# Infection-related mortality in children in two European countries, 2015–2023: An interrupted time-series analysis

Manon Jaboyedoff, Pierre Alex Crisinel, Zaba Valtuille, Inès Fafi, Margherita Plebani, Yves Fougère, Karim Abawi, Romain Basmaci, Naïm Ouldali, François Angoulvant

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Manon Jaboyedoff, Pierre Alex Crisinel, Zaba Valtuille, Inès Fafi, Margherita Plebani, et al., Infection-related mortality in children in two European countries, 2015–2023: An interrupted time-series analysis. Journal of Infection, 2026, 92, 10.1016/j.jinf.2026.106688. hal-05503525

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Infectious Disease Practice

# Infection-related mortality in children in two European countries, 2015–2023: An interrupted time-series analysis

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Manon Jaboyedoff<sup>a,b,*</sup>, Pierre Alex Crisinel<sup>a</sup>, Zaba Valtuille<sup>b,c</sup>, Inès Fafi<sup>b,c,d</sup>, Margherita Plebani<sup>a</sup>, Yves Fougère<sup>a</sup>, Karim Abawi<sup>e</sup>, Romain Basmaci<sup>b,f</sup>, Naïm Ouldali<sup>b,d,1</sup>, François Angoulvant<sup>g,1</sup>

ARTICLE INFO

Article history:

Accepted 6 January 2026

Available online 9 January 2026

Keywords:

Communicable diseases

Mortality

Child mortality

COVID-19

Interrupted time series analysis

Child

Infant

Adolescent

SUMMARY

**Background:** Infections remain a leading cause of childhood mortality. Non-pharmaceutical interventions (NPI) implemented during COVID-19 pandemic altered the circulation of communicable pathogens. We aimed to assess how these changes affected paediatric infection-related mortality.

**Methods:** We conducted a population-based interrupted time-series analysis using national data from France and Switzerland (2015 to 2023), including deaths among individuals < 18 years. Monthly infection-related mortality was analysed using quasi-Poisson regression models seasonally adjusted. Mortality rate ratios (MRR) were calculated to compare infection-related mortality among birth cohorts exposed to NPI or post-NPI periods versus pre-NPI cohorts.

**Results:** Among 32,619 paediatric deaths during the study period, 8272 were related to an infection. During the NPI period, infection-related mortality declined by 16% (95% CI: -23% to -7%), corresponding to an estimated reduction of 221 (95% CI: 90 to 371) deaths. Compared to pre-NPI birth cohorts, 2019 and 2020 cohorts had significantly lower infection-related MRR (0·80, 95% CI 0·66 to 0·98 and 0·80, 95% CI 0·65 to 0·98).

**Conclusion:** The reduction in paediatric infection-related deaths during the NPI period underscores the ongoing burden of preventable paediatric mortality and suggests that targeted preventive strategies may sustainably reduce infection-related deaths beyond pandemic settings.

© 2026 The Authors. Published by Elsevier Ltd on behalf of British Infection Association. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

**Abbreviations:** ATIH, Technical Agency for Hospital Information; FSO, Federal Statistical Office; ICD-10, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision; INSEE, National Institute of Statistics and Economic Studies (“Institut national de la statistique et des études économiques”); NCMD, National Child Mortality Database; NPI, Non-pharmacological interventions; PMSI, French Medicalization of Information Systems Program (“Programme de Médicalisation des Systèmes d'Information”); URTI, Upper Respiratory Tract Infections; WHO, World Health Organization

* Correspondence to: Unit of Pediatric Infectious Diseases and Vaccinology, Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital, 50, Rue du Bugnon, 1011 Lausanne, Switzerland.

E-mail address: manon.jaboyedoff@chuv.ch (M. Jaboyedoff).

¹ Contributed equally.

<footnote><sup>a</sup>Unit of Pediatric Infectious Diseases and Vaccinology, Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 50, 1011 Lausanne, Switzerland</footnote>

<footnote><sup>b</sup>Paris Cité University, INSERM UMR 1137, Infection, Antimicrobials, Modelling, Evolution (IAME), 16 rue Henri Huchard, 75018 Paris, France</footnote>

<footnote><sup>c</sup>Centre of Clinical Investigations, INSERM CIC 1426, Robert Debré University Hospital, Assistance Publique - Hôpitaux de Paris, Paris Cité Université, 48 Bd Sérurier, 75019 Paris, France</footnote>

<footnote><sup>d</sup>Department of General Pediatrics, Pediatric Infectious Disease and Internal Medicine, Robert Debré University Hospital, Assistance Publique - Hôpitaux de Paris, Paris Cité Université, 48 Bd Sérurier, 75019 Paris, France</footnote>

<footnote><sup>e</sup>Federal Statistical Office, Espace de l'Europe 10, 2000 Neuchâtel, Switzerland</footnote>

<footnote><sup>f</sup>Pediatric Emergency Department and General Pediatrics Department, Louis Mourier University Hospital, Assistance Publique - Hôpitaux de Paris, Paris Cité Université, 178 Rue des Renouillers, 92700 Colombes, France</footnote>

<footnote><sup>g</sup>Service of Pediatrics, Department Women-Mother-Child, Lausanne University Hospital and University of Lausanne, Rue du Bugnon 50, 1011 Lausanne, Switzerland</footnote>
## Introduction

Infectious diseases continue to be one of the leading cause of mortality among children and adolescents beyond the neonatal period globally, accounting for an estimated 3 million deaths each year.¹ While many infection-related deaths are preventable through effective public health measures or avoidable with timely healthcare interventions, a substantial number of children, including those who are otherwise healthy, continue to die from infections each year, even in countries with robust immunisation programmes, access to antibiotics, and availability of advanced life support measures.²⁻⁶

COVID-19-related non-pharmacological interventions (NPI) led to a marked decrease in the incidence of many paediatric infectious diseases, followed by an unprecedented resurgence of communicable infectious diseases after their relaxation.⁷ While these epidemiological shifts are well documented, changes in infection-related paediatric mortality remain poorly characterised, both during the implementation of NPI and during the subsequent surge in infectious diseases following their relaxation. Assessing whether the temporary suppression of infections during the pandemic translated into measurable reductions in mortality is important to inform future public health strategies, as understanding the extent to which targeted infection control measures may further reduce paediatric deaths could help refine strategies for infection prevention. This is particularly relevant in settings where infection-related deaths persist despite available interventions.

The aim of this study was to assess how epidemic variations of communicable infectious diseases in the context of COVID-19 related NPI modified infection-related mortality among children in France and Switzerland.

## Methods

### Study design

We conducted a population-based interrupted time-series analysis over 9 years, from January 1, 2015, to December 31, 2023, in two countries of the European region, France and Switzerland. We used hospital-based French national surveillance data and Swiss national mortality data.

### Participants

The population of interest was children and adolescents under 18 years living in France or Switzerland during the study period. We included all recorded events of deaths in this population, with the exclusion of stillbirths identified by corresponding International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes (Supplementary Materials). The sex variable in both datasets reflects administrative sex as recorded in official documents.

### Procedures

We used two sources of data, one for France and one for Switzerland. French data were obtained from hospital data originating from the French Medicalization of Information Systems Program ("Programme de Médicalisation des Systèmes d'Information, PMSI"), a comprehensive national medico-administrative database encompassing all patients admitted to both public and private hospitals in France. For each hospital stay, administrative and medical data are recorded. This includes length of stay, age, sex, principal and related diagnoses, and discharge disposition including death. Diagnoses made during hospital stays are classified using the ICD-10 and adhere to a national coding guideline provided by the Technical Agency for Hospital Information (ATIH). Swiss data were obtained from the Causes

of Death Statistics of the Swiss Federal Statistical Office (FSO), which is based on the medical cause of death certificates filled by the physician certifying the death. Several causes of deaths can be reported according to the rules defined by the World Health Organization (WHO): Immediate, underlying, and up to two concomitant diseases.⁸ The FSO then codes all causes of deaths according to the ICD-10.⁹

Data used as denominator to calculate mortality rates, such as age-specific French and Swiss population data for each year of the study and annual number of live births were provided by the National Institute of Statistics and Economic Studies (INSEE) for France and by the FSO for Switzerland.

We defined infection-related death as a death with an infectious disease diagnosis reported during the hospital stay during which death occurred in the PMSI and as principal, underlying, or concomitant cause of death in the Causes of Death Statistics from the FSO. We identified infectious diseases ICD-10 codes across all ICD-10 chapters (Supplementary Materials, Table S1). We therefore included all ICD-10 codes from the chapter I "Certain infectious and parasitic diseases" but also ICD-10 codes from other chapters such as respiratory infections which are listed in the chapter X "Diseases of the respiratory system" or septic shock which is listed in the chapter XVIII "Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified". For each ICD-10 code pertaining to an infectious diagnosis, we defined, when possible, one or more modes of transmission (droplet/airborne, faecal-oral, bloodborne/sexual, direct contact, and/or vertical) and the pathogen classification (bacterial or viral). We also specifically identified codes referring to certain pathogens known to play a significant role in paediatric mortality, such as *Streptococcus pneumoniae*, *Streptococcus pyogenes*, *Haemophilus influenzae*, *Neisseria meningitidis*, *Staphylococcus aureus*, *Bordetella pertussis*, influenza viruses, respiratory syncytial virus (RSV), enterovirus, metapneumovirus, varicella-zoster virus (VZV), and adenovirus.¹⁰ The Supplementary Material (Table S1) provides a detailed mapping of infection-related ICD-10 codes, including their attribution to pathogen, pathogen classification, and specific pathogen categories.

To define life-limiting conditions, we used the "Directory of life-limiting conditions" which is a practical tool developed to identify most paediatric life-limiting conditions using ICD-10 codes.¹¹ We excluded infectious disease diagnoses from this list (A17 Tuberculosis of nervous system, B20 to B24 Human immunodeficiency virus disease, A81.0 Creutzfeldt-Jakob disease, A81.1 Subacute sclerosing pannencephalitis). We defined three time periods according to NPI implementation and lifting: 1) pre-NPI period, from January 1, 2015 to February 29, 2020, 2) NPI period, from March 1, 2020 to August 31, 2021 and 3) post-NPI period, from September 1, 2021 to December 31, 2023. The NPI period is therefore defined as the time from the initial implementation of non-pharmaceutical interventions to the start of the first school year, marking social interactions among children, and coinciding with their substantial relaxation as reflected by the decline in the Oxford COVID-19 Government Response Stringency Index.¹²

We also constructed nominal birth cohorts based on birth year.

Access to the French PMSI was granted by the National Commission on Information and Liberty. As part of a continuous public health surveillance mission using anonymized, aggregated data, this study did not require ethical committee approval or written informed consent, in accordance with the French Data Protection Act. The Swiss cause of death statistics are collected by the FSO in accordance with the Ordinance on the Execution of Federal Statistical Surveys and complies with the Swiss Federal Data Protection Act. All data are anonymized, and no ethical approval was required for the use of these routinely collected data.

### Outcomes

The primary outcome was the monthly infection-related mortality rate per 100,000 children aged under 18 years. Secondary outcomes
were 1) monthly infection-related mortality rate by country, 2) by age group (0–1 year, 2–4 years, 5–9 years, and 10–17 years), 3) by life-limiting condition, 4) by pathogen, 5) by infectious disease transmission mode, 6) the monthly all-cause mortality rate, and 7) the cumulative non-neonatal infection-related mortality rate during the first two years of life. We analysed the non-infection-related mortality rate as a control outcome. Analyses stratified by country, age group, life-limiting condition, pathogen, and transmission mode were specified to explore heterogeneity in infection-related mortality trends.

## Statistical analysis

All outcomes, with the exception of the infection-related cumulative mortality rate during the first two years of life, were analysed using a quasi-Poisson regression model, accounting for seasonality by using periodic B-splines of month with 4 degrees of freedom, consistent with standard practice in environmental time-series analyses using monthly data.<sup>13,14</sup> This specification provides adequate flexibility to capture broad seasonal patterns while avoiding overfitting. The time unit was set to 1 month.

The observed monthly mortality rate was fitted by the model for each time-point of the study period, with NPI implementation and lifting included as explanatory categorical variables. Mortality rates observed during the reference period were used to estimate the expected monthly mortality rate without NPI. We then estimated the changes in mortality rates following NPI implementation and NPI lifting, compared to the expected values of the outcome based on the pre-NPI trend. This allowed us to compute the mortality burden associated with the intervention based on the observed mortality in the post-intervention period. The validity of the quasi-Poisson regression models was assessed by visual inspection of correlograms and residuals analysis.

To analyse the secondary outcome of non-neonatal infection-related mortality over the first two years of life, we constructed nominal birth cohorts (e.g., 2019 birth cohort) and calculated both annual and cumulative two-year non-neonatal infection-related mortality rates. We therefore excluded neonatal infection-related deaths, which were identified with the ICD-10 codes of the "Certain conditions originating in the perinatal period" chapter (codes P00-P96), as they represent about half of first-year deaths and have distinct causes.<sup>15</sup> The mean cumulative two-year non-neonatal infection-related mortality rate across three pre-NPI birth cohorts (2015–2017) served as the reference. Infection-related mortality rate ratios and their 95% confidence intervals were calculated to compare each NPI (2019, 2020) and post-NPI (2021, 2022) birth cohort to the reference rate.

We performed several sensitivity analyses on the primary outcome: 1) a quasi-Poisson regression model accounting for seasonality by including harmonic terms (sines and cosines with 12-, 6- and 3-month periods), 2) a segmented linear regression model accounting for seasonality using periodic B-splines of month (4 degrees of freedom), 3) a segmented linear regression using an additive model to remove seasonality, 4) a negative binomial regression model accounting for seasonality using periodic B-splines of month (4 degrees of freedom), 5) a quasi-Poisson regression model excluding neonatal deaths, 6) a quasi-Poisson regression model for infection-related deaths coded as principal diagnosis only, and 7) a quasi-Poisson regression model with the NPI period defined from March 1, 2020 to February 28, 2021. We also performed a quasi-Poisson regression model on the control-outcome of non-infection-related deaths. Moreover, to assess whether infections unrelated to the fatal outcome were captured in our definition, we examined the number of deaths associated with upper respiratory tract infections (URTI), which are common but rarely fatal in children.

Statistical tests were two-sided, and a p value of less than 0.05 was considered to indicate statistical significance. All analyses were performed using R Statistical Software (v4.4.2; R Core Team 2021).

## Role of the funding sources

The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

## Results

### Baseline characteristics

Between January 1, 2015 and December 31, 2023, 87,077 deaths among children < 18 years were recorded in both countries. After exclusion of stillbirths, we included 32,619 deaths in the analysis (Supplementary material, Figs. S1 and S2). Infection-related deaths accounted for 8272 (25%) of cases. The median (IQR) age at death was 0 (0–1) years overall and 0 (0–4) among children who died with an infection. Of all children, 18,259 (56%) were males. An underlying life-limiting condition was present for 20,361 (62%) children among all deaths and for 5995 (72%) children among infection-related deaths. The age group with the highest monthly infection-related mortality rate was 0 to 1 year old, while the 5 to 9 years old age group had the lowest rate. A higher number of infection-related deaths were attributed to bacterial infections than to viral infections (N=5287 and N=1694 respectively). Among bacterial pathogens, *S. aureus* accounted for the highest number of deaths (N=656), followed by *S. pneumoniae* (N=204). Among viral pathogens, influenza virus accounted for the highest number of deaths (N=228), followed by RSV (N=200), and adenovirus (N=142). Viral-bacterial co-infections accounted for 738 deaths. Infections transmitted via the respiratory routes accounted for the highest number of deaths followed by infection transmitted by contact and by the faecal-oral route (Table 1).

### Changes in infection-related mortality rates during and after non-pharmaceutical interventions

There were 4793 infection-related deaths over the 62 months before NPI implementation, 1198 deaths over the 18 months during NPI, and 2281 during the 28 months post-NPI, corresponding to a monthly infection-related mortality rate of 0.48 (95% CI 0.46–0.49), 0.41 (95% CI 0.39–0.44), and 0.51 (95% CI 0.49–0.53) per 100,000 children respectively. After NPI implementation in March 2020, in-infection-related mortality rate decreased significantly (- 15.6%, 95% CI -23.3% to -7.0%), corresponding to an estimated reduction of 221 (95% CI 90 to 371) deaths. After NPI lifting, the infection-related mortality rate was not significantly different compared to the pre-NPI period (+0.9%, 95% CI -10.2% to +13.4%) (Fig. 1 and Table 2).

### Change in infection-related mortality by country, age, life-limiting conditions, pathogen type and transmission mode

The decrease in infection-related death during NPI was observed in the two countries. It was the most pronounced among the age category 0 to 1 year old (-18.3%, 95% CI -27.0% to -8.6%), corresponding to an estimated reduction of 189 (95% CI: 79 to 318) deaths. Conversely, in the post-NPI period, there was a significant increase in infection-related mortality among older children aged 10 to 17 years (+39.5%, 95% CI 6.4% to 83.5%), corresponding to an estimated 109 excess deaths (95% CI: 18 to 175) (Table 2 and Fig. 2). When analysed by associated life-limiting conditions, children with neurologic and congenital life-limiting conditions experienced the most substantial mortality reductions (-28.6%, 95% CI: -43.4% to -10.0% and -17.5%, 95% CI: -28.3% to -5.2%, respectively). Following NPI lifting, infection-related mortality increased significantly in children with
<table><caption>**Table 1**
Monthly paediatric mortality rates and number of deaths, by time period (Jan 2015–Dec 2023).</caption><thead><tr><th rowspan="2"></th><th colspan="2">Pre-NPI period Jan 2015-Feb 2020 (62 months)</th><th colspan="2">NPI period Mar 2020-Aug 2021 (18 months)</th><th colspan="2">Post-NPI period Sep 2021-Dec 2023 (28 months)</th><th colspan="2">All periods Jan 2015-Dec 2023 (108 months)</th></tr><tr><th>Monthly mortality rate per 100'000 individuals (95% CI)</th><th>N</th><th>Monthly mortality rate per 100'000 individuals (95% CI)</th><th>N</th><th>Monthly mortality rate per 100'000 individuals (95% CI)</th><th>N</th><th>Monthly mortality rate per 100'000 individuals (95% CI)</th><th>N</th></tr></thead><tbody><tr><td><strong>All-cause mortality</strong></td><td>1.9 (1.88-1.93)</td><td>19,165</td><td>1.73 (1.68-1.78)</td><td>5006</td><td>1.89 (1.85-1.93)</td><td>8448</td><td>1.87 (1.85-1.89)</td><td>32,619</td></tr><tr><td><strong>Infection-related mortality</strong></td><td>0.48 (0.46-0.49)</td><td>4793</td><td>0.41 (0.39-0.44)</td><td>1198</td><td>0.51 (0.49-0.53)</td><td>2281</td><td>0.47 (0.46-0.48)</td><td>8272</td></tr><tr><td><strong>All-cause mortality, sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>1.71 (1.67-1.75)</td><td>8394</td><td>1.54 (1.48-1.61)</td><td>2169</td><td>1.74 (1.69-1.80)</td><td>3797</td><td>1.69 (1.66-1.72)</td><td>14,360</td></tr><tr><td>Male</td><td>2.09 (2.05-2.13)</td><td>10,771</td><td>1.92 (1.85-1.99)</td><td>2837</td><td>2.03 (1.97-2.09)</td><td>4651</td><td>2.05 (2.02-2.08)</td><td>18,259</td></tr><tr><td><strong>Infection-related mortality, sex</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Female</td><td>0.42 (0.40-0.44)</td><td>2079</td><td>0.37 (0.34-0.40)</td><td>523</td><td>0.49 (0.46-0.52)</td><td>1062</td><td>0.43 (0.42-0.44)</td><td>3664</td></tr><tr><td>Male</td><td>0.53 (0.51-0.55)</td><td>2714</td><td>0.46 (0.43-0.50)</td><td>675</td><td>0.53 (0.50-0.56)</td><td>1219</td><td>0.52 (0.51-0.54)</td><td>4608</td></tr><tr><td><strong>Infection-related mortality, country</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>France</td><td>0.5 (0.49-0.52)</td><td>4603</td><td>0.45 (0.42-0.47)</td><td>1164</td><td>0.54 (0.52-0.57)</td><td>2196</td><td>0.51 (0.49-0.52)</td><td>7963</td></tr><tr><td>Switzerland</td><td>0.2 (0.17-0.23)</td><td>190</td><td>0.12 (0.08-0.17)</td><td>34</td><td>0.19 (0.15-0.24)</td><td>85</td><td>0.19 (0.16-0.21)</td><td>309</td></tr><tr><td><strong>All-cause mortality, age group</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 to 1 years</td><td>14.04 (13.81-14.27)</td><td>14,517</td><td>13.33 (12.91-13.76)</td><td>3808</td><td>14.32 (13.97-14.68)</td><td>6223</td><td>13.99 (13.82-14.17)</td><td>24,548</td></tr><tr><td>2 to 4 years</td><td>0.67 (0.63-0.71)</td><td>1090</td><td>0.58 (0.51-0.65)</td><td>261</td><td>0.77 (0.71-0.84)</td><td>526</td><td>0.68 (0.65-0.71)</td><td>1877</td></tr><tr><td>5 to 9 years</td><td>0.38 (0.36-0.41)</td><td>1096</td><td>0.34 (0.3-0.38)</td><td>279</td><td>0.41 (0.38-0.45)</td><td>516</td><td>0.38 (0.37-0.4)</td><td>1891</td></tr><tr><td>10 to 17 years</td><td>0.54 (0.52-0.56)</td><td>2462</td><td>0.49 (0.45-0.53)</td><td>658</td><td>0.56 (0.53-0.59)</td><td>1183</td><td>0.54 (0.52-0.55)</td><td>4303</td></tr><tr><td><strong>Infection-related mortality, age group</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 to 1 years</td><td>3.16 (3.05-3.26)</td><td>3263</td><td>2.94 (2.75-3.15)</td><td>841</td><td>3.38 (3.21-3.56)</td><td>1469</td><td>3.18 (3.09-3.26)</td><td>5573</td></tr><tr><td>2 to 4 years</td><td>0.26 (0.24-0.29)</td><td>430</td><td>0.2 (0.16-0.25)</td><td>92</td><td>0.32 (0.28-0.36)</td><td>217</td><td>0.27 (0.25-0.29)</td><td>739</td></tr><tr><td>5 to 9 years</td><td>0.12 (0.11-0.14)</td><td>355</td><td>0.1 (0.08-0.13)</td><td>83</td><td>0.17 (0.15-0.19)</td><td>210</td><td>0.13 (0.12-0.14)</td><td>648</td></tr><tr><td>10 to 17 years</td><td>0.16 (0.15-0.18)</td><td>745</td><td>0.14 (0.12-0.16)</td><td>182</td><td>0.18 (0.16-0.2)</td><td>385</td><td>0.16 (0.16-0.17)</td><td>1312</td></tr><tr><td><strong>Infection-related mortality, association with life-limiting conditions</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>0.13 (0.13-0.14)</td><td>1358</td><td>0.11 (0.09-0.12)</td><td>304</td><td>0.14 (0.13-0.15)</td><td>615</td><td>0.13 (0.13-0.14)</td><td>2277</td></tr><tr><td>Any</td><td>0.34 (0.33-0.35)</td><td>3435</td><td>0.31 (0.29-0.33)</td><td>894</td><td>0.37 (0.35-0.39)</td><td>1666</td><td>0.34 (0.34-0.35)</td><td>5995</td></tr><tr><td>Cancer</td><td>0.05 (0.05-0.06)</td><td>551</td><td>0.05 (0.04-0.06)</td><td>142</td><td>0.05 (0.05-0.06)</td><td>232</td><td>0.05 (0.05-0.06)</td><td>925</td></tr><tr><td>Congenital</td><td>0.2 (0.19-0.21)</td><td>2051</td><td>0.2 (0.18-0.21)</td><td>566</td><td>0.22 (0.2-0.23)</td><td>972</td><td>0.21 (0.2-0.21)</td><td>3589</td></tr><tr><td>Metabolic</td><td>0.01 (0.01-0.02)</td><td>150</td><td>0.02 (0.01-0.02)</td><td>47</td><td>0.02 (0.02-0.02)</td><td>86</td><td>0.02 (0.01-0.02)</td><td>283</td></tr><tr><td>Neurologic</td><td>0.07 (0.06-0.07)</td><td>684</td><td>0.06 (0.05-0.07)</td><td>162</td><td>0.08 (0.07-0.09)</td><td>358</td><td>0.07 (0.07-0.07)</td><td>1204</td></tr><tr><td>Other</td><td>0.14 (0.13-0.15)</td><td>1430</td><td>0.13 (0.11-0.14)</td><td>362</td><td>0.15 (0.14-0.16)</td><td>668</td><td>0.14 (0.14-0.15)</td><td>2460</td></tr><tr><td><strong>Infection-related mortality, specific causes</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Bacterial infections</td><td>0.31 (0.3-0.32)</td><td>3080</td><td>0.27 (0.25-0.28)</td><td>768</td><td>0.32 (0.31-0.34)</td><td>1439</td><td>0.3 (0.3-0.31)</td><td>5287</td></tr><tr><td>Viral infections</td><td>0.09 (0.09-0.1)</td><td>945</td><td>0.06 (0.05-0.07)</td><td>173</td><td>0.13 (0.12-0.14)</td><td>576</td><td>0.1 (0.09-0.1)</td><td>1694</td></tr><tr><td>Viral-bacterial co-infections</td><td>0.04 (0.04-0.05)</td><td>422</td><td>0.02 (0.02-0.03)</td><td>70</td><td>0.05 (0.05-0.06)</td><td>246</td><td>0.04 (0.04-0.05)</td><td>738</td></tr><tr><td><em>Streptococcus pneumoniae</em></td><td>0.01 (0.01-0.01)</td><td>120</td><td>0.01 (0-0.01)</td><td>19</td><td>0.01 (0.01-0.02)</td><td>65</td><td>0.01 (0.01-0.01)</td><td>204</td></tr><tr><td><em>Streptococcus pyogenes</em></td><td>0 (0-0)</td><td>35</td><td>0 (0-0)</td><td>5</td><td>0 (0-0.01)</td><td>18</td><td>0 (0-0)</td><td>58</td></tr><tr><td><em>Neisseria meningitidis</em></td><td>0.01 (0-0.01)</td><td>62</td><td>0 (0-0)</td><td>6</td><td>0 (0-0.01)</td><td>16</td><td>0 (0-0.01)</td><td>84</td></tr><tr><td><em>Haemophilus influenzae</em></td><td>0.01 (0.01-0.01)</td><td>98</td><td>0.01 (0-0.01)</td><td>21</td><td>0.01 (0.01-0.01)</td><td>48</td><td>0.01 (0.01-0.01)</td><td>167</td></tr><tr><td><em>Staphylococcus aureus</em></td><td>0.03 (0.03-0.04)</td><td>341</td><td>0.03 (0.02-0.04)</td><td>82</td><td>0.03 (0.03-0.04)</td><td>142</td><td>0.03 (0.03-0.04)</td><td>565</td></tr><tr><td><em>Bordetella pertussis</em></td><td>0 (0-0)</td><td>29</td><td>0 (0-0)</td><td>2</td><td>0 (0-0)</td><td>4</td><td>0 (0-0)</td><td>35</td></tr><tr><td>Influenzae</td><td>0.01 (0.01-0.02)</td><td>150</td><td>0 (0-0)</td><td>6</td><td>0.02 (0.01-0.02)</td><td>72</td><td>0.01 (0.01-0.01)</td><td>228</td></tr><tr><td>Respiratory syncytial virus</td><td>0.01 (0.01-0.01)</td><td>106</td><td>0.01 (0-0.01)</td><td>18</td><td>0.02 (0.01-0.02)</td><td>76</td><td>0.01 (0.01-0.01)</td><td>200</td></tr><tr><td>Metapneumovirus</td><td>0 (0-0)</td><td>20</td><td>0 (0-0.01)</td><td>9</td><td>0 (0-0.01)</td><td>17</td><td>0 (0-0)</td><td>46</td></tr><tr><td>Enterovirus</td><td>0 (0-0.01)</td><td>47</td><td>0 (0-0.01)</td><td>8</td><td>0.01 (0.01-0.01)</td><td>44</td><td>0.01 (0-0.01)</td><td>99</td></tr><tr><td>Adenovirus</td><td>0.01 (0.01-0.01)</td><td>78</td><td>0 (0-0.01)</td><td>14</td><td>0.01 (0.01-0.01)</td><td>50</td><td>0.01 (0.01-0.01)</td><td>142</td></tr><tr><td>Varicella-zoster virus</td><td>0 (0-0)</td><td>34</td><td>0 (0-0)</td><td>5</td><td>0 (0-0.01)</td><td>16</td><td>0 (0-0)</td><td>55</td></tr><tr><td><strong>Infection-related mortality, transmission mode</strong></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Droplet/airborne</td><td>0.12 (0.12-0.13)</td><td>1248</td><td>0.09 (0.08-0.1)</td><td>250</td><td>0.16 (0.15-0.18)</td><td>729</td><td>0.13 (0.12-0.13)</td><td>2227</td></tr><tr><td>Contact</td><td>0.07 (0.07-0.08)</td><td>730</td><td>0.06 (0.05-0.07)</td><td>166</td><td>0.07 (0.06-0.08)</td><td>316</td><td>0.07 (0.07-0.07)</td><td>1212</td></tr><tr><td>Faecal-oral</td><td>0.04 (0.03-0.04)</td><td>364</td><td>0.03 (0.03-0.04)</td><td>93</td><td>0.05 (0.04-0.05)</td><td>212</td><td>0.04 (0.04-0.04)</td><td>669</td></tr><tr><td>Blood/sexual</td><td>0.02 (0.01-0.02)</td><td>153</td><td>0.01 (0.01-0.01)</td><td>29</td><td>0.01 (0.01-0.01)</td><td>50</td><td>0.01 (0.01-0.02)</td><td>232</td></tr><tr><td>Vertical</td><td>0.03 (0.03-0.03)</td><td>288</td><td>0.02 (0.02-0.03)</td><td>66</td><td>0.03 (0.03-0.04)</td><td>136</td><td>0.03 (0.03-0.03)</td><td>490</td></tr></tbody></table>

Data are shown as monthly mortality rates per 100,000 individuals and number of deaths (N) during the pre-NPI period (Jan 2015-Feb 2020), NPI period (Mar 2020-Aug 2021), post-NPI period (Sep 2021-Dec 2023), and across the full study period.

Abbreviations: CI, confidence interval, NPI, non-pharmaceutical interventions.

cancer/haematological life-limiting conditions (+57.6%, 95% CI: +14.2% to +118.2%) (Table 2 and Supplementary material, Fig. S3).

The impact of NPI also varied by pathogen type. During the NPI period, bacterial and viral infection-related mortality decreased, with a reduction in viral infection-related deaths more pronounced than in bacterial infection-related deaths (-37.6%, 95% CI: -52.7% to

-18.1% and -17.1%, 95% CI: -26.6% to -6.3% respectively). The pathogens associated with mortality with the most pronounced decrease during NPI were *S. pneumoniae* (-51.3%, 95% CI: -75.1% to -7.7%) and influenza virus (-87.1%, 95% CI: -97.7% to -54.8%) (Fig. 3).

Regarding transmission routes, deaths related to infections transmitted via droplet/airborne were reduced significantly (-26.7%,
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Evolution of the monthly infection-related mortality rate in France and Switzerland, January 2015–December 2023. Monthly incidence of infection-related mortality per 100,000 children aged less than 18 years. The grey lines show the observed data. The black line shows the fitted model, with grey shaded area showing the 95% confidence intervals. The blue line shows the expected incidence based on data before NPI implementation, with blue shaded area showing the 95% confidence intervals. The vertical lines show the limit between periods (pre-NPI, NPI, post-NPI). Abbreviations: CI, confidence interval; NPI, non-pharmaceutical intervention.</figcaption></figure>

95% CI: -41.8% to -7.9%), as those related to infections transmitted via direct contact (-28.3%, 95% CI: -44.5% to -7.6%). After NPI lifting, there was only an increase in mortality related to infection transmitted via droplet/airborne (+33.2%, 95% CI: +2.9% to +72.8%) (Supplemental material, Fig. S4).

## Differences in infection-related mortality across birth cohorts

Infection-related mortality rates varied significantly across birth cohorts during the study period (Fig. 4). During their first year of life, children born in 2020 had the lowest rate (4.9 per 100,000 livebirths), while those born in 2022 had the highest (9.6 per 100,000 livebirths). Analysing cumulative infection-related mortality during the first two years of life, birth cohorts from the NPI period showed significantly lower mortality compared to pre-NPI cohorts. Specifically, the 2019 and 2020 birth cohorts had both a mortality rate ratio of 0.80 (95% CI 0.66 to 0.98 and 0.65 to 0.98, respectively). These reductions correspond to an estimated reduction of 30 deaths in each cohort (95% CI: 3 to 52 and 3 to 51, respectively). In contrast, the 2022 cohort, born after the NPI period, showed a trend toward higher mortality with a rate ratio of 1.18 (95% CI 0.99 to 1.41), suggesting approximately 27 excess deaths (95% CI -1 to 60), though this increase did not reach statistical significance (Table 3).

## Control outcome and sensitivity analyses

As a control measure, we examined non-infection-related mortality, which showed no significant change during the NPI period but increased after NPI lifting (+9.4%, 95% CI: +1.7% to +17.8%) (Fig. 5). When restricting infection-related deaths to those coded as the principal diagnosis only, infection-related mortality rate decreased significantly during the NPI period (-26.5%, 95% CI: -41.5% to -7.6%) and was not

significantly different compared to the pre-NPI period (+16.8%, 95% CI: -9.9% to +51.5%). When redefining the NPI period as March 2020 to February 2021, results were similar (-20.1%, 95% CI: -27.8% to -11.7% during NPI; +0.1%, 95% CI: -10.0% to +11.5% after NPI).

Correlograms and residuals analyses indicated a satisfactory quality of the model and sensitivity analyses yielded results consistent with the main analysis. In particular, (Supplementary material, Table S2, Figs. S5 and S6). In particular, URTI were classified as the cause of death in only 113 cases during the entire study period (1.4% of all infection-related deaths, incidence per 100,000 children 0-01, 95% CI 0-01 to 0-01).

## Discussion

In this 9-year population-based nationwide cohort study from France and Switzerland, we found that paediatric infection-related mortality decreased during the NPI period without an increase of the same magnitude in the post-NPI period, suggesting a lasting survival benefit for a subset of children. This benefit was not universal across birth cohorts, nor across age groups, or comorbidity profiles. Children born in 2019 and 2020 who experienced their early years in a pandemic-altered environment had lower infection-related mortality rates than expected, whereas those born in 2022 who entered infancy amid a surge of infectious diseases had higher rates. Some infants therefore bore the disproportionate burden of post-pandemic infectious disease rebounds without having benefited from the protective measures that safeguarded pandemic period cohorts. Overall, children younger than 2 years of age benefited from the reduction in pathogen circulation induced by NPI with a reduction in infection-related mortality without experiencing an increase in the post-NPI period. By contrast, those aged 10 to 17 years were negatively impacted, as infection-related mortality did not decrease
<table><caption>**Table 2**
Relative and absolute changes in paediatric infection-related mortality during and after the period of NPI compared to the pre-NPI period.</caption><thead><tr><th rowspan="2"></th><th colspan="3">NPI period Mar 2020–Aug 2021</th><th colspan="3">Post-NPI period Sep 2021–Dec 2023</th></tr><tr><th>Relative change in incidence (95% CI)</th><th>p value</th><th>Absolute change in number of deaths (95% CI)</th><th>Relative change in incidence (95% CI)</th><th>p value</th><th>Absolute change in number of deaths (95% CI)</th></tr></thead><tbody><tr><td><strong>Infection-related mortality</strong></td><td>-15.6% (-23.3%–-7.0%)</td><td>0.0006</td><td>-221 (-371–-90)</td><td>0.9% (-10.2%–-13.4%)</td><td>0.88</td><td>+20 (-274–+269)</td></tr><tr><td><strong>Infection-related mortality, country</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>France</td><td>-14.6% (-22.6%–-5.8%)</td><td>0.0016</td><td>-200 (-347–-72)</td><td>1.1% (-10.2%–14%)</td><td>0.86</td><td>+25 (-264–+269)</td></tr><tr><td>Switzerland</td><td>-37.7% (-61.2%–-1.1%)</td><td>0.047</td><td>-21 (-55–0)</td><td>-3.2% (-42.5%–-64.4%)</td><td>0.903</td><td>-3 (-67–+33)</td></tr><tr><td><strong>Infection-related mortality, age group</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 to 1 years</td><td>-18.3% (-27%–-8.6%)</td><td>0.0005</td><td>-189 (-318–-79)</td><td>-13% (-24.3%–0%)</td><td>0.049</td><td>-220 (-484–-1)</td></tr><tr><td>2 to 4 years</td><td>-19.5% (-39.3%–-6.3%)</td><td>0.13</td><td>-22 (-61–+6)</td><td>25.5% (-9.3%–-74.1%)</td><td>0.17</td><td>+44 (-26–+92)</td></tr><tr><td>5 to 9 years</td><td>-21.3% (-44.4%–-10.9%)</td><td>0.17</td><td>-22 (-68–+8)</td><td>22.7% (-17.9%–-84.4%)</td><td>0.32</td><td>+39 (-51–+96)</td></tr><tr><td>10 to 17 years</td><td>-1.3% (-21.4%–-23.9%)</td><td>0.91</td><td>-2 (-52–+35)</td><td>39.5% (6.4%–83.5%)</td><td>0.017</td><td>+109 (+18–+175)</td></tr><tr><td><strong>Infection-related mortality, association with life-limiting conditions</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>None</td><td>-15.0% (-28.9%–-1.4%)</td><td>0.072</td><td>-54 (-127–+4)</td><td>12.3% (-9%–38.7%)</td><td>0.28</td><td>+67 (-68–+171)</td></tr><tr><td>Any</td><td>-15.9% (-24.3%–-6.6%)</td><td>0.0012</td><td>-170 (-293–-64)</td><td>-3.3% (-15–10%)</td><td>0.61</td><td>-57 (-305–+150)</td></tr><tr><td>Cancer</td><td>26% (-3%–63.8%)</td><td>0.083</td><td>+29 (-6–+55)</td><td>57.6% (14.2%–118.2%)</td><td>0.0059</td><td>+85 (+25–+125)</td></tr><tr><td>Congenital</td><td>-17.5% (-28.3%–-5.2%)</td><td>0.0068</td><td>-120 (-228–-31)</td><td>-15.9% (-29.3%–0%)</td><td>0.050</td><td>-184 (-414–-1)</td></tr><tr><td>Metabolic</td><td>-32.2% (-55.7%–-3.5%)</td><td>0.072</td><td>-22 (-61–+2)</td><td>-39.3% (-64.4%–-3.9%)</td><td>0.067</td><td>-56 (-162–+3)</td></tr><tr><td>Neurologic</td><td>-28.6% (-43.4%–-10%)</td><td>0.0044</td><td>-65 (-127–-18)</td><td>-8.1% (-30.1%–-21.2%)</td><td>0.55</td><td>-32 (-161–+62)</td></tr><tr><td>Other</td><td>-12.8% (-25.9%–-2.5%)</td><td>0.096</td><td>-53 (-130–+9)</td><td>1.9% (-16.3%–-24.2%)</td><td>0.85</td><td>+13 (-137–+130)</td></tr><tr><td><strong>Infection-related mortality, specific causes</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Bacterial infections</td><td>-17.1% (-26.6%–-6.3%)</td><td>0.0027</td><td>-158 (-284–-52)</td><td>-2.3% (-15.7%–-13.4%)</td><td>0.76</td><td>-33 (-281–+170)</td></tr><tr><td>Viral infections</td><td>-37.6% (-52.7%–-18%)</td><td>0.0008</td><td>-104 (-197–-38)</td><td>25.3% (-7.3%–69.9%)</td><td>0.14</td><td>+116 (-55–+236)</td></tr><tr><td>Viral-bacterial co-infections</td><td>-44.3% (-60.4%–-22.2%)</td><td>0.0007</td><td>-56 (-109–-20)</td><td>22.5% (-14.7%–-76.8%)</td><td>0.27</td><td>+45 (-48–+106)</td></tr><tr><td><em>Streptococcus pneumoniae</em></td><td>-51.3% (-75.1%–-7.7%)</td><td>0.0303</td><td>-20 (-58–-1)</td><td>-1.7% (-50.8%–-99.5%)</td><td>0.96</td><td>-1 (-72–+32)</td></tr><tr><td><em>Streptococcus pyogenes</em></td><td>-50.1% (-87.7%–-75.2%)</td><td>0.29</td><td>-5 (-34–+2)</td><td>10.9% (-71%–-352.3%)</td><td>0.88</td><td>+2 (-50–+14)</td></tr><tr><td><em>Neisseria meningitidis</em></td><td>-49.6% (-82.2%–-28.3%)</td><td>0.17</td><td>-6 (-27–+1)</td><td>-5.4% (-64.1%–154.2%)</td><td>0.91</td><td>-1 (-31–+10)</td></tr><tr><td><em>Haemophilus influenzae</em></td><td>-18.5% (-55.6%–-48%)</td><td>0.504</td><td>-5 (-27–+7)</td><td>26.2% (-36.9%–156.7%)</td><td>0.52</td><td>+10 (-31–+29)</td></tr><tr><td><em>Staphylococcus aureus</em></td><td>-20.6% (-46.4%–-17.2%)</td><td>0.25</td><td>-21 (-73–+12)</td><td>-12.1% (-45.2%–42%)</td><td>0.60</td><td>-20 (-124–+42)</td></tr><tr><td><em>Bordetella pertussis</em></td><td>-88.7% (-98.9%–-40.3%)</td><td>0.023</td><td>-16 (-124–-1)</td><td>-90.1% (-98.6%–-38.2%)</td><td>0.015</td><td>-37 (-283–-2)</td></tr><tr><td>Influenzae</td><td>-87.1% (-97.7%–-54.8%)</td><td>0.0049</td><td>-40 (-201–-5)</td><td>-9.7% (-64.2%–134.9%)</td><td>0.83</td><td>-8 (-141–+41)</td></tr><tr><td>Respiratory syncytial virus</td><td>-24.2% (-65.5%–-60.2%)</td><td>0.48</td><td>-6 (-35–+7)</td><td>63% (-25.6%–267.2%)</td><td>0.23</td><td>+29 (-31–+55)</td></tr><tr><td>Enterovirus</td><td>-44.8% (-80%–-42.4%)</td><td>0.23</td><td>-7 (-32–+2)</td><td>83.0% (-32.8%–420.6%)</td><td>0.25</td><td>+20 (-26–+35)</td></tr><tr><td>Adenovirus</td><td>-28.5% (-64.5%–-40.6%)</td><td>0.34</td><td>-6 (-26–+4)</td><td>79.2% (-14.7%–285.8%)</td><td>0.13</td><td>+22 (-11–+37)</td></tr><tr><td>Varicella-zoster virus</td><td>-38.2% (-80.9%–-85.7%)</td><td>0.401</td><td>-3 (-21–+2)</td><td>79.1% (-46.2%–534.2%)</td><td>0.35</td><td>+7 (-16–+13)</td></tr><tr><td>Vaccine-preventable diseases</td><td>-30.9% (-45.8%–-12.1%)</td><td>0.0027</td><td>-60 (-115–-18)</td><td>1.1% (-23.4%–33.9%)</td><td>0.94</td><td>+3 (-100–+77)</td></tr><tr><td><strong>Infection-related mortality, transmission mode</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Droplet/airborne</td><td>-26.7% (-41.8%–-7.9%)</td><td>0.0078</td><td>-91 (-184–-21)</td><td>33.2% (2.9%–72.8%)</td><td>0.0301</td><td>+182 (+11–+306)</td></tr><tr><td>Contact</td><td>-28.3% (-44.5%–-7.6%)</td><td>0.0105</td><td>-66 (-136–-14)</td><td>-13.5% (-36.3%–-17.6%)</td><td>0.35</td><td>-50 (-187–+47)</td></tr><tr><td>Faecal-oral</td><td>-9.4% (-31.8%–20.2%)</td><td>0.49</td><td>-10 (-45–+16)</td><td>37.5% (-1.9%–93.6%)</td><td>0.067</td><td>+58 (-8–+102)</td></tr><tr><td>Blood/sexual</td><td>-35.7% (-61.4%–-6.3%)</td><td>0.087</td><td>-16 (-47–+2)</td><td>-24.4% (-58.4%–-38.5%)</td><td>0.36</td><td>-16 (-74–+14)</td></tr><tr><td>Vertical</td><td>-31.2% (-52.2%–-1.3%)</td><td>0.043</td><td>-30 (-74–-1)</td><td>-13.7% (-43.9%–-33.5%)</td><td>0.505</td><td>-22 (-112–+34)</td></tr><tr><td><strong>All-cause mortality</strong></td><td>-4.4% (-9.6%–-1.1%)</td><td>0.11</td><td>-229 (-543–+54)</td><td>7.3% (0.2%–14.9%)</td><td>0.045</td><td>+573 (-13–+1095)</td></tr><tr><td><strong>All-cause mortality, age group</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>0 to 1 years</td><td>-4.8% (-10.4%–-1.1%)</td><td>0.11</td><td>-192 (-453–+42)</td><td>2.6% (-4.8%–10.5%)</td><td>0.51</td><td>+155 (-338–+591)</td></tr><tr><td>2 to 4 years</td><td>-8.7% (-26.3%–-12.9%)</td><td>0.40</td><td>-25 (-96–+30)</td><td>27.1% (-1.5%–64.5%)</td><td>0.07</td><td>+112 (-15–+206)</td></tr><tr><td>5 to 9 years</td><td>-8.9% (-24.5%–-9.7%)</td><td>0.32</td><td>-27 (-93–+25)</td><td>13.3% (-9.7%–-42.3%)</td><td>0.28</td><td>+61 (-62–+153)</td></tr><tr><td>10 to 17 years</td><td>-3.3% (-16.3%–-11.8%)</td><td>0.66</td><td>-21 (-134–+70)</td><td>12.3% (-6%–34.4%)</td><td>0.20</td><td>+130 (-86–+302)</td></tr><tr><td><strong>Control outcome: Non-infection related mortality</strong></td><td>-0.3% (-6%–-5.8%)</td><td>0.92</td><td>-11 (-256–+208)</td><td>9.4% (1.7%–17.8%)</td><td>0.02</td><td>+532 (+81–+932)</td></tr></tbody></table>

Relative and absolute changes in monthly paediatric infection-related mortality rates during the NPI period (March 2020 to August 2021) and the post-NPI period (September 2021 to December 2023), compared with the pre-NPI period (January 2015 to February 2020).

Abbreviations: CI, confidence interval; NPI, non-pharmaceutical intervention.

during the NPI period in this age-group but increased in the post-NPI period. Children with neurological life-limiting conditions had a lower mortality rate during NPI period and children with cancer and haematological conditions a higher in the post-NPI period.

We therefore did not observe evidence of mortality displacement, even among vulnerable children with underlying conditions. Mortality displacement (or “harvesting effect”) typically refers to a phenomenon in which a period of excess mortality is followed by a subsequent decline in deaths, as observed in events such as heat-waves, but has also been used to describe the reverse effect such as in the context of reduced circulation of infectious diseases, where mortality may be deferred due to temporary reductions in

exposure.¹⁶ This could occur through mechanisms such as delayed deaths among vulnerable individuals or the immune debt phenomenon.¹⁷ However, rather than a uniform displacement effect, we found that the impact of NPI on infection-related mortality was heterogeneous across paediatric populations. In comparison, in England, where all deaths of children aged 0 to 17 years are reviewed and gathered by the National Child Mortality Database (NCMD) since 2019, investigators also observed a reduction in infection-related mortality during the first year of the COVID-19 pandemic (2020–2021), but an increase during the second (2022–2023).⁶,¹⁸,¹⁹

The reduced community transmission of pathogens during NPI likely drove infection-related mortality reduction, as suggested by
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Evolution of the monthly infection-related mortality rate across age groups in France and Switzerland, January 2015–December 2023. Monthly incidence of infection-related mortality per 100,000 children by age groups. The grey lines show the observed data. The black line shows the fitted model, with grey shaded area showing the 95% confidence intervals. The blue line shows the expected incidence based on data before NPI implementation, with blue shaded area showing the 95% confidence intervals. The vertical lines show the limit between periods (pre-NPI, NPI, post-NPI). Abbreviations: CI, confidence interval; NPI, non-pharmaceutical intervention.</figcaption></figure>

differential effects of NPI on mortality by transmission route which was most pronounced for respiratory and contact transmission, and by the well described changes in the incidence of paediatric infectious diseases during these periods.⁷,²⁰,²¹ This is further supported by international observations: no paediatric influenza deaths were reported in Canada during the 2020/2021 season, and paediatric in-hospital mortality from pneumonia decreased by about 50% during NPI in Brazil.²²,²³

Our study has several limitations. First, while Swiss data provide an exhaustive record of child mortality at the national level, French data are hospital-based and therefore capture only deaths occurring in the hospital, representing 71% of total child deaths.²⁴ As a result, both averted and excess mortality estimates may be underestimated. However, this limitation is unlikely to have affected temporal trends, as most infection-related paediatric deaths occur in hospitals, and the proportion of out-of-hospital child deaths remained stable over

the study period (Supplementary material, Table S3).²⁵ Second, the use of hospital discharge diagnoses to define causes of death in the French data may differ from causes recorded on death certificates (in contrast to Swiss data, where causes of death are derived from death certificates). Unlike death certificates, which summarise the sequence of conditions leading to death, hospital records reflect diagnoses made during care. It is therefore possible that infections documented during hospitalisation did not contribute to the fatal outcome. To address this concern, we examined deaths associated with URTI, which are common but rarely fatal in children, and found they were only marginally represented among infection-related deaths. This supports our assumption that incidental or non-contributory infections were rarely misclassified as causes of death in our dataset. Third, infection-related deaths were defined based on the presence of an infectious diagnosis, regardless of whether it was the primary or underlying cause. This approach may have led to an
<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Evolution of the monthly infection-related mortality rate by pathogen in France and Switzerland, January 2015–December 2023. Monthly (bacteria, viruses, Influenzae, RSV, viral-bacterial co-infection) and quarterly (S. pneumoniae, S. pyogenes, N. meningitidis, H. influenzae, S. aureus, Metapneumovirus, Enterovirus, Adenovirus, VZV) incidence of infection-related mortality per 100,000 children by pathogen. The grey lines show the observed data. The black line shows the fitted model, with grey shaded area showing the 95% confidence intervals. The blue line shows the expected incidence based on data before NPI implementation, with blue shaded area showing the 95% confidence intervals. The vertical lines show the limit between periods (pre-NPI, NPI, post-NPI). Abbreviations: CI, confidence interval; NPI, non-pharmaceutical intervention.</figcaption></figure>

overestimation of infection-attributable mortality by including cases where infection did not play role in the fatal outcome. However, our sensitivity analysis restricting the definition to cases with an

infectious diagnosis as the principal cause of death yielded similar trends. Our approach of including all diagnoses in the definition of infection-related death is supported by evidence showing that
<figure><img src="image_8.png" /><figcaption>**Fig. 4.** Non-neonatal infection-related mortality rates per 100,000 children by birth year and age at death. Each cell represents the infection-related mortality rate (deaths per 100,000 children) for individuals born in a given year (y-axis) who died at a specific age (x-axis). Colour intensity reflects mortality rate by age at death, with lighter colours representing lower mortality rate and darker colours higher mortality rate.</figcaption></figure>

<table><caption>**Table 3**
Cumulative 2-first years of life non-neonatal infection-related mortality rates and infection-related mortality rate ratios by birth cohort.</caption><thead><tr><th>Birth cohort</th><th>Cumulative 2-first years of life infection-related mortality rate per 100,000 livebirths</th><th>Rate ratio (95% CI) (Reference period 2015–2017)</th></tr></thead><tbody><tr><td>2022</td><td>21.3 (18.1–24.5)</td><td>1.18 (0.99–1.41)</td></tr><tr><td>2021</td><td>18.0 (15.1–20.9)</td><td>1.00 (0.83–1.21)</td></tr><tr><td>2020</td><td>14.4 (11.8–17.0)</td><td>0.80 (0.65–0.98)</td></tr><tr><td>2019</td><td>14.4 (11.8–17.0)</td><td>0.80 (0.66–0.98)</td></tr><tr><td>2018</td><td>19.7 (16.7–22.7)</td><td>1.10 (0.92–1.31)</td></tr><tr><td>2017</td><td>18.2 (15.3–21.1)</td><td>Reference period</td></tr><tr><td>2016</td><td>16.9 (14.1–19.6)</td><td>Reference period</td></tr><tr><td>2015</td><td>18.9 (16.0–21.7)</td><td>Reference period</td></tr></tbody></table>

Abbreviations: CI, confidence interval.

restricting the analysis to principal diagnoses alone underestimates the true burden of infections in childhood mortality.²⁶ Fourth, although subgroup analyses were pre-specified to explore heterogeneity across populations and outcomes, the possibility of false-positive findings due to multiple comparisons cannot be excluded. Finally, as this study was conducted in only two high-income European countries, the generalisability of our findings to other geographic or healthcare settings may be limited. Further studies in diverse contexts are warranted to assess whether similar trends are observed elsewhere.

Historically, advances in public health, vaccination, and medical care have significantly reduced infection-related paediatric mortality. Despite these achievements, infection-related deaths still occur among children in countries where they are readily available. The differential impact of NPI across subgroups highlights the potential for targeted prevention strategies, against specific pathogens and by specific age groups and comorbidity profiles. In our study,

influenza virus and *S. pneumoniae* were important contributors to infection-related paediatric mortality, which was decreased for both during NPI. Strategies to mitigate deaths related to these pathogens could include infant RSV immunisation, maternal immunisation against RSV and influenza, and universal paediatric influenza virus vaccination – currently not implemented in France nor Switzerland – for their direct effect on the virus but also for its potential indirect effect on invasive pneumococcal disease, which is partly triggered by viruses.²⁷⁻³⁰ Our findings therefore support the implementation and expansion of these immunisation programmes, including full reimbursement to minimise financial barriers. Very young children and those living with neurological and congenital life-limiting conditions may benefit from targeted, societally acceptable NPI, while older children from targeted interventions in the aftermath of recurring widespread implementation of NPI. Beyond immunisation and NPI, several complementary public health measures could reduce the burden of infection-related paediatric mortality. These include expanding access to rapid and accurate diagnostic testing to guide early management, and strengthening national mortality and morbidity registries to enable real-time monitoring of severe paediatric infections. In addition, reinforcing early-warning surveillance systems, including sentinel paediatric networks, would allow timely detection of unusual circulation patterns and facilitate rapid public health responses. Together, these measures could improve the prevention, detection, and management of severe infections in children and help sustain the mortality gains observed during the NPI period.

In conclusion, the reduction in paediatric infection-related deaths during the NPI period highlights the ongoing burden of preventable paediatric mortality. The heterogeneous mortality outcomes across birth cohorts suggest that the timing and intensity of exposure to pathogens influence early-life mortality risk. These findings indicate that targeted preventive strategies could sustainably reduce infection-related deaths in children beyond pandemic settings.
<figure><img src="image_9.png" /><figcaption>**Fig. 5.** Evolution of the monthly non-infection-related mortality rate (control outcome) in France and Switzerland, January 2015–December 2023. Monthly incidence of non-infection-related mortality per 100,000 children aged less than 18 years. The grey lines show the observed data. The black line shows the fitted model, with grey shaded area showing the 95% confidence intervals. The blue line shows the expected incidence based on data before NPI implementation, with blue shaded area showing the 95% confidence intervals. The vertical lines show the limit between periods (pre-NPI, NPI, post-NPI). Abbreviations: CI, confidence interval; NPI, non-pharmaceutical intervention.</figcaption></figure>

## Author contributions

MJ, FA and NO take responsibility for the content of the manuscript, including the integrity of the data and the accuracy of the data analysis. MJ, FA, NO and PAC conceptualized the study. MJ led the literature review. MJ led the data analysis and visualization. MJ, FA, NO, PAC and RB led the data interpretation. MJ drafted the manuscript. FA, NO, PAC and RB commented on the draft report. All authors contributed to critical revision of the manuscript for important intellectual content. All authors read and approved the final draft of the manuscript and had final responsibility for the decision to submit for publication.

## Funding

This study was performed with the financial support of the Fondation de l'Assistance Publique – Hôpitaux de Paris, Lausanne University, Lausanne University Hospital, SICPA Foundation, Gottfried und Julia Bangerter-Rhyner Foundation.

## Data availability

Aggregated, anonymized data are available on reasonable request to the principal investigator (MJ).

## Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RB declares receiving fees from Sanofi and MSD for medical conferences or scientific meetings. NO declares receiving travel

grants from MSD, Pfizer and Sanofi. MJ, PAC, ZB, IF, MP, YF, KA, FA have no conflicts of interest to disclose.

## Appendix A. Supporting information

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.jinf.2026.106688.

## References

1. The unfinished agenda of communicable diseases among children and adolescents before the COVID-19 pandemic, 1990–2019: a systematic analysis of the Global Burden of Disease Study 2019. Lancet;2023;402:313–35.

2. OECD, Eurostat. Avoidable mortality: OECD/Eurostat lists of preventable and treatable causes of death. OECD/Eurostat; 2022(https://www.oecd.org/health/health-systems/avoidable-mortality-2019-Joint-OECD-Eurostat-List-preventable-treatable-causes-of-death.pdf) [Accessed June 10, 2025].

3. Nolte E, McKee M. Does health care save lives? Avoidable mortality revisited. Nuffield Trust; 2004.

4. Ladhani S, Pebody RG, Ramsay ME, Lamagni TL, Johnson AP, Sharland M. Continuing impact of infectious diseases on childhood deaths in England and Wales, 2003–2005. Pediatr Infect Dis J 2010;29:310–3.

5. Sidebotham P, Fraser J, Fleming P, Ward-Platt M, Hain R. Patterns of child death in England and Wales. Lancet 2014;384:904–14.

6. Infection-related deaths in children and young people in England. National Child Mortality Database Programme, Healthcare Quality Improvement Partnership; 2023.

7. Nygaard U, Holm M, Rabie H, Rytter M. The pattern of childhood infections during and after the COVID-19 pandemic. Lancet Child Adolesc Health 2024;8:910–20.

8. WHO recommendations for conducting an external inspection of a body and filling in the Medical Certificate of Cause of Death. Geneva: World Health Organization; 2022.

9. Blohm C, Junker C, Weitkunat R, von, Murat K. Official statistics on deaths, excess mortality, causes of death and notifiable diseases. Methodological explanations. Federal Statistical Office (FSO); 2022.

10. Naghavi M, Mestrovic T, Gray A, Gershberg Hayoon A, Swetschinski LR, Robles Aguilar G, et al. Global burden associated with 85 pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Infect Dis 2024;24:868–95.
11. Hain R, Devins M, Hastings R, Noyes J. Paediatric palliative care: development and pilot study of a 'Directory' of life-limiting conditions. BMC Palliat Care 2013;12:43.

12. Roser M. What is the COVID-19 stringency index? Our World Data 2021 published online Dec 24 [Accessed May 7, 2025]. (https://ourworldindata.org/metrics-explained-covid19-stringency-index).

13. Bernal JL, Cummins S, Gasparrini A. Interrupted time series regression for the evaluation of public health interventions: a tutorial. Int J Epidemiol 2017;46:348-55.

14. Bhaskaran K, Gasparrini A, Hajat S, Smeeth L, Armstrong B. Time series regression studies in environmental epidemiology. Int J Epidemiol 2013;42:1187-95.

15. Trinh NTH, Visme S de, Cohen JF, Bruckner T, Lelong N., Adnot P, et al. Recent historic increase of infant mortality in France: a time-series analysis, 2001 to 2019. Lancet Reg Health Eur 2022;16:100339. https://doi.org/10.1016/j.lanepe.2022.100339

16. Saha MV, Davis RE, Hondula DM. Mortality displacement as a function of heat event strength in 7 US cities. Am J Epidemiol 2014;179:467-74.

17. Cohen R, Levy C, Rybak A, Angoulvant F, Ouldali N, Grimprel E. Immune debt: recrudescence of disease and confirmation of a contested concept. Infect Dis Now 2023;53:104638.

18. Odd D, Stoianova S, Williams T, Fleming P, Luyt K. Child mortality in England after national lockdowns for COVID-19: an analysis of childhood deaths, 2019-2023. PLOS Med 2025;22:1004417.

19. Odd D, Stoianova S, Williams T, Fleming P, Luyt K. Child mortality in England during the first 2 years of the COVID-19 pandemic. JAMA Netw Open 2023;6:2249191.

20. Fafi I, Assad Z, Lenglart L, Valtuille Z, Kaguelidou F, Aupiais C, et al. Did the resurgence of childhood lower respiratory infections offset the initial benefit of COVID-19-related non-pharmaceutical interventions in children? A time-series analysis. BMC Med 2025;23:66.

21. Lenglart L, Titomanlio L, Bognar Z, Bressan S, Buonsenso D, De T, et al. Surge of pediatric respiratory tract infections after the COVID-19 pandemic and the concept of 'immune debt'. J Pediatr 2025;284:114420.

22. Groves HE, Papenburg J, Mehta K, Bettinger JA, Sadarangani M, Halperin SA, et al. The effect of the COVID-19 pandemic on influenza-related hospitalization, intensive care admission and mortality in children in Canada: a population-based study. Lancet Reg Health Am 2022;7:100132.

23. Dias CF, Sarria EE, Scheffel C, Delatorre LB, Sapiro A, Baldissera M, et al. COVID-19 prevention policies reduce pediatric hospital mortality due to community-acquired pneumonia. Arch Bronconeumol 2022;58:197-9.

24. Deaths in 2023 and over long time series ('Les décès en 2023 et en séries longues'). INSEE (National Institute of Statistics and Economic Studies) (https://www.insee.fr/fr/statistiques/8233816) [Accessed April 7, 2025].

25. Lorton F, Chalumeau M, Martinot A, Assathiany R, Roué JM, Bourgoin P, et al. Prevalence, characteristics, and determinants of suboptimal care in the initial management of community-onset severe bacterial infections in children. JAMA Netw Open 2022;5:2216778.

26. Ferreras-Antolín L, Oligbu G, Okike IO, Ladhani S. Infection is associated with one in five childhood deaths in England and Wales: analysis of national death registrations data, 2013–15. Arch Dis Child 2020;105:857-63.

27. Flannery B, Reynolds SB, Blanton L, Santibanez TA, O'Halloran A, Lu PJ, et al. Influenza vaccine effectiveness against pediatric deaths: 2010–2014. Pediatrics 2017;139:e20164244.

28. Rybak A, Levy C, Angoulvant F, Auvignon A, Gembara P, Danis K, et al. Association of nonpharmaceutical interventions during the COVID-19 pandemic with invasive pneumococcal disease, pneumococcal carriage, and respiratory viral infections among children in France. JAMA Netw Open 2022;5:2218959.

29. Rybak A, Assad Z, Levy C, Bonarcorsi S, Béchet S, Werner A, et al. Age-specific resurgence in invasive pneumococcal disease incidence in the COVID-19 pandemic era and its association with respiratory virus and pneumococcal carriage dynamics: a time-series analysis. Clin Infect Dis 2024;78:855-9.

30. Ouldali N, Deceuninck G, Lefebvre B, Gilca R, Quach Q, Brousseau N, et al. Increase of invasive pneumococcal disease in children temporally associated with RSV outbreak in Quebec: a time-series analysis. Lancet Reg Health Am 2023;19:100448. https://doi.org/10.1016/j.lana.2023.100448