriate antibiotic therapy.10–12 The median excess LOS as a result of VAP in adults has been estimated at 7.7 days, and the attributable mortality has been estimated at 10%.3,9,13 Thus, VAP is considered to be the important cause of infection-related death in the ICU and is thought to have a negative influence on patients’ outcome.14–20 Whereas severity of underlying disease and the acute illness of adult patients with VAP are known to contribute to poor outcomes, there are limited data with respect to the incidence, characteristics, risk factors, and outcomes of VAP in critically ill newborns. A study in pediatric ICU patients identified genetic syndromes, reintubation, and transport out of the pediatric ICU as independent risk factors for VAP in these patients.21 Because neonates have different anatomy, physiology, and underlying diseases and undergo different invasive procedures compared with adults and older children, specific studies of risk factors and outcomes for VAP in neonates are needed. We performed a prospective cohort study of neonates who had birth weight <2000 g and were admitted to the St Louis’ Children Hospital neonatal ICU (NICU) from October 1, 2000, to July 31, 2001, to determine risk factors and outcomes of VAP in extremely premature neonates.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Setting
St Louis Children’s Hospital is a 235-bed academic tertiary care center affiliated with Washington University School of Medicine. St Louis Children’s Hospital has a 300-mile radius referral base in southeastern Missouri and southwestern Illinois. The St Louis’s Children Hospital NICU is a level 3, 52-bed NICU with 700 to 750 admissions per year and an average census of 50 patients. The NICU is staffed by 3 neonatologists, 2 fellows in newborn medicine, 5 pediatric housestaff, and several nurse practitioners. All rotate monthly. The estimated patient-to-nurse ratio is 1 to 1 for neonates with estimated gestational age (EGA) <28 and 2 to 1 for neonates with EGA ≥28 weeks.

Patients
From October 1, 2000, to July 31, 2001, all patients who had birth weight ≤2000 g and were admitted to the NICU for >48 hours were included in the study. Patients who were transferred to the NICU from an outside hospital were included, even when their admission weight to the NICU was >2000 g, as long as their birth weight was ≤2000 g. The exclusion criteria included death within 48 hours of the NICU admission. All eligible patients were followed for the development of nosocomial infection from the day of the NICU admission until their discharge from the NICU. When the patients were discharged to another St Louis’s Children Hospital location or the nursery of an affiliated university hospital (Barnes-Jewish Hospital), they were followed for an additional 48 hours after NICU discharge. Institutional Review Board and NICU Review Board approval were obtained before initiation of the study.

Data Collection
Medical records, including charts, daily flow sheets, and laboratory and radiographic reports, were reviewed prospectively by 1 of the investigators (G.H.P). Data on patient demographics, underlying diseases, medications, central venous and arterial catheters, invasive procedures, ventilator use, LOS in the NICU, and concurrent nosocomial infections were recorded. Admission severity of illness was calculated using the Score of Neonatal Acute Physiology-Perinatal Extension (SNAP-PE) score in the first 24 hours of NICU admission, according to the method of Richardson and colleagues.22,23 Medications recorded included dexamethasone, skin lubricant (Aquaphor), histamine type 2 antagonists, surfactant, intravenous immunoglobulin, and therapeutic antibiotics. In our NICU, dexamethasone was administered only to neonates who required ventilator support for >2 weeks and were expected to survive but not for neonates who were not expected to survive. For patients with VAP, risk factors were evaluated from the time of admission until the onset of VAP. For patients who did not develop VAP, risk factors were evaluated for their entire NICU stay.

Definitions
The Centers for Diseases Control and Prevention/National Nosocomial Infection Surveillance (NNIS) definitions for infants ≤12 months were used for nosocomial infections, specifically bloodstream infections (BSIs) and VAP.24 A nosocomial infection was defined as an infection not present or incubating at the time of NICU admission and occurring >48 hours after NICU admission. For the diagnosis of VAP, the patient was also required to have received at least 48 hours of mechanical ventilation and developed new and persistent radiographic evidence of focal infiltrates 48 hours or more after the initiation of mechanical ventilation. In addition, these patients had to receive antibiotics for treatment of VAP for at least 7 days. NICU attending physicians reviewed all radiographs to confirm the diagnosis of VAP and to rule out other possible diagnoses, such as hyaline membrane disease, meconium aspiration, early development of bronchopulmonary dysplasia, and atelectasis. The pediatric infectious disease fellow (G.H.P.) retrospectively confirmed all diagnosis of VAP on the basis of review of the medical records; there was 100% agreement in the diagnosis of VAP between the NICU attending physicians and the pediatric infectious disease fellow. VAP-associated organisms were designated as organisms recovered from tracheal aspirates on the day of diagnosis. Ballard score and the date of the patient’s mother’s last menstrual period were used to define EGA. When the results of these measures were different by ≥1 week, Ballard score was documented. All gestational ages were specified in weeks. Extremely preterm neonate was defined as a neonate with EGA <28 weeks.

Data Analysis
A nested case-control method was used to analyze risk factors and outcomes of VAP. Data analysis was performed using SPSS Version 10.0 (SPSS, Chicago, IL). Categorical variables were compared using {chi}2 or Fisher exact test, as appropriate. Continuous variables were compared using the Wilcoxon rank sum test. All P values were two tailed; P < .05 was considered statistically significant. Adjusted odds ratios and 95% confidence intervals (CIs) were computed for the significant factors. Because the pulmonary physiology and the mortality rates of neonates with EGA <28 weeks are different from those of neonates with EGA ≥28 weeks,25–28 we performed analyses to determine the rates, risk factors, and outcomes of VAP in extremely preterm neonates with EGA <28 weeks. The primary outcome measured was the development of VAP, and secondary outcomes were death and NICU LOS. Variables that were present in >10% of VAP patients with P < .20 or that had a priori clinical significance were entered into backward stepwise logistic regression models. Significant variables that were thought to covary were grouped, and only 1 variable from each group was chosen for entry into the model. The final model was chosen on the basis of biological plausibility and by selecting the logistic regression model with the lowest –2 log likelihood function.29


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 229 patients were enrolled from October 1, 2000, to July 31, 2001. The median gestational age was 29 weeks (range: 22–39 weeks). Sixty-seven (29%) patients had EGA <28 weeks, and 162 (71%) patients had EGA ≥28 weeks. The median LOS in the NICU was 76 days (range: 4–361 days) for patients with EGA <28 weeks and 17 days (range: 3–150 days) for patients with EGA ≥28 weeks. Twenty-four neonates were transferred to our institution from outside hospitals. Five (21%) of these neonates had EGA <28 weeks. The median duration from birth to transfer to our hospital was 26 days (range: 19–85 days). One of these neonates (1 of 5 [20%]) developed VAP 21 days after transfer to our hospital. Ten patients had invasive procedures before the onset of VAP in the cohort of extremely preterm neonates. These invasive procedures included patent ductus arteriosus ligation (9) and tracheostomy (1). The median duration from the time of invasive procedure to the onset of VAP was 28 days (range: 5–68 days). Patient demographics, underlying diseases, medications, and outcomes are summarized in Table 1.


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  		TABLE 1. NICU Patient Characteristics: Demographics, Underlying Diseases, Medications, and Outcomes

 
Of all 229 patients, 211 (92%) required intubation for >48 hours. Of the 211 mechanically ventilated patients, 26 (12.3%) episodes of VAP occurred in 24 patients. Two patients had 2 episodes of VAP. Reintubations were performed in 134 (63.5%) patients. Nineteen patients with EGA <28 weeks (19 of 67 [28%]) developed VAP, and 5 patients with EGA ≥28 weeks (5 of 144 [3.5%]) developed VAP (P < .001). VAP rates were 6.5 per 1000 ventilator days for patients with EGA <28 weeks and 4 per 1000 ventilator days for EGA >28 weeks (P = .34). The rate of VAP stratified by EGA is shown in Fig 1. Twenty-four patients died. Of these patients, 18 had EGA <28 weeks. The higher VAP incidence in the neonates with EGA <28 weeks supports our decision to analyze specifically risk factors and outcomes in this group.


Figure 1
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  		Fig 1. Distribution of VAP rates per 1000 ventilator days among neonates with gestational age between 22 and 24, 25 and 27, 28 and 30, and 31 and 33 weeks.

 
The most common clinical symptoms associated with VAP included hypothermia and tachypnea, whereas purulent tracheal aspirates (>25 white blood cells/high-powered field on tracheal aspirate Gram stain) was the most common laboratory finding (Table 2). Microorganisms associated with purulent tracheal aspirates in extremely preterm neonates include Pseudomonas species (2), Enterobacter species (2). Klebsiella species (2), and Staphylococcus aureus (1). Multiple organisms were isolated from respiratory secretions in 11 episodes (11 of 19 [58%]) of VAP. Gram-negative bacteria were isolated from respiratory secretions in 18 (18 of 19 [94%]) VAP episodes. The microbiology of VAP is summarized in Table 3.


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  		TABLE 2. Clinical Symptoms and Laboratory Characteristics of VAP

 

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  		TABLE 3. Microorganisms Recovered From Respiratory Secretions of VAP

 
On univariate analysis of neonates with EGA <28 weeks, the only significant risk factor for VAP included previous BSI; the duration of endotracheal intubation before the onset of VAP was marginally significant (Table 4). Patients with VAP had significantly prolonged LOS in the NICU (median: 138 days vs 82 days; P = .003) and had a higher crude risk of mortality (odds ratio: 3.9; 95% CI: 1.1–14.6). There were no significant differences between patients with and without VAP with respect to other characteristics and risk factors examined (Table 4). Multivariate logistic regression was used to identify independent risk factors for VAP. The final model included previous BSI and duration of endotracheal intubation before VAP. BSI was significant in the multivariate analysis, whereas the duration of endotracheal intubation was marginally significant (Table 5). Micro-organism associated with BSI included Escherichia coli (4 of 12 [33.3%]), Pseudomonas species (2 of 12 [16.6%]), Enterobacter species (2 of 12 [16.6%]), S aureus (2 of 12 [16.6%]), Coagulase-negative Staphylococcus (1 of 12 [8.3%]), and Candida species (1 of 12 [8.3%]). None of the VAP patients had pneumonia caused by the same organism that caused their BSI. The median duration of endotracheal intubation before the development of VAP was 37 days (range: 3–157 days), and the median time from BSI to the diagnosis of VAP was 28 days (range: 1–116 days). There was no difference in the distribution of micro-organism associated with BSI among patients who developed VAP and those who did not develop VAP.


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  		TABLE 4. Univariate Analysis of Extremely Preterm Intubated Neonates With and Without VAP

 

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  		TABLE 5. Logistic Regression Analysis of Factors Associated With VAP in Extremely Preterm NICU Patients

 
In the univariate analysis of mortality, the presence of an arterial catheter before VAP, SNAP-PE score, and VAP were significant risk factors for mortality, whereas receipt of dexamethasone before VAP had a protective effect on mortality (Table 6). Multivariate logistic regression was used to identify independent risk factors for mortality. The final model included VAP and the presence of an arterial catheter. Because dexamethasone was administered only to neonates who required ventilator support for >2 weeks and were expected to survive, it was not entered in the multivariate models. VAP was the only significant risk factor for mortality, whereas the presence of an arterial catheter was marginally significant (Table 7). A strong association between VAP and mortality was observed in 56 patients who stayed in the NICU at least 30 days (7 of 17 [42%] vs 2 of 39 [5%]; relative risk 8.0; 95% CI: 1.9–35.0; P < .001) but not for the 11 patients who stayed <30 days (2 of 2 [100%] vs 7 of 9 [77.8]; relative risk: 1.3; 95% CI: 0.9–1.8; P = .48). For those who died, the median duration from the onset of VAP to death was 25 days (range: 1–196 days).


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  		TABLE 6. Univariate Analysis of Factors Associated With Death in Extremely Preterm Intubated Patients

 

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  		TABLE 7. Logistic Regression of Factors Associated With Death in NICU Patients

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, previous BSI was a significant independent risk factor associated with the development of VAP, and the duration of endotracheal intubation was marginally significant in extremely preterm neonates. VAP was found to be significantly associated with mortality in extremely preterm neonates who stayed in the NICU for at least 30 days. Severity of illness, as measured by the SNAP-PE score, has not been used as a measure of severity of illness measurement in neonates. The SNAP-PE score is more sensitive and specific than either the SNAP score or birth weight alone in predicting mortality.22,23 It provides a simple additive score including birth weight (<750 g vs 750–999 g), Apgar score at 5 minutes, and the effect of small for gestational age (<5th percentile) to the severity of illness measurement (SNAP score). Although the effects of severity of illness seem to be completely independent of birth weight, Richardson et al22 suggested that the effects of birth weight added to the SNAP score are powerful in predicting mortality in the population of extremely preterm neonates (<750 g). Because the majority of the extremely preterm neonates in our cohort (48 of 67 [72%]) had birth weight <750 g, SNAP-PE score may be a better severity measurement score to evaluate for nosocomial infections. To our knowledge, this study is the first to characterize risk factors and outcomes of VAP in extremely preterm NICU patients using the SNAP-PE score to measure for severity of illness.

There are no published data comparing rates of VAP stratified by gestational age. According to NNIS, median VAP rates were 4.8, 3.6, and 2.9 per 1000 ventilator days for patients ≤1000 g, 1001 to 1500 g, and 1501 to 2000 g, respectively.30,31 VAP rates at our institution compared with NNIS were approximately the 50th to 75th percentile for patients <1000 g and 1001 to 1500 g and at the 75th to 90th percentile for patients 1501 to 2000 g. Because many NNIS hospitals use only microbiology reports to identify patients with VAP, NNIS rates may underestimate the true incidence of VAP. In addition, the NNIS participants consist of a heterogeneous group of NICUs. In contrast, the St Louis’s Children Hospital NICU is a tertiary care center with a large volume of admissions and patients with relatively high severity of illness. Therefore, our VAP rates are probably more representatives of NICUs in large academic tertiary care centers than is the national data.

The NNIS criteria for the diagnosis of VAP for patients ≤12 months of age uses the combination of clinical characteristics, microbiology, radiography, and histopathologic evidence of pneumonia.24 These criteria lack specificity and contribute to the difficulty in clearly defining risks of VAP.32 Attempts should be made to develop more specific definitions to help define NICU patients who are at risk for VAP. The cause of most VAP in NICU patients is polymicrobial.33,34 Bacterial micro-organisms responsible for nosocomial pneumonia are most commonly aerobic Gram-negative bacilli such as K pneumoniae, E coli, and P aeruginosa and Gram-positive cocci such as S aureus.33,34 The distribution of causative micro-organisms that we found is similar to that reported in the literature.

Low birth weight, the presence of central venous or arterial catheters, indomethacin for treatment of patent ductus arteriosus, broad-spectrum antibiotic therapy, and total parenteral nutrition with lipid emulsions all have been shown to be associated with nosocomial infections in NICU patients.35–42 However, data on risk factors for VAP in this population are scarce. In one study, prolonged endotracheal intubation was found to be an independent risk factor for VAP in a high-risk nursery.43 We found previous BSI to be a significant risk factor for VAP, and duration of endotracheal intubations was only marginally significant, which was probably attributable to the low power of the study and the restriction of the analysis to neonates with EGA <28 weeks. Because severity of illness (SNAP-PE) was measured in the first 24 hours after admission and the majority of patients in our cohort developed late VAP (median: 36 days), the SNAP-PE score used in our study may not be a good marker for the severity of illness immediately preceding VAP. Because none of the VAP patients developed pneumonia caused by the same organism that caused their BSI, it is unlikely that VAP occurred as a direct consequence of BSI. BSI might serve as a surrogate marker for severity of illness in our population of VAP patients. In our analysis, the risk of VAP increased by 11% for every additional week that the patient was on the ventilator (Table 6). This finding supports the role of prolonged endotracheal intubation as a potential risk factor for VAP in NICU patients.

Several studies have reported a relationship between nosocomial pneumonia and mortality in adult ICU patients.1–5,44–46 It is unclear whether VAP contributes to higher mortality in NICU patients. We identified VAP, SNAP-PE score, and the presence of arterial catheter as significant risk factors for mortality in the univariate analysis, whereas receipt of dexamethasone was associated with lower mortality. Because dexamethasone was administered only to neonates who were expected to survive, it was not surprising to see its protective effect. VAP was a significant risk factor for mortality, particularly for neonates who stayed at least 30 days but not with those who stayed <30 days in NICU. This difference is that patients who stayed <30 days in NICU had a high mortality rate unrelated to nosocomial infection and had less time to develop VAP. The presence of arterial catheters might also be a surrogate marker for severity of illness.

Infections early in life have a huge impact on LOS in the NICU but less on the overall length of hospital stay.47 Previous studies found a mean excess length of hospital stay of 5.2 to 24 days for hospital-acquired infections in NICU patients47–49; however, data on excess LOS specifically caused by VAP were lacking. We found extremely preterm patients with VAP to have a median excess crude length of NICU stay of 56 days. Because we analyzed only extremely preterm VAP patients, our results might not be applicable to patients of different gestational ages or to patients with different types of nosocomial infections.

There are several limitations in our study. We recognize that EGA results may not be completely accurate. Nevertheless, this bias is conservative, because the majority of patients (92.5%) in our study with EGA <28 weeks had birth weight <1000 g. Our small sample size limits the statistical power to detect other possible independent risk factors for VAP and for mortality. There are also limitations to the NNIS definition of VAP, which lacks specificity; however, there is no current gold standard for defining or diagnosing VAP. Because tracheal aspiration was used as a means to identify organisms associated with VAP, we found that the majority of our VAP patients (58%) had multiple organisms isolated. This finding, in addition to the finding that the majority of VAP patients (63%) did not have purulent tracheal aspirates, suggests that some of these VAP episodes may represent colonization rather than true VAP. Nevertheless, this limitation was minimized because our NICU attending physician and pediatric infectious disease fellow reviewed the radiographs for all patients and concurred with the diagnosis of VAP. Our data did not include the indication for reintubation, which may also be a relevant risk factor for VAP. Because the majority of our NICU patients developed late pneumonia, it is likely that the SNAP-PE score determined within 24 hours after admission was not as informative as a SNAP-PE score calculation immediately before the onset of VAP. Because many of the NICU patients had concurrent nosocomial infections during their NICU stay, the attributable morbidity and mortality associated with VAP cannot be determined from our study.

VAP occurred at high rates in extremely preterm neonates in the NICU and was associated with previous BSI and with prolonged duration of endotracheal intubation. Patients with VAP were more likely to die and had significantly prolonged NICU LOS. Systematic surveillance programs to identify VAP rates in NICU patients may be helpful in guiding daily practice and as a measure of quality improvement. Interventions to prevent BSIs and reduce the duration of endotracheal intubation may help to prevent VAP in NICU patients. Additional studies of rates, risk factors, and outcomes as well as studies to determine the attributable LOS and mortality as a result of VAP in NICU patients are needed.


   ACKNOWLEDGMENTS
 
This work was supported by a grant from the National Foundation for Infectious Diseases (Dr Holzmann-Pazgal) and in part by the Centers for Disease Control and Prevention Cooperative Agreement UR8/CCU715087 (Dr Fraser).

We thank J. Russell Little, MD, Hilary Babcock, MD, and Gregory Storch, MD, for critical review of our manuscript.


   FOOTNOTES
 
Received for publication Dec 10, 2002; Accepted Apr 30, 2003.

Address correspondence to Anucha Apisarnthanarak, MD, Thammasart University Hospital, Pratumthani, Thailand 12120. E-mail: anapisarn{at}yahoo.com

Reprint requests to (V.J.F.) Washington University School of Medicine, Campus Box 8051, 660 South Euclid Ave, St Louis, MO 63110. E-mail: vfraser{at}im.wustl.edu


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 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics



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