Keywords infant - premature - antibodies - monoclonal - respiratory syncytial virus - health
policy
Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants
in the first year of life, with the highest rates in those under 6 months of age.[1 ]
[2 ] From 2002 until 2023, the only intervention to reduce the risk of serious RSV-associated
illness in Canadian infants was the anti-RSV F monoclonal antibody palivizumab (Synagis®,
AstraZeneca Canada Inc.) administered monthly up to five times during the RSV season.
In 2023, a higher efficacy, longer-acting monoclonal antibody (nirsevimab, Sanofi),
and a maternal RSV vaccine (RSV-preF, Pfizer) were authorized in Canada, dramatically
changing the opportunities for RSV prevention. in 2024, the Canadian National Advisory
Committee on Immunization recommended that jurisdictions work toward nirsevimab programs
for all infants, depending on feasibility.[3 ] For the 2024–2025 season, most provinces will not introduce universal nirsevimab
programs.
Recommendations for eligibility for palivizumab by jurisdictions varied from 2002
to 2022, generally restricting access over time. In 2014, the American Academy of
Pediatrics (AAP) advised that prophylaxis may be administered to premature infants
without lung or heart disease born before 290/7 weeks gestation (WG) and younger than 12 months at the start of the RSV season.[4 ]
[5 ] In 2015, the Canadian Pediatric Society (CPS) updated its guidance to exclude otherwise
healthy very preterm infants born above 30 WG; in 2016, the province of Nova Scotia
revised its eligibility criteria to align with this guidance.
As jurisdictions plan and implement their RSV prevention programs, it will be important
to assess their impact. In this study, we aimed to determine if the revised provincial
policy was associated with a change in the burden of illness associated with RSV in
children no longer eligible for prophylaxis, as measured by a change in hospital admissions,
deaths, or ambulatory visits associated with RSV.
Materials and Methods
Study Design
This was an observational, retrospective cohort study.
Setting
Nova Scotia is a Canadian province on the Atlantic seaboard, with a population of
1 million, and universal health care.
Data Sources
The inception cohort of eligible preterm newborns and their RSV-associated illness
in the first year of life was assembled by linking six provincial databases. The population-based
Reproductive Care Program (RCP) Nova Scotia Atlee Perinatal Database (NSAPD) identified
each infant at birth and gestational age. Eligibility criteria were determined using
the Nova Scotia Provincial Blood Coordinating Program Palivizumab Database, the IWK
Cardiology Database, and the Vital Statistics Database. Outcomes were determined from
the Medical Services Insurance (MSI) Database, and the Canadian Institutes for Health
Information Discharge Abstract Database (CIHI-DAD).
The data were available as part of a data sharing agreement between the Nova Scotia
government Department of Health and Wellness, and two health authorities, Nova Scotia
Health and the IWK Health Centre. We obtained Research Ethics Board approval from
the IWK Health Centre. As this was a secondary use of existing data on events over
two decades, the risk of identification was very low, and parental/guardian consent
was not deemed necessary.
Participant Identification
To identify the eligible cohort, all infants born in Nova Scotia between 30 and 37
WG from April 1, 2012, to September 30, 2019, were identified in the NSAPD. The unique
provincial health card number (HCN) was used to link each child to their data in the
five other databases. HCNs were substituted with random identifiers prior to export
for analysis.
Infants were excluded if their gestational age information was not available, were
born after 320/7 weeks gestational age (WG), were not a resident of Nova Scotia, died in the neonatal
period (<28 days of age), or were eligible for palivizumab prophylaxis due to chronic
lung disease or requiring supplemental oxygen within 6 months of the RSV season or
had hemodynamically significant congenital heart disease (CHD), or received one or
more doses of palivizumab. Each infant was followed for the outcomes of interest from
birth throughout the first year of life. The last participant completed their follow-up
in 2020.
Outcomes
The primary outcome measure was RSV-H in the first year of life. RSV-H events were
defined as one or more of the RSV-specific International Statistical Classification
of Diseases and Related Health Problems (ICD) diagnostic codes (B97.4, J20.5, J21.0,
and J12.1) for that child in the CIHI-DAD or the MSI databases.
The secondary outcomes were ambulatory visits to a physician (RSV-A), deaths associated
with RSV, and the percentage of children receiving palivizumab over time.
Data linkage and Analysis
The eligible population was described. The frequency of RSV-H, RSV-A, RSV-associated
death, and palivizumab use was described for each of the 9 study years. Risk differences
before and after the policy change, with 95% confidence intervals, were calculated.
Means were utilized to report the total percentage of infants who received palivizumab
prior to and after the policy change.
Results
Population
There were 4,835 infants born in Nova Scotia between 30 and 37 WG from April 1, 2012,
to September 30, 2019. of these, 337 were born between 30 and 320/7 WG ([Fig. 1 ]). After excluding infants with hemodynamically significant heart disease and/or
lung disease, or receipt of palivizumab, 250 healthy preterm infants constituted the
inception cohort.
Fig. 1 Identification of a cohort of very preterm infants born at 30 to 32 weeks gestation.
WGA, weeks of gestational age.
Outcomes
Respiratory Syncytial Virus-Associated Hospitalizations
RSV-H increased following the policy change, with no admissions prior to the 2016–2017
season and 12 admissions in the first year of life after restricted access to prophylaxis
(12/127; 9.4%, 95% CI 5.0, 15.0). The risk difference of RSV-H in the pre- and post-policy
periods was 9.4% (12/127 − 0/123 = 0.094, 95% CI 0.04, 0.145), or a nearly 10-fold
increase in risk.
Respiratory Syncytial Virus-Associated Ambulatory Visits
Ambulatory visits to physicians increased after the introduction of the new policy
restricting access to these very preterm infants. In the period prior to the policy
change, population with RSV-associated visits occurred in 5.7% (7/123; 95% CI 2.3%,
11.4%) whereas post-policy change, 17.3% of infants (11/127; 95% CI 11.2%, 25.0%)
had RSV-associated ambulatory care events, representing a risk difference of 11% (95%
CI 0.03, 0.19).
Respiratory Syncytial Virus-Associated Mortality
There were no deaths associated with RSV during the study period in the study population.
Palivizumab Coverage
Use of palivizumab declined in the cohort after the 2016–2017 season provincial policy
change, with 40.9% (72/195) of otherwise healthy preterm infants born between 30 and
32 WG receiving palivizumab between before, and 3.8% (5/132) in receipt after.
Discussion
In this province-wide, population-based, retrospective cohort study, we found that
implementing a recommendation to remove access to RSV prevention with palivizumab
in healthy preterm infants of 30 to 32 WG was associated with an increase in RSV-associated
hospitalizations and ambulatory visits, but not with mortality. In the RSV seasons
following the AAP and CPS guideline changes, several observational studies have shown
a decline in palivizumab eligibility is associated with an increase in rates of bronchiolitis,
hospitalizations, intensive care use, and ambulatory visits associated with RSV.[6 ]
[7 ]
[8 ] Our study adds to the growing body of data that suggest very preterm babies born
between 30 and 32 WGA, and with no comorbidities, are at a significantly higher risk
of RSV-associated disease significant enough to warrant medical attention.
The results of this study also support recent recommendations from the United States,
Canada, and several European countries to offer universal RSV prevention programs
with the long-acting monoclonal antibody nirsevimab (Beyfortus®, Sanofi) to infants
entering or born during their first RSV season, or maternal RSV vaccine. While making
this recommendation in 2024, Canada's National Advisory Immunization Committee recognized
that it may not be possible to offer universal programs immediately and recommended
prioritizing the highest-risk infants for nirsevimab and using palivizumab according
to previous recommendations from 2022.[3 ]
[9 ] We note that the 2022 recommendations exclude infants with 30 WGA and older and
therefore urge jurisdictions to carefully consider whether infants 300/7 to 32 WGA can be offered prevention in a risk-based nirsevimab or palivizumab program.
Based on this study Nova Scotia reversed its 2016 decision and is offering prophylaxis
to infants <320/7 WG as of the 2023–2024 season.
Physicians and health care providers can use the study results to counsel families
with an infant born between 30 and 32 weeks of GA about their risk of severe RSV disease
so that parents can make informed decisions about protecting their child during their
child's first RSV season. These results may also affect the decision-making of the
physicians themselves when caring for this population, and their willingness to refer
the patient for an anti-RSV monoclonal antibody. Finally, physicians may choose to
advocate for policy change if they practice in a jurisdiction that does not currently
offer RSV prevention to these babies.
Limitations
As this cohort was constructed from secondary datasets, it could be subject to coding
limitations and data entry errors. We expect that RSV-associated illness is underreported
in our databases as routine virologic testing is not standard of practice for all
patients presenting with respiratory symptoms, and therefore the burden of disease
is likely underestimated. This is a descriptive study so causality cannot be attributed.
The study population was exclusively from Nova Scotian which may limit generalizability
to other geographic areas due to differing health care, socioeconomic, and climate
circumstances. Finally, studies using secondary data are limited in their ability
to control confounders.
Conclusion
Nova Scotian infants born between 30 and 32 WGA had higher rates of severe RSV disease
after becoming ineligible for palivizumab, but no increase in mortality. Evaluation
of health care policy is essential to assessing benefits and risks.
