Original Article
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Receipt of Palivizumab before Birth Hospitalization Discharge among Preterm Infants in the United States Edmund F. La Gamma, MD1 Veena R. Kumar, MD, MPH2 Rajan Wadhawan, MD, MMM3 Sherry Ye, MSc4 Frangiscos Sifakis, PhD, MPH2 Joseph Ycas, PhD4 Christopher S. Ambrose, MD2 1 Maria Fareri Children’s Hospital, Westchester Medical Center-
New York Medical College, Valhalla, New York 2 AstraZeneca, Gaithersburg, Maryland 3 Florida Hospital for Children, Orlando, Florida 4 AstraZeneca Pharmaceuticals, Wilmington, Delaware
Address for correspondence Veena R. Kumar, MD, MPH, US Medical Affairs, AstraZeneca, One MedImmune Way, Gaithersburg, MD 20878 (e-mail: [email protected]).
Abstract
Keywords
► palivizumab ► preterm infants ► respiratory syncytial virus ► vitamin K ► hepatitis B vaccine
Objective This study aims to determine predischarge palivizumab receipt prevalence among infants 36 weeks’ gestational age. Study Design This retrospective cohort study used hospital discharge records from the Premier Perspective database (Premier Inc., Charlotte, NC) of infants 36 weeks’ gestational age who were discharged home after birth hospitalization during the November–March respiratory syncytial virus (RSV) seasons from 2006 to 2011. Descriptive statistics were performed and logistic regression was employed to identify differences in categorical variables. Results Among infants 36 weeks’ gestational age discharged home during the RSV seasons, 21.4 to 27.0% had a record of palivizumab receipt before discharge. Among infants 30 weeks’ gestational age, palivizumab receipt was 82.3 to 88.8%. Receipt varied considerably at the hospital level, from 0 to 100%. Conclusion This study improves our understanding of characteristics associated with predischarge palivizumab administration. The identified gaps in recommended care can help inform future implementation of palivizumab and other interventions to help improve the health of high-risk preterm infants in the United States.
Respiratory syncytial virus (RSV) is a significant pathogen of infants and young children, causing annual epidemics of bronchiolitis and pneumonia worldwide.1,2 The greatest morbidity and mortality occur among children in specific high-risk populations, including preterm infants born at 35 weeks’ gestational age (wGA), children 24 months of age with chronic lung disease of prematurity (CLDP), and children 24 months of age with hemodynamically significant congenital heart disease (CHD).1,2 Preterm infants are at an increased risk for developing severe RSV disease due to
smaller lung volumes at birth, immature immune systems,3 and incomplete transfer of maternal antibodies.4 Palivizumab is a monoclonal antibody that has been shown to significantly reduce RSV-related hospitalizations in high-risk children, including preterm infants.5 In preterm infants without bronchopulmonary dysplasia, two randomized, placebo-controlled trials demonstrated that prophylaxis with palivizumab reduced hospitalizations due to severe RSV disease by 72 to 82%.5,6 Palivizumab is recommended to be administered as a monthly injection immediately before the
received July 11, 2014 accepted after revision December 5, 2014 published online April 15, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1543951. ISSN 0735-1631.
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Am J Perinatol 2015;32:1017–1023.
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start of the RSV season and continued throughout the season.7 From November 1998 to July 2014, the American Academy of Pediatrics (AAP) RSV prophylaxis guidelines have stated that preterm infants born at < 32 wGA are eligible to receive palivizumab during the RSV season to help prevent severe RSV disease.8–11 From 1998 to 2009, those born at 32 to 35 wGA were also eligible for dosing during the season if they had certain risk factors. From 2003 to 2009, RSV prophylaxis was recommended for infants 32 to 35 wGA if two or more of the following risk factors were present: childcare attendance, school-aged siblings, exposure to environmental air pollutants, congenital abnormalities of the airways, or severe neuromuscular disease.9,10 In 2009, eligibility was modified to only include infants born at 32 to 34 wGA who had at least one of the following two risk factors: childcare attendance or sibling < 5 years of age; 35 wGA infants were no longer eligible to receive palivizumab.11 Hospital dosing practices could vary considerably by institution and may have changed over time. This study assessed US in-hospital palivizumab receipt prevalence among infants 36 wGA discharged home during the RSV season from 2006 to 2011.
Methods Study Design This retrospective cohort study used hospital discharge records collected from Premier’s Perspective database (Premier Inc., Charlotte, NC). Records of US infants 36 wGA who were discharged home after birth hospitalization during the RSV season (predefined as November 1 through March 31) from 2006 to 2011 were included. Infants with an International Classification of Disease (ICD)-9 discharge diagnosis code 36 wGA who were born between January 1, 2006 and March 31, 2011 were included in the analysis. Infants were excluded if no GA was recorded, they had a missing birth month or year, missing discharge month or year, died before discharge, were discharged outside of the predefined RSV season, or were transferred to another institution during the RSV season.
Data Source and Compliance The Premier Perspective database is the largest hospitalbased, service-level database in the United States, representing approximately 20% of US nonfederal short-term hospital discharges from more than 500 hospitals, which are weighted to provide national estimates. It includes data at the individual patient level on all billed services on a total of approximately 5 million hospital discharge records per year, and is maintained in compliance with the Health Insurance Portability and Accountability Act. The number of hospitals that provide data changes modestly; the year-to-year hospital retention rate is > 95%, data used in this study were deidentified and aggregated before retrieval from the Premier Perspective database; as such, use of the information for research purposes did not require institutional review board approval. American Journal of Perinatology
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Data Extraction and Analysis The primary outcome variable was the proportion of infants 36 wGA who received palivizumab before discharge from the birth hospitalization during the five consecutive RSV seasons. The discharges were captured from all hospitals in the Premier Perspective database, including but not limited to children’s hospitals. As ICD-9 diagnosis codes are delineated in successive 2-wGA increments, it was not possible to distinguish infants 31-wGA from infants 32-wGA or 35and 36-wGA (who have had different palivizumab recommendations based on the AAP guidelines). To provide context, secondary outcome comparisons were the standard receipt of hepatitis B vaccine and vitamin K before discharge from the birth hospitalization during the same time period. Descriptive analyses used hospital discharge data that were projected to estimate the total US population. The American Hospital Association 2012 Annual Survey was utilized by Premier to identify the universe of US hospitals and to generate the projection weights at the hospital level. The hospital-level weights were then applied to individual discharges. Both unweighted (observed) and weighted (projected) estimates were calculated for each study variable. Projected estimates were used to adjust for changes in the annual sample and to provide an estimate at the national level. The pooled prevalence of receipt of a hospital dose of palivizumab was calculated across all five RSV seasons and locations by calculating the proportion of infants who received a hospital dose of palivizumab over the total number of infants included in the analysis. The prevalence of the primary outcome was separately calculated for each RSV season, discharge month, hospital regional location, hospital size (by number of beds), and hospital type, overall and by GA category ( 30, 31–34, and 35–36 wGA).
Statistical Analyses In-depth analysis of patient characteristics and logistic regression analyses of predictive factors were restricted to the universally eligible group of infants 30 wGA. A stepwise logistic regression analysis (entry criterion p 0.10) was conducted to assess the association between > 90% palivizumab receipt and hospital characteristics, including the number of beds, urban/rural setting, regional location, and teaching/ nonteaching status. When exploring the possible relationships between hospital characteristics and hospital-averaged outcomes, hospital data were weighted to reflect the number of infants in the sample, placing more weight on hospitals with greater numbers of patients. A stepwise logistic regression analysis was also used to evaluate the association of palivizumab receipt with clinical characteristics of infants 30 wGA. When exploring possible interrelationships between patient characteristics and outcomes, analyses used unweighted data as received from the Premier Perspective database, with hospital as a predictor class variable to account for clustering.
Results The projected number of infants 36 wGA who were discharged home during the November through March RSV
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Palivizumab Receipt before Hospital Discharge season from 2006 to 2011 in the United States was 554,125. The majority (56.2%) of these infants were 35 to 36 wGA. Among all infants, as recorded GA increased, the median hospital length of stay (LOS) incrementally decreased as expected. For recipients and nonrecipients of palivizumab, the hospital LOS was similar between GA groups. Among infants who received palivizumab, the respective hospital LOS by GA group was 108 days (24 wGA), 87 days (25–26 wGA), 64 days (27–28 wGA), 44 days (29–30 wGA), 28 days (31–32 wGA), 15 days (33–34 wGA), and 11 days (35–36 wGA). Among infants who did not receive palivizumab, the respective hospital LOS by GA group was 84 days (24 wGA), 88 days (25–26 wGA), 59 days (27–28 wGA), 43 days (29–30 wGA),
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23 days (31–32 wGA), 12 days (33–34 wGA), and 3 days (35–36 wGA). Across all five RSV seasons, the projected proportion of infants 36 wGA who received palivizumab before discharge from the birth hospitalization was 23.8%, with a peak of 27.0% in the 2010 to 2011 RSV season (►Table 1). The proportion of infants who received palivizumab decreased over the discharge months from 25.2% in November to 21.9% in March. Across all five RSV seasons, projected palivizumab receipt proportions were highest in infants 30 wGA (►Table 1). Among infants 31 to 34 wGA, the proportion who received palivizumab increased from 37.9% in 2008 to 2009 to 45.3% in 2009 to 2010, and was higher still in 2010 to
Palivizumab receipt among infants discharged home n (%) 36 wGA (Total N ¼ 554,125)
30 wGA (Total N ¼ 50,705)
31–34 wGA (Total N ¼ 192,153)
35–36 wGA (Total N ¼ 311,267)
2006–2007
23,954 (21.4)
7,692 (83.3)
14,040 (36.2)
2,222 (3.5)
2007–2008
25,655 (22.2)
8,588 (82.3)
14,567 (35.9)
2,501 (3.9)
RSV season
2008–2009
26,497 (23.2)
8,762 (85.2)
15,118 (37.9)
2,617 (4.1)
2009–2010
28,158 (25.7)
9,552 (87.4)
17,184 (45.3)
1,422 (2.3)
2010–2011
27,841 (27.0)
8,723 (88.8)
17,694 (50.7)
1,424 (2.4)
Overall: 2006–2011
132,105 (23.8)
43,317 (85.4)
78,602 (40.9)
10,186 (3.3)
27,523 (25.2)
8,549 (83.2)
16,756 (43.6)
2,218 (3.7)
December
27,848 (24.4)
9,450 (86.8)
16,173 (40.2)
2,226 (3.5)
January
26,855 (23.9)
8,615 (85.8)
16,171 (42.8)
2,068 (3.2)
February
24,905 (23.9)
8,048 (87.8)
14,784 (41.4)
2,073(3.5)
24,974 (21.9)
8,655 (83.8)
14,717 (36.8)
1,602 (2.5)
Midwest
21,457 (18.5)
5,172 (77.0)
13,982 (37.0)
2,302 (3.2)
Northeast
16,904 (18.4)
5,441 (67.3)
10,308 (33.4)
1,155 (2.2)
Discharge month November
March Hospital regional location
a
South
67,443 (29.3)
24,518 (94.0)
37,990 (45.8)
4,935 (4.1)
West
26,302 (22.7)
8,186 (83.3)
16,321 (40.2)
1,794 (2.7)
1–199
5,333 (8.9)
1,197 (58.6)
3,636 (22.5)
499 (1.2)
200–299
15,059 (18.8)
2,653 (59.9)
9,858 (37.5)
2,549 (5.2)
300–399
33,700 (21.9)
10,627 (82.7)
20,467 (37.2)
2,606 (3.0)
400–499
27,431 (26.5)
8,206 (91.9)
17,512 (48.1)
1,713 (2.9)
500
50,581 (32.2)
20,634 (91.9)
27,129 (46.5)
2,819 (3.7)
Nonteaching
88,322 (22.0)
25,155 (82.6)
55,093 (40.9)
8,074 (3.4)
Teaching
43,786 (28.8)
18,163 (89.6)
23,508 (41.0)
2,112 (2.8)
Number of hospital beds
Hospital type
Abbreviations: GA, gestational age; RSV, respiratory syncytial virus; wGA, weeks’ gestational age. a For reference, the distribution of the 2010 US population by US Census Bureau Regions was 21.7% Midwest, 17.9% Northeast, 37.1% South, and 23.3% West.19 American Journal of Perinatology
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Table 1 Palivizumab receipt among infants 36 wGA discharged home during November through March RSV season (2006–2011) overall and by GA category (projected)
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2011 (50.7%) (►Table 1). Palivizumab receipt decreased over time in infants 35 to 36 wGA; 3.5 to 4.1% in 2006 to 2009 versus 2.3 to 2.4% in 2009 to 2011 (►Table 1).
Hospital Characteristics Among infants 36 wGA, by hospital location and size, the highest proportions of palivizumab receipt were observed in the South and West and in hospitals with 400 beds (►Table 1). In addition, a higher proportion (28.8%) of infants in teaching hospitals received palivizumab compared with nonteaching hospitals (22.0%) (►Table 1). Among infants 30 wGA, palivizumab receipt was higher (90.9%) in hospitals located in rural areas than in urban areas (85.3%), the latter having discharged the majority (98.2%) of infants; receipt was highest in the South and lowest in the Northeast (94.0 and 67.3%, respectively) (►Table 1). The frequency of palivizumab receipt was higher in teaching hospitals than in nonteaching hospitals (89.6 and 82.6%, respectively) (►Table 1). Receipt proportions were highest in hospitals with 300 beds (►Table 1). Multivariate analysis of hospital characteristics that correlated with > 90% palivizumab receipt among infants 30 wGA found a statistically significant association with hospital size (odds ratio [OR] ¼ 1.003 per one-bed increment; 95% confidence interval [CI] 1.003, 1.004; p < 0.001). With respect to hospital nursery levels, the majority of infants were discharged home from a Level II combined nursery (i.e., Level II continuing care nursery and Level II boarder baby nursery) (36.7%) or Level III intermediate care nursery (32.5%). Of these infants, 88.9% received palivizumab. The proportion with reported palivizumab receipt was lower (70.8%) for those discharged from a Level IV intensive care nursery.
Patient Characteristics among Infants 30 wGA Projected palivizumab receipt proportions were higher for non-White infants. With respect to payers, the highest (> 90%) palivizumab receipt proportions were observed for infants covered by indigent, capitated and noncapitated Medicare, and worker’s compensation (100% each); and capitated managed care (94.2%). The lowest (31.7%) receipt proportion was observed in those with charity care. The mean (standard deviation; SD) hospital LOS was 65.1 (30.9) days, while the mean neonatal intensive care unit (NICU) LOS was 62.5 (31.6) days. Projected palivizumab receipt proportions were highest ( 81%) in infants weighing < 500 to 1,999 g, lower (68.3%) in infants 2,000 to 2,499 g, and lowest (13.6%) in the small number of infants weighing 2,500 g. By comorbid condition, palivizumab was most frequently (> 80%) administered to those infants with reported diagnoses of immunocompromised state, Down syndrome, CHD, CLDP, gastrointestinal disease, and congenital abnormality of the airway; whereas, the lowest proportion of palivizumab receipt (48.6%) was observed in the small number of infants with cystic fibrosis (►Table 2). Palivizumab receipt proportions were high and similar ( 86%) in infants with other medical needs such as supplemental oxygen, mechanical ventilation, and bronchodilator, steroid and/or American Journal of Perinatology
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diuretic therapy (►Table 2). Across all RSV seasons, the proportions of infants who received vitamin K and hepatitis B vaccine were lower than those of infants who received palivizumab (►Fig. 1). At the patient level, adjusting for hospital, logistic regression revealed birth weight was a robust predictor of palivizumab receipt. With < 500 g as the reference weight, infants who weighed 2,500 g demonstrated markedly lower palivizumab receipt (OR ¼ 0.094, 95% CI 0.021, 0.417; p < 0.001). Records of infants 30 wGA with birth weight 2,500 g were rare (0.7%), consistent with GA coding errors. Palivizumab receipt was positively correlated with NICU LOS (OR ¼ 1.027, 95% CI 1.021, 1.034) and mechanical ventilation use (OR ¼ 2.112, 95% CI 1.557, 2.864; nominal p < 0.01).
Outlier Hospitals With respect to infants 30 wGA, the proportion of hospitals that reported 0% palivizumab receipt decreased from 18.2% during the 2006 to 2007 RSV season to 10.3% during the 2010 to 2011 RSV season; by respective season, these hospitals represented 9.1 to 3.4% of eligible infants (►Fig. 2). The proportion of hospitals that reported 100% palivizumab receipt showed a trend toward an increase across the RSV seasons from 2006 to 2007 through 2009 to 2010; a decrease was observed in the 2010 to 2011 RSV season (►Fig. 2). In hospitals that administered palivizumab during the 2010 to 2011 RSV season, the median receipt proportion was 90.3%.
Discussion Overall, across all five consecutive RSV seasons from 2006 to 2011, the proportion of palivizumab receipt by GA category among infants 36 wGA was generally consistent with AAP recommendations in effect during the study period; that is, as expected, receipt proportions decreased with increasing GA. The RSV season was defined as November through March, and the lack of palivizumab administration could have been due to local variability in RSV season timing. However, palivizumab receipt rates during each discharge month were similar; suggesting that the effect of local variability in RSV season timing was not a major factor for nonreceipt. Although palivizumab receipt among infants 30 wGA was high, it was incomplete. Across all seasons, 11.2 to 17.7% of eligible infants 30 wGA who were discharged home did not report palivizumab receipt before discharge. It is encouraging, however, that the lowest proportion of nonreceipt among eligible infants was observed during the most recent RSV season (2010–2011) studied. It is possible that palivizumab was administered immediately postdischarge to some infants, as this would not be reported in the Premier Perspective database. However, administration of the first palivizumab dose immediately postdischarge may not occur due to failure to identify eligible infants, communication gaps at handoff, and logistical difficulties. Speer et al12 assessed infants who received palivizumab from 2000 to 2004, and found a mean time to palivizumab receipt of 26 days (range, 1 day to > 4 months after discharge) for those receiving their initial dose in the
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Table 2 Palivizumab receipt among infants 30 wGA discharged home during November through March RSV season (2006–2011) by clinical characteristics (projected) Total population discharged home (N ¼ 50,705)
Receipt of palivizumab among infants discharged home n (%)
Multiple births Single
35,320
30,418 (86.1)
Twins
11,676
9,762 (83.6)
Other multiple
2,162
1,791 (82.9)
CLD/CLDP
43,654
37,691 (86.3)
CHD
14,737
13,199 (89.6)
Congenital abnormalities of airway
1,720
1,390 (80.8)
Neuromuscular disease
72
57 (78.5)
Down syndrome
95
90 (94.5)
Cystic fibrosis
21
10 (48.6)
Immunocompromised state
76
76 (100)
Gastrointestinal disease
3,357
2,914 (86.8)
31,777
28,251 (88.9)
Other medical needs Supplemental oxygen Noninvasive mechanical ventilation
35,554
30,611 (86.1)
Mechanical ventilation
36,378
31,336 (86.1)
Surfactant receipt
5,984
4,730 (79.0)
Bronchodilator receipt
16,840
15,430 (91.6)
Diuretic receipt
28,129
25,172 (89.5)
Steroid receipt
9,059
8,194 (90.4)
Abbreviations: CLD, chronic lung disease; CLDP, chronic lung disease of prematurity; CHD, cyanotic and/or complicated congenital heart disease; RSV, respiratory syncytial virus; wGA, weeks’ gestational age.
outpatient setting. This finding is supported by data from specialty pharmacies, which show a mean time of 10 days from outpatient referral to palivizumab dispensing during the peak of the RSV season, which does not account for the time required to identify the patient or complete the necessary
Fig. 1 Receipt of palivizumab, vitamin K, and hepatitis B vaccine among infants 30 wGA discharged home during November through March (2006–2011) by RSV season (projected). RSV, respiratory syncytial virus; wGA, weeks’ gestational age.
paperwork.13 Delay in palivizumab initiation potentially places these infants at continued risk of developing severe RSV disease.14 Relative to the receipt of vitamin K and hepatitis B vaccine, which were prespecified to be used as benchmarks, the administration of palivizumab captured within this dataset appears robust. The validity of the results is further supported by the reported proportion of hepatitis B vaccination receipt before hospital discharge which was consistent with the 55% by 3 days after birth described in recent Centers for Disease Control and Prevention surveys.15 Given that all newborns should receive vitamin K as the standard of care, the low proportions with recorded receipt may reflect administration being noted on the mother’s record instead of the infant’s record. To the best of our knowledge, no estimates of predischarge vitamin K receipt among US infants have been published. Because of the low proportions with recorded receipt, vitamin K receipt had little value as a benchmark in the current study. The partial implementation of palivizumab administration among approximately one-third of hospitals suggests that there is inconsistency in preterm infant care in these American Journal of Perinatology
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Comorbid conditions
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Fig. 2 Percentage of hospitals by reported receipt of palivizumab among eligible infants 30 wGA discharged home during November through March RSV season (2006–2011). RSV, respiratory syncytial virus; wGA, weeks’ gestational age.
hospitals. In hospitals with few eligible infants, 0% palivizumab administration could be due to database recording errors such as incorrect recording of the infant’s GA or transfer of the infant to another hospital with inaccurate coding of discharge to home. In larger hospitals with 0% palivizumab administration, the hospitals may have a policy against predischarge palivizumab administration. There is considerable confusion and misperception regarding hospital reimbursement of inpatient administration of palivizumab. In general, the diagnosis-related group payment to hospitals for all births is designed to encompass the totality of care the infant requires, including medications administered before discharge, such as palivizumab.16,17 Limitations of this study include those inherent to retrospective analyses of a large health care utilization database. Medical record data are subject to errors and inconsistencies and may be affected by the absence of documentation of pertinent clinical data; it is possible that palivizumab doses were administered but not recorded. There were no data available regarding the precise timing of palivizumab receipt relative to the date of discharge. In addition, due to the structure of ICD-9 diagnosis codes, infants 31- and 32-wGA and infants 35- and 36-wGA were grouped together; these infants have had different RSV prophylaxis recommendations based on the AAP guidelines and could not be distinguished in this claims data analysis. Despite these limitations, this study provides important information regarding the prevalence of receipt of palivizumab before discharge from the birth hospitalization during the RSV season among infants 36 wGA. In addition, these findings improve our understanding of medical and socioeconomic characteristics associated with palivizumab receipt and nonreceipt. The results suggest a gap in recommended care which could be ameliorated by enhanced efforts to identify preterm infants eligible to receive palivizumab during the RSV season.
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In July 2014, the AAP released an updated guidance for prophylaxis with palivizumab among infants at increased risk of hospitalization due to severe RSV disease.18 One of the several significant changes is the absence of recommendation of palivizumab for infants 29 wGA who do not have evidence of CLDP after birth. For infants < 29 wGA, the recommendation to administer palivizumab before discharge from the birth hospitalization during RSV season remains unchanged.18 This study can help inform future implementation of palivizumab and other interventions to help improve the health of high-risk preterm infants in the United States.
Clinical Perspective •
•
•
Across all seasons, the proportion of palivizumab receipt among infants 36 wGA was generally consistent with AAP recommendations; that is, as expected, receipt proportions decreased with increasing GA. Across all seasons, 11.2 to 17.7% of eligible infants 30 wGA did not report palivizumab receipt before hospital discharge. These findings suggest a gap in recommended palivizumab receipt which could be ameliorated by better identification of eligible preterm infants. Conflict of Interest E. F. L. is an independent investigator who received travel support from MedImmune to present this work at the 2013 AAP Annual Meeting, Section on Perinatal Medicine and at the 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Annual Meeting. V. R. K., F. S., J. Y., and C. S. A. are employees of AstraZeneca and may hold stock or stock options. R. W. has served on an advisory board for MedImmune. S. Y. was a consultant for AstraZeneca at the time of study and analysis.
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Acknowledgments Medical writing assistance was provided by John E. Fincke, PhD and Anny Wu, PharmD of Complete Healthcare Communications, Inc. (Chadds Ford, PA), and funded by MedImmune.
References
9 American Academy of Pediatrics Committee on Infectious Diseases
10
11
12
1 Horn SD, Smout RJ. Effect of prematurity on respiratory syncytial
2
3
4
5
6
7 8
virus hospital resource use and outcomes. J Pediatr 2003;143(5, Suppl):S133–S141 Langley GF, Anderson LJ. Epidemiology and prevention of respiratory syncytial virus infections among infants and young children. Pediatr Infect Dis J 2011;30(6):510–517 Bont L, Kimpen JL. Immunological mechanisms of severe respiratory syncytial virus bronchiolitis. Intensive Care Med 2002;28(5): 616–621 Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C. Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentrations of plasma immunoglobulins and patterns of infections. Pediatr Res 1986;20(9):899–904 The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102(3 Pt 1):531–537 Blanken MO, Rovers MM, Molenaar JM, et al; Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013;368(19):1791–1799 Palivizumab. Full Prescribing Information. MedImmune: Gaithersburg, MD; 2014 American Academy of Pediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998;102(5):1211–1216
1023
13 14
15
16
17
18
19
and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003;112(6 Pt 1):1442–1446 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:560–566 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:560–569 Speer ME, Boron M, McLaurin K, Cohen A, Rankin M, Groothuis J. Palivizumab outcomes registry 2000 to 2004: delayed prophylaxis in children at high risk of respiratory syncytial virus (RSV) disease. Neonatology Today 2007;2(4):1–5 Palivizumab distribution network. Data on File. MedImmune: Gaithersburg, MD; 2012–2013 Golombek SG, Berning F, Lagamma EF. Compliance with prophylaxis for respiratory syncytial virus infection in a home setting. Pediatr Infect Dis J 2004;23(4):318–322 Centers for Disease Control and Prevention (CDC). National, state, and local area vaccination coverage among children aged 19-35 months - United States, 2008. MMWR Morb Mortal Wkly Rep 2009;58(33):921–926 2011/2012 Medicaid RSV infection prophylaxis update. Available at: http://dhhs.ne.gov/medicaid/Documents/pb1152.pdf. Accessed May 6, 2014 Health services provider manual: policies and procedures. Available at: http://www.scdhhs.gov/internet/pdf/manuals/Hospital/ Section%202.pdf. Accessed May 6, 2014 American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014;134(2): 415–420 Mackun P, Wilson S. Population distribution and change: 2000 to 2010. Available at: http://www.census.gov/prod/cen2010/briefs/ c2010br-01.pdf. Accessed May 6, 2014
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Sources of Funding This study was sponsored by MedImmune.
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Receipt of Palivizumab before Birth Hospitalization Discharge among Preterm Infants in the United States Edmund F. La Gamma, MD1 Veena R. Kumar, MD, MPH2 Rajan Wadhawan, MD, MMM3 Sherry Ye, MSc4 Frangiscos Sifakis, PhD, MPH2 Joseph Ycas, PhD4 Christopher S. Ambrose, MD2 1 Maria Fareri Children’s Hospital, Westchester Medical Center-
New York Medical College, Valhalla, New York 2 AstraZeneca, Gaithersburg, Maryland 3 Florida Hospital for Children, Orlando, Florida 4 AstraZeneca Pharmaceuticals, Wilmington, Delaware
Address for correspondence Veena R. Kumar, MD, MPH, US Medical Affairs, AstraZeneca, One MedImmune Way, Gaithersburg, MD 20878 (e-mail: [email protected]).
Abstract
Keywords
► palivizumab ► preterm infants ► respiratory syncytial virus ► vitamin K ► hepatitis B vaccine
Objective This study aims to determine predischarge palivizumab receipt prevalence among infants 36 weeks’ gestational age. Study Design This retrospective cohort study used hospital discharge records from the Premier Perspective database (Premier Inc., Charlotte, NC) of infants 36 weeks’ gestational age who were discharged home after birth hospitalization during the November–March respiratory syncytial virus (RSV) seasons from 2006 to 2011. Descriptive statistics were performed and logistic regression was employed to identify differences in categorical variables. Results Among infants 36 weeks’ gestational age discharged home during the RSV seasons, 21.4 to 27.0% had a record of palivizumab receipt before discharge. Among infants 30 weeks’ gestational age, palivizumab receipt was 82.3 to 88.8%. Receipt varied considerably at the hospital level, from 0 to 100%. Conclusion This study improves our understanding of characteristics associated with predischarge palivizumab administration. The identified gaps in recommended care can help inform future implementation of palivizumab and other interventions to help improve the health of high-risk preterm infants in the United States.
Respiratory syncytial virus (RSV) is a significant pathogen of infants and young children, causing annual epidemics of bronchiolitis and pneumonia worldwide.1,2 The greatest morbidity and mortality occur among children in specific high-risk populations, including preterm infants born at 35 weeks’ gestational age (wGA), children 24 months of age with chronic lung disease of prematurity (CLDP), and children 24 months of age with hemodynamically significant congenital heart disease (CHD).1,2 Preterm infants are at an increased risk for developing severe RSV disease due to
smaller lung volumes at birth, immature immune systems,3 and incomplete transfer of maternal antibodies.4 Palivizumab is a monoclonal antibody that has been shown to significantly reduce RSV-related hospitalizations in high-risk children, including preterm infants.5 In preterm infants without bronchopulmonary dysplasia, two randomized, placebo-controlled trials demonstrated that prophylaxis with palivizumab reduced hospitalizations due to severe RSV disease by 72 to 82%.5,6 Palivizumab is recommended to be administered as a monthly injection immediately before the
received July 11, 2014 accepted after revision December 5, 2014 published online April 15, 2015
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1543951. ISSN 0735-1631.
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Am J Perinatol 2015;32:1017–1023.
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start of the RSV season and continued throughout the season.7 From November 1998 to July 2014, the American Academy of Pediatrics (AAP) RSV prophylaxis guidelines have stated that preterm infants born at < 32 wGA are eligible to receive palivizumab during the RSV season to help prevent severe RSV disease.8–11 From 1998 to 2009, those born at 32 to 35 wGA were also eligible for dosing during the season if they had certain risk factors. From 2003 to 2009, RSV prophylaxis was recommended for infants 32 to 35 wGA if two or more of the following risk factors were present: childcare attendance, school-aged siblings, exposure to environmental air pollutants, congenital abnormalities of the airways, or severe neuromuscular disease.9,10 In 2009, eligibility was modified to only include infants born at 32 to 34 wGA who had at least one of the following two risk factors: childcare attendance or sibling < 5 years of age; 35 wGA infants were no longer eligible to receive palivizumab.11 Hospital dosing practices could vary considerably by institution and may have changed over time. This study assessed US in-hospital palivizumab receipt prevalence among infants 36 wGA discharged home during the RSV season from 2006 to 2011.
Methods Study Design This retrospective cohort study used hospital discharge records collected from Premier’s Perspective database (Premier Inc., Charlotte, NC). Records of US infants 36 wGA who were discharged home after birth hospitalization during the RSV season (predefined as November 1 through March 31) from 2006 to 2011 were included. Infants with an International Classification of Disease (ICD)-9 discharge diagnosis code 36 wGA who were born between January 1, 2006 and March 31, 2011 were included in the analysis. Infants were excluded if no GA was recorded, they had a missing birth month or year, missing discharge month or year, died before discharge, were discharged outside of the predefined RSV season, or were transferred to another institution during the RSV season.
Data Source and Compliance The Premier Perspective database is the largest hospitalbased, service-level database in the United States, representing approximately 20% of US nonfederal short-term hospital discharges from more than 500 hospitals, which are weighted to provide national estimates. It includes data at the individual patient level on all billed services on a total of approximately 5 million hospital discharge records per year, and is maintained in compliance with the Health Insurance Portability and Accountability Act. The number of hospitals that provide data changes modestly; the year-to-year hospital retention rate is > 95%, data used in this study were deidentified and aggregated before retrieval from the Premier Perspective database; as such, use of the information for research purposes did not require institutional review board approval. American Journal of Perinatology
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Data Extraction and Analysis The primary outcome variable was the proportion of infants 36 wGA who received palivizumab before discharge from the birth hospitalization during the five consecutive RSV seasons. The discharges were captured from all hospitals in the Premier Perspective database, including but not limited to children’s hospitals. As ICD-9 diagnosis codes are delineated in successive 2-wGA increments, it was not possible to distinguish infants 31-wGA from infants 32-wGA or 35and 36-wGA (who have had different palivizumab recommendations based on the AAP guidelines). To provide context, secondary outcome comparisons were the standard receipt of hepatitis B vaccine and vitamin K before discharge from the birth hospitalization during the same time period. Descriptive analyses used hospital discharge data that were projected to estimate the total US population. The American Hospital Association 2012 Annual Survey was utilized by Premier to identify the universe of US hospitals and to generate the projection weights at the hospital level. The hospital-level weights were then applied to individual discharges. Both unweighted (observed) and weighted (projected) estimates were calculated for each study variable. Projected estimates were used to adjust for changes in the annual sample and to provide an estimate at the national level. The pooled prevalence of receipt of a hospital dose of palivizumab was calculated across all five RSV seasons and locations by calculating the proportion of infants who received a hospital dose of palivizumab over the total number of infants included in the analysis. The prevalence of the primary outcome was separately calculated for each RSV season, discharge month, hospital regional location, hospital size (by number of beds), and hospital type, overall and by GA category ( 30, 31–34, and 35–36 wGA).
Statistical Analyses In-depth analysis of patient characteristics and logistic regression analyses of predictive factors were restricted to the universally eligible group of infants 30 wGA. A stepwise logistic regression analysis (entry criterion p 0.10) was conducted to assess the association between > 90% palivizumab receipt and hospital characteristics, including the number of beds, urban/rural setting, regional location, and teaching/ nonteaching status. When exploring the possible relationships between hospital characteristics and hospital-averaged outcomes, hospital data were weighted to reflect the number of infants in the sample, placing more weight on hospitals with greater numbers of patients. A stepwise logistic regression analysis was also used to evaluate the association of palivizumab receipt with clinical characteristics of infants 30 wGA. When exploring possible interrelationships between patient characteristics and outcomes, analyses used unweighted data as received from the Premier Perspective database, with hospital as a predictor class variable to account for clustering.
Results The projected number of infants 36 wGA who were discharged home during the November through March RSV
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Palivizumab Receipt before Hospital Discharge season from 2006 to 2011 in the United States was 554,125. The majority (56.2%) of these infants were 35 to 36 wGA. Among all infants, as recorded GA increased, the median hospital length of stay (LOS) incrementally decreased as expected. For recipients and nonrecipients of palivizumab, the hospital LOS was similar between GA groups. Among infants who received palivizumab, the respective hospital LOS by GA group was 108 days (24 wGA), 87 days (25–26 wGA), 64 days (27–28 wGA), 44 days (29–30 wGA), 28 days (31–32 wGA), 15 days (33–34 wGA), and 11 days (35–36 wGA). Among infants who did not receive palivizumab, the respective hospital LOS by GA group was 84 days (24 wGA), 88 days (25–26 wGA), 59 days (27–28 wGA), 43 days (29–30 wGA),
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23 days (31–32 wGA), 12 days (33–34 wGA), and 3 days (35–36 wGA). Across all five RSV seasons, the projected proportion of infants 36 wGA who received palivizumab before discharge from the birth hospitalization was 23.8%, with a peak of 27.0% in the 2010 to 2011 RSV season (►Table 1). The proportion of infants who received palivizumab decreased over the discharge months from 25.2% in November to 21.9% in March. Across all five RSV seasons, projected palivizumab receipt proportions were highest in infants 30 wGA (►Table 1). Among infants 31 to 34 wGA, the proportion who received palivizumab increased from 37.9% in 2008 to 2009 to 45.3% in 2009 to 2010, and was higher still in 2010 to
Palivizumab receipt among infants discharged home n (%) 36 wGA (Total N ¼ 554,125)
30 wGA (Total N ¼ 50,705)
31–34 wGA (Total N ¼ 192,153)
35–36 wGA (Total N ¼ 311,267)
2006–2007
23,954 (21.4)
7,692 (83.3)
14,040 (36.2)
2,222 (3.5)
2007–2008
25,655 (22.2)
8,588 (82.3)
14,567 (35.9)
2,501 (3.9)
RSV season
2008–2009
26,497 (23.2)
8,762 (85.2)
15,118 (37.9)
2,617 (4.1)
2009–2010
28,158 (25.7)
9,552 (87.4)
17,184 (45.3)
1,422 (2.3)
2010–2011
27,841 (27.0)
8,723 (88.8)
17,694 (50.7)
1,424 (2.4)
Overall: 2006–2011
132,105 (23.8)
43,317 (85.4)
78,602 (40.9)
10,186 (3.3)
27,523 (25.2)
8,549 (83.2)
16,756 (43.6)
2,218 (3.7)
December
27,848 (24.4)
9,450 (86.8)
16,173 (40.2)
2,226 (3.5)
January
26,855 (23.9)
8,615 (85.8)
16,171 (42.8)
2,068 (3.2)
February
24,905 (23.9)
8,048 (87.8)
14,784 (41.4)
2,073(3.5)
24,974 (21.9)
8,655 (83.8)
14,717 (36.8)
1,602 (2.5)
Midwest
21,457 (18.5)
5,172 (77.0)
13,982 (37.0)
2,302 (3.2)
Northeast
16,904 (18.4)
5,441 (67.3)
10,308 (33.4)
1,155 (2.2)
Discharge month November
March Hospital regional location
a
South
67,443 (29.3)
24,518 (94.0)
37,990 (45.8)
4,935 (4.1)
West
26,302 (22.7)
8,186 (83.3)
16,321 (40.2)
1,794 (2.7)
1–199
5,333 (8.9)
1,197 (58.6)
3,636 (22.5)
499 (1.2)
200–299
15,059 (18.8)
2,653 (59.9)
9,858 (37.5)
2,549 (5.2)
300–399
33,700 (21.9)
10,627 (82.7)
20,467 (37.2)
2,606 (3.0)
400–499
27,431 (26.5)
8,206 (91.9)
17,512 (48.1)
1,713 (2.9)
500
50,581 (32.2)
20,634 (91.9)
27,129 (46.5)
2,819 (3.7)
Nonteaching
88,322 (22.0)
25,155 (82.6)
55,093 (40.9)
8,074 (3.4)
Teaching
43,786 (28.8)
18,163 (89.6)
23,508 (41.0)
2,112 (2.8)
Number of hospital beds
Hospital type
Abbreviations: GA, gestational age; RSV, respiratory syncytial virus; wGA, weeks’ gestational age. a For reference, the distribution of the 2010 US population by US Census Bureau Regions was 21.7% Midwest, 17.9% Northeast, 37.1% South, and 23.3% West.19 American Journal of Perinatology
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Table 1 Palivizumab receipt among infants 36 wGA discharged home during November through March RSV season (2006–2011) overall and by GA category (projected)
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2011 (50.7%) (►Table 1). Palivizumab receipt decreased over time in infants 35 to 36 wGA; 3.5 to 4.1% in 2006 to 2009 versus 2.3 to 2.4% in 2009 to 2011 (►Table 1).
Hospital Characteristics Among infants 36 wGA, by hospital location and size, the highest proportions of palivizumab receipt were observed in the South and West and in hospitals with 400 beds (►Table 1). In addition, a higher proportion (28.8%) of infants in teaching hospitals received palivizumab compared with nonteaching hospitals (22.0%) (►Table 1). Among infants 30 wGA, palivizumab receipt was higher (90.9%) in hospitals located in rural areas than in urban areas (85.3%), the latter having discharged the majority (98.2%) of infants; receipt was highest in the South and lowest in the Northeast (94.0 and 67.3%, respectively) (►Table 1). The frequency of palivizumab receipt was higher in teaching hospitals than in nonteaching hospitals (89.6 and 82.6%, respectively) (►Table 1). Receipt proportions were highest in hospitals with 300 beds (►Table 1). Multivariate analysis of hospital characteristics that correlated with > 90% palivizumab receipt among infants 30 wGA found a statistically significant association with hospital size (odds ratio [OR] ¼ 1.003 per one-bed increment; 95% confidence interval [CI] 1.003, 1.004; p < 0.001). With respect to hospital nursery levels, the majority of infants were discharged home from a Level II combined nursery (i.e., Level II continuing care nursery and Level II boarder baby nursery) (36.7%) or Level III intermediate care nursery (32.5%). Of these infants, 88.9% received palivizumab. The proportion with reported palivizumab receipt was lower (70.8%) for those discharged from a Level IV intensive care nursery.
Patient Characteristics among Infants 30 wGA Projected palivizumab receipt proportions were higher for non-White infants. With respect to payers, the highest (> 90%) palivizumab receipt proportions were observed for infants covered by indigent, capitated and noncapitated Medicare, and worker’s compensation (100% each); and capitated managed care (94.2%). The lowest (31.7%) receipt proportion was observed in those with charity care. The mean (standard deviation; SD) hospital LOS was 65.1 (30.9) days, while the mean neonatal intensive care unit (NICU) LOS was 62.5 (31.6) days. Projected palivizumab receipt proportions were highest ( 81%) in infants weighing < 500 to 1,999 g, lower (68.3%) in infants 2,000 to 2,499 g, and lowest (13.6%) in the small number of infants weighing 2,500 g. By comorbid condition, palivizumab was most frequently (> 80%) administered to those infants with reported diagnoses of immunocompromised state, Down syndrome, CHD, CLDP, gastrointestinal disease, and congenital abnormality of the airway; whereas, the lowest proportion of palivizumab receipt (48.6%) was observed in the small number of infants with cystic fibrosis (►Table 2). Palivizumab receipt proportions were high and similar ( 86%) in infants with other medical needs such as supplemental oxygen, mechanical ventilation, and bronchodilator, steroid and/or American Journal of Perinatology
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diuretic therapy (►Table 2). Across all RSV seasons, the proportions of infants who received vitamin K and hepatitis B vaccine were lower than those of infants who received palivizumab (►Fig. 1). At the patient level, adjusting for hospital, logistic regression revealed birth weight was a robust predictor of palivizumab receipt. With < 500 g as the reference weight, infants who weighed 2,500 g demonstrated markedly lower palivizumab receipt (OR ¼ 0.094, 95% CI 0.021, 0.417; p < 0.001). Records of infants 30 wGA with birth weight 2,500 g were rare (0.7%), consistent with GA coding errors. Palivizumab receipt was positively correlated with NICU LOS (OR ¼ 1.027, 95% CI 1.021, 1.034) and mechanical ventilation use (OR ¼ 2.112, 95% CI 1.557, 2.864; nominal p < 0.01).
Outlier Hospitals With respect to infants 30 wGA, the proportion of hospitals that reported 0% palivizumab receipt decreased from 18.2% during the 2006 to 2007 RSV season to 10.3% during the 2010 to 2011 RSV season; by respective season, these hospitals represented 9.1 to 3.4% of eligible infants (►Fig. 2). The proportion of hospitals that reported 100% palivizumab receipt showed a trend toward an increase across the RSV seasons from 2006 to 2007 through 2009 to 2010; a decrease was observed in the 2010 to 2011 RSV season (►Fig. 2). In hospitals that administered palivizumab during the 2010 to 2011 RSV season, the median receipt proportion was 90.3%.
Discussion Overall, across all five consecutive RSV seasons from 2006 to 2011, the proportion of palivizumab receipt by GA category among infants 36 wGA was generally consistent with AAP recommendations in effect during the study period; that is, as expected, receipt proportions decreased with increasing GA. The RSV season was defined as November through March, and the lack of palivizumab administration could have been due to local variability in RSV season timing. However, palivizumab receipt rates during each discharge month were similar; suggesting that the effect of local variability in RSV season timing was not a major factor for nonreceipt. Although palivizumab receipt among infants 30 wGA was high, it was incomplete. Across all seasons, 11.2 to 17.7% of eligible infants 30 wGA who were discharged home did not report palivizumab receipt before discharge. It is encouraging, however, that the lowest proportion of nonreceipt among eligible infants was observed during the most recent RSV season (2010–2011) studied. It is possible that palivizumab was administered immediately postdischarge to some infants, as this would not be reported in the Premier Perspective database. However, administration of the first palivizumab dose immediately postdischarge may not occur due to failure to identify eligible infants, communication gaps at handoff, and logistical difficulties. Speer et al12 assessed infants who received palivizumab from 2000 to 2004, and found a mean time to palivizumab receipt of 26 days (range, 1 day to > 4 months after discharge) for those receiving their initial dose in the
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Table 2 Palivizumab receipt among infants 30 wGA discharged home during November through March RSV season (2006–2011) by clinical characteristics (projected) Total population discharged home (N ¼ 50,705)
Receipt of palivizumab among infants discharged home n (%)
Multiple births Single
35,320
30,418 (86.1)
Twins
11,676
9,762 (83.6)
Other multiple
2,162
1,791 (82.9)
CLD/CLDP
43,654
37,691 (86.3)
CHD
14,737
13,199 (89.6)
Congenital abnormalities of airway
1,720
1,390 (80.8)
Neuromuscular disease
72
57 (78.5)
Down syndrome
95
90 (94.5)
Cystic fibrosis
21
10 (48.6)
Immunocompromised state
76
76 (100)
Gastrointestinal disease
3,357
2,914 (86.8)
31,777
28,251 (88.9)
Other medical needs Supplemental oxygen Noninvasive mechanical ventilation
35,554
30,611 (86.1)
Mechanical ventilation
36,378
31,336 (86.1)
Surfactant receipt
5,984
4,730 (79.0)
Bronchodilator receipt
16,840
15,430 (91.6)
Diuretic receipt
28,129
25,172 (89.5)
Steroid receipt
9,059
8,194 (90.4)
Abbreviations: CLD, chronic lung disease; CLDP, chronic lung disease of prematurity; CHD, cyanotic and/or complicated congenital heart disease; RSV, respiratory syncytial virus; wGA, weeks’ gestational age.
outpatient setting. This finding is supported by data from specialty pharmacies, which show a mean time of 10 days from outpatient referral to palivizumab dispensing during the peak of the RSV season, which does not account for the time required to identify the patient or complete the necessary
Fig. 1 Receipt of palivizumab, vitamin K, and hepatitis B vaccine among infants 30 wGA discharged home during November through March (2006–2011) by RSV season (projected). RSV, respiratory syncytial virus; wGA, weeks’ gestational age.
paperwork.13 Delay in palivizumab initiation potentially places these infants at continued risk of developing severe RSV disease.14 Relative to the receipt of vitamin K and hepatitis B vaccine, which were prespecified to be used as benchmarks, the administration of palivizumab captured within this dataset appears robust. The validity of the results is further supported by the reported proportion of hepatitis B vaccination receipt before hospital discharge which was consistent with the 55% by 3 days after birth described in recent Centers for Disease Control and Prevention surveys.15 Given that all newborns should receive vitamin K as the standard of care, the low proportions with recorded receipt may reflect administration being noted on the mother’s record instead of the infant’s record. To the best of our knowledge, no estimates of predischarge vitamin K receipt among US infants have been published. Because of the low proportions with recorded receipt, vitamin K receipt had little value as a benchmark in the current study. The partial implementation of palivizumab administration among approximately one-third of hospitals suggests that there is inconsistency in preterm infant care in these American Journal of Perinatology
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Comorbid conditions
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Fig. 2 Percentage of hospitals by reported receipt of palivizumab among eligible infants 30 wGA discharged home during November through March RSV season (2006–2011). RSV, respiratory syncytial virus; wGA, weeks’ gestational age.
hospitals. In hospitals with few eligible infants, 0% palivizumab administration could be due to database recording errors such as incorrect recording of the infant’s GA or transfer of the infant to another hospital with inaccurate coding of discharge to home. In larger hospitals with 0% palivizumab administration, the hospitals may have a policy against predischarge palivizumab administration. There is considerable confusion and misperception regarding hospital reimbursement of inpatient administration of palivizumab. In general, the diagnosis-related group payment to hospitals for all births is designed to encompass the totality of care the infant requires, including medications administered before discharge, such as palivizumab.16,17 Limitations of this study include those inherent to retrospective analyses of a large health care utilization database. Medical record data are subject to errors and inconsistencies and may be affected by the absence of documentation of pertinent clinical data; it is possible that palivizumab doses were administered but not recorded. There were no data available regarding the precise timing of palivizumab receipt relative to the date of discharge. In addition, due to the structure of ICD-9 diagnosis codes, infants 31- and 32-wGA and infants 35- and 36-wGA were grouped together; these infants have had different RSV prophylaxis recommendations based on the AAP guidelines and could not be distinguished in this claims data analysis. Despite these limitations, this study provides important information regarding the prevalence of receipt of palivizumab before discharge from the birth hospitalization during the RSV season among infants 36 wGA. In addition, these findings improve our understanding of medical and socioeconomic characteristics associated with palivizumab receipt and nonreceipt. The results suggest a gap in recommended care which could be ameliorated by enhanced efforts to identify preterm infants eligible to receive palivizumab during the RSV season.
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In July 2014, the AAP released an updated guidance for prophylaxis with palivizumab among infants at increased risk of hospitalization due to severe RSV disease.18 One of the several significant changes is the absence of recommendation of palivizumab for infants 29 wGA who do not have evidence of CLDP after birth. For infants < 29 wGA, the recommendation to administer palivizumab before discharge from the birth hospitalization during RSV season remains unchanged.18 This study can help inform future implementation of palivizumab and other interventions to help improve the health of high-risk preterm infants in the United States.
Clinical Perspective •
•
•
Across all seasons, the proportion of palivizumab receipt among infants 36 wGA was generally consistent with AAP recommendations; that is, as expected, receipt proportions decreased with increasing GA. Across all seasons, 11.2 to 17.7% of eligible infants 30 wGA did not report palivizumab receipt before hospital discharge. These findings suggest a gap in recommended palivizumab receipt which could be ameliorated by better identification of eligible preterm infants. Conflict of Interest E. F. L. is an independent investigator who received travel support from MedImmune to present this work at the 2013 AAP Annual Meeting, Section on Perinatal Medicine and at the 2014 Pediatric Academic Societies and Asian Society for Pediatric Research Annual Meeting. V. R. K., F. S., J. Y., and C. S. A. are employees of AstraZeneca and may hold stock or stock options. R. W. has served on an advisory board for MedImmune. S. Y. was a consultant for AstraZeneca at the time of study and analysis.
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Acknowledgments Medical writing assistance was provided by John E. Fincke, PhD and Anny Wu, PharmD of Complete Healthcare Communications, Inc. (Chadds Ford, PA), and funded by MedImmune.
References
9 American Academy of Pediatrics Committee on Infectious Diseases
10
11
12
1 Horn SD, Smout RJ. Effect of prematurity on respiratory syncytial
2
3
4
5
6
7 8
virus hospital resource use and outcomes. J Pediatr 2003;143(5, Suppl):S133–S141 Langley GF, Anderson LJ. Epidemiology and prevention of respiratory syncytial virus infections among infants and young children. Pediatr Infect Dis J 2011;30(6):510–517 Bont L, Kimpen JL. Immunological mechanisms of severe respiratory syncytial virus bronchiolitis. Intensive Care Med 2002;28(5): 616–621 Ballow M, Cates KL, Rowe JC, Goetz C, Desbonnet C. Development of the immune system in very low birth weight (less than 1500 g) premature infants: concentrations of plasma immunoglobulins and patterns of infections. Pediatr Res 1986;20(9):899–904 The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102(3 Pt 1):531–537 Blanken MO, Rovers MM, Molenaar JM, et al; Dutch RSV Neonatal Network. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med 2013;368(19):1791–1799 Palivizumab. Full Prescribing Information. MedImmune: Gaithersburg, MD; 2014 American Academy of Pediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998;102(5):1211–1216
1023
13 14
15
16
17
18
19
and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003;112(6 Pt 1):1442–1446 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006:560–566 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:560–569 Speer ME, Boron M, McLaurin K, Cohen A, Rankin M, Groothuis J. Palivizumab outcomes registry 2000 to 2004: delayed prophylaxis in children at high risk of respiratory syncytial virus (RSV) disease. Neonatology Today 2007;2(4):1–5 Palivizumab distribution network. Data on File. MedImmune: Gaithersburg, MD; 2012–2013 Golombek SG, Berning F, Lagamma EF. Compliance with prophylaxis for respiratory syncytial virus infection in a home setting. Pediatr Infect Dis J 2004;23(4):318–322 Centers for Disease Control and Prevention (CDC). National, state, and local area vaccination coverage among children aged 19-35 months - United States, 2008. MMWR Morb Mortal Wkly Rep 2009;58(33):921–926 2011/2012 Medicaid RSV infection prophylaxis update. Available at: http://dhhs.ne.gov/medicaid/Documents/pb1152.pdf. Accessed May 6, 2014 Health services provider manual: policies and procedures. Available at: http://www.scdhhs.gov/internet/pdf/manuals/Hospital/ Section%202.pdf. Accessed May 6, 2014 American Academy of Pediatrics Committee on Infectious Diseases; American Academy of Pediatrics Bronchiolitis Guidelines Committee. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014;134(2): 415–420 Mackun P, Wilson S. Population distribution and change: 2000 to 2010. Available at: http://www.census.gov/prod/cen2010/briefs/ c2010br-01.pdf. Accessed May 6, 2014
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Sources of Funding This study was sponsored by MedImmune.
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