Healthy Late-preterm infants born 33–36 + 6 weeks gestational age have higher risk for respiratory syncytial virus hospitalization
Introduction
Respiratory syncytial virus (RSV) is one of the leading causes of hospitalizations in children < 1 year old and infects nearly all children by age two [1], [2]. RSV-related hospitalizations account for 24% of an estimated 5.5 million lower respiratory tract infections (LRTI) in children < 5 years of age, which is an estimated 132,000 to 172,000 hospitalized children annually [3]. LRTI may account for up to 55% of pediatric intensive care unit (PICU) admissions, with a significant proportion (30%) of these hospitalizations occurring in premature infants [4]. Overall, RSV disease in children (and particularly in preterm infants) incurs both a significant cost and resource burden on the US health system [5], [6].
Palivizumab is a monoclonal antibody that is used for immunoprophylaxis against RSV, specifically to reduce disease severity in high-risk populations. High-risk children are considered those < 2 years old who require therapy for chronic lung disease (CLD) or hemodynamically-significant congenital heart disease (CHD), are unable to handle respiratory secretions from neuromuscular disease or anatomical airway abnormalities, are severely immunodeficient, and/or have premature birth [7], [8], [9], [10], [11], [12], [13]. A recent study also shows Down syndrome as a risk factor for severe RSV disease with increased risk for hospitalization [14]. In the phase III trial used to support licensure, palivizumab reduced RSV-related hospitalizations by 80% in infants born 32 through 35 weeks gestational age (WGA) [7].
After initial licensure, and until recommendations were revised in 2009, palivizumab was used for premature infants born between 32 and 35 WGA, who were less than six months of age at the beginning of the RSV season with at least two of five additional risk factors. In 2009, in an attempt to reduce overall healthcare cost and better target those born between 32 and 35 WGA at highest risk for severe RSV disease, the American Academy of Pediatrics (AAP) Committee on Infectious Diseases narrowed the guidelines for palivizumab immunoprophylaxis use in these premature infants [15]. The 2009 guidelines re-emphasize that, when prematurity is the only risk factor for severe RSV disease, both gestational and chronological age should determine if palivizumab is warranted. However, in 2014 these guidelines were updated and eliminated late preterm infants as a high risk group. The AAP now recommends limiting palivizumab immunoprophylaxis to premature infants born less than or equal to 29 + 0 WGA, unless an additional concomitant risk factor is present [16].
Premature births < 37 WGA accounted for 11.4% of all births in the US in 2013, of which 70% were infants born 34 to 36 WGA [17]. Late preterm (LPT) infants, as defined by the AAP and the American College of Obstetricians and Gynecologists (ACOG), are infants born between 34 + 0 and 36 + 6 WGA [18]. When compared to term infants, LPT infants have a three- to five-fold higher rate for overall mortality and are at higher risk of developing medical complications during infancy [19], [20]. McLaurin et al. studied different causes of hospitalization for LPT and term infants during the first year of life. Their study demonstrated that LPT infants were almost twice as likely to be hospitalized than term infants, with over 50% of the hospitalizations due to respiratory or gastrointestinal disorders [2].
Although LPT infants were no longer recommended to receive RSV immunoprophylaxis by the 2014 AAP guidelines, the risk of RSV hospitalization and burden of disease in this population may be significantly higher than in term children. Our objective is to assess whether healthy LPT infants born at 33 + 0 to 36 + 6 WGA, who did not receive palivizumab prophylaxis, are at greater risk for RSV hospitalization as compared to healthy term infants. We hypothesized that healthy LPT infants who did not receive palivizumab prophylaxis have increased rates of RSV hospitalization and more severe RSV disease than healthy term infants.
Section snippets
Study design and source
We conducted a retrospective cohort study to compare the risk and rate of RSV hospitalization among healthy LPT infants to those of healthy term infants utilizing the Military Health System (MHS) database. The Department of Defense's health care program, known as TRICARE, provides benefits to members of the uniformed services and their families. TRICARE billing data of all beneficiaries is recorded in the MHS database, and contains inpatient, outpatient, and outpatient pharmacy data from both
Results
A total of 599,535 children under 24 months-old and 1,216,382 person-years were studied, of which 25,890 (4.3%) were healthy LPT children (Fig. 1). There was a higher proportion of males who were LPT within the studied cohort than term (53% vs. 51%; P < 0.001). Overall, 7,597 children were admitted for RSV and 8.5% of these hospitalizations occurred in LPT children.
LPT infants had an absolute hospitalization rate (AHR) of 2.5%, while term infants had an AHR of 1.3% (P < 0.001). Within the two LPT
Discussion
Our study demonstrates that LPT infants without other risk factors had both a significantly higher risk for RSV hospitalization and requirement for respiratory support than healthy term infants. The IDRSV of 12.1 per 1000 person-years was one-and-a-half times as high for LPT infants as compared to term infants. We also found that infants in the 33–34 WGA cohort had the highest adjusted hazard ratio for RSV hospitalization at 2.45 (95% CI 1.96–3.07).
Prematurity interrupts the development of the
Conclusions
LPT birth is an independent risk factor for severe RSV disease and need for hospitalization. Although LPT infants are often medically managed similarly to term infants, they are at significantly higher risk for severe RSV disease, resulting in a greater risk of hospitalization, longer stay, and higher rate of requirement for respiratory support. Further studies are needed to identify why LPT is a risk factor for severe disease, and whether additional specific risk factors can be identified.
Conflict of Interest Statement
The authors have no conflicts of interest to disclose.
Disclaimer
The views expressed in this article are those of the authors and do not reflect the official policy or position of the United States Armed Forces, Department of Defense, or the U.S. Government.
Contributor's Statement
Alison M. Helfrich: Dr. Helfrich interpreted the results, drafted and edited the initial manuscript and approved the final manuscript as submitted.
Cade M. Nylund: Dr. Nylund carried out the data analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted.
Matthew D. Eberly: Dr. Eberly conceptualized and designed the study, reviewed and revised the manuscript, and approved the final manuscript as submitted.
Matilda B. Eide: Ms. Eide designed the data collection
Acknowledgements
The authors would like to thank Drs. Martin Ottolini, Gregory Gorman, Michael Rajnik and Kathleen Madden for their critical review of the manuscript.
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