Long-lasting effects of COVID-19 pandemic on hospitalizations and severity of bronchiolitis

Abstract

Bronchiolitis is a common cause of hospitalization in infants. The long-lasting impact of hygiene and social behavior changes during the pandemic on this disease is debated. We investigated the prevalence of hospitalized cases, clinical severity, and underlying risk factors before and during pandemic. The study was conducted in 27 hospitals in Italy and included infants hospitalized for bronchiolitis during the following four periods: July 2018-March 2019, July 2020-March 2021, July 2021-March 2022, and July 2022-March 2023. Data on demographics, neonatal gestational age, breastfeeding history, underlying chronic diseases, presence of older siblings, etiologic agents, clinical course and outcome were collected. A total of 5330 patients were included in the study. Compared to 2018–19 (n = 1618), the number of hospitalizations decreased in 2020–21 (n = 121). A gradual increase was observed in 2021–22 (n = 1577) and 2022–23 (n = 2014). A higher disease severity (need and length of O 2 -supplementation, need for non-invasive ventilation, hospital stay) occurred in the 2021–22 and, especially, the 2022–23 periods compared to 2018–19. This tendency persisted after adjusting for risk factors associated with bronchiolitis severity.
Conclusions : Compared to adults, COVID-19 in infants is often asymptomatic or mildly symptomatic and rarely results in hospitalization. This study indicates that the pandemic has indirectly induced an increased burden of bronchiolitis among hospitalized infants. This shift, which is not explained by the recognized risk factors, suggests the existence of higher infant vulnerability during the last two seasons. What is known: • The pandemic led to a change in epidemiology of respiratory diseases • Large data on severity of bronchiolitis and underlying risk factors before and during COVID-19 pandemic are scarce

What is new: • Compared to pre-pandemic period, hospitalizations for bronchiolitis decreased in 2020–21 and gradually increased in 2021–22 and 2022–23 • Compared to pre-pandemic period, higher disease burden occurred in 2021–22 and, especially, in 2022–23. This tendency persisted after adjusting for risk factors associated with bronchiolitis severity • The interplay among viruses, preventive measures, and the infant health deserves to be further investigated

Full text

Vol.:(0123456789)
European Journal of Pediatrics
https://doi.org/10.1007/s00431-023-05395-1
RESEARCH
Long‑lasting effects ofCOVID‑19 pandemic onhospitalizations
andseverity ofbronchiolitis
GregorioPaoloMilani1,2· AndreaRonchi3· CarloAgostoni1,2· PaolaMarchisio1,4· GiovannaChidini5·
NicolaPesenti3· AnitaBellotti2· MarcoCugliari2· RiccardoCrimi2· ValentinaFabiano6,7· CarloPietrasanta2,3·
LorenzaPugni3· FabioMosca2,3· IRIDE study group
Received: 15 November 2023 / Revised: 14 December 2023 / Accepted: 17 December 2023
© The Author(s) 2024
Abstract
Bronchiolitis is a common cause of hospitalization in infants. The long-lasting impact of hygiene and social behavior changes
during the pandemic on this disease is debated. We investigated the prevalence of hospitalized cases, clinical severity, and
underlying risk factors before and during pandemic. The study was conducted in 27 hospitals in Italy and included infants
hospitalized for bronchiolitis during the following four periods: July 2018-March 2019, July 2020-March 2021, July 2021-
March 2022, and July 2022-March 2023. Data on demographics, neonatal gestational age, breastfeeding history, underlying
chronic diseases, presence of older siblings, etiologic agents, clinical course and outcome were collected. A total of 5330
patients were included in the study. Compared to 2018–19 (n = 1618), the number of hospitalizations decreased in 2020–21
(n = 121). A gradual increase was observed in 2021–22 (n = 1577) and 2022–23 (n = 2014). A higher disease severity (need
and length of O2-supplementation, need for non-invasive ventilation, hospital stay) occurred in the 2021–22 and, especially,
the 2022–23 periods compared to 2018–19. This tendency persisted after adjusting for risk factors associated with bronchi-
olitis severity.
 Conclusions:Compared to adults, COVID-19 in infants is often asymptomatic or mildly symptomatic and rarely results
in hospitalization. This study indicates that the pandemic has indirectly induced an increased burdenof bronchiolitis among
hospitalized infants. This shift, which is not explained by the recognized risk factors, suggests the existence of higher infant
vulnerability during the last two seasons.
What is known:
• The pandemic led to a change in epidemiology of respiratory diseases
•Large data on severity of bronchiolitis and underlying risk factors before and during COVID-19 pandemic are scarce
What is new:
•Compared to pre-pandemic period, hospitalizations for bronchiolitis decreased in 2020–21 and gradually increased in 2021–22 and
2022–23
•Compared to pre-pandemic period, higher disease burden occurred in 2021–22 and, especially, in 2022–23.This tendency persisted after
adjusting for risk factors associated with bronchiolitis severity
•The interplay among viruses, preventive measures, and the infant health deserves to be further investigated
Keywords Bronchiolitis· Epidemiology· Pandemic· Risk factors· Immune debt
List of abbreviations
COVID-19 Coronavirus Disease 2019
ECMO Extracorporeal Membrane Oxygenation
Introduction
Bronchiolitis, a lower respiratory tract infection affecting
the small airways, is a common cause of hospitalization
in infancy [1]. In the Northern Hemisphere, bronchiolitis
Communicated by Daniele De Luca
Gregorio Paolo Milani and Andrea Ronchi contributed equally as
co-first authors.
Lorenza Pugni and Fabio Mosca contributed equally as co-senior
authors.
Extended author information available on the last page of the article

European Journal of Pediatrics
typically occurs from October to March and is a recog-
nized burden for hospital services [2–4]. A drastic reduc-
tion in bronchiolitis cases was observed during the first
pandemic year (2020–21) [5, 6]. Social distancing, reduc-
tion of day care attendance, hygienic practices such as
handwashing with antiseptic gels, and the use of protec-
tive masks by adults and older children are believed to be
responsible for this shift [7]. During the second year of
the pandemic (2021–22), an increased number of bron-
chiolitis with more severe cases often occurring before
the autumn-winter season has been observed [8, 9]. Some
authors hypothesized that the limited exposure to micro-
organisms during the first pandemic year led to a higher
number of severe cases than suggested by historical data
[8]. However, other factors that emerged during the pan-
demic have also been claimed to favor this shift. First,
a drastic change in respiratory syncytial virus epidemi-
ology, the main cause of bronchiolitis [10, 11]. Second,
a decrease in breastfeeding practice, a protective factor
against severe bronchiolitis [12–14]. Finally, older sib-
lings, who had not been exposed to respiratory viruses
during the initial pandemic phase, might have facilitated
an increased viral transmission after the relaxation of pre-
ventive measures in the following years [15, 16].
Limited epidemiological data support these hypotheses
[10]. Furthermore, little evidence is available on bronchi-
olitis during the season 2022–23. We conducted a multi-
center study on infants hospitalized for bronchiolitis in
the Lombardy region (Italy), which is considered the first
COVID-19 epicenter in Europe. The primary aim of this
study was to assess the prevalence and clinical severity of
hospitalized cases before and during the pandemic. The
secondary aim was to test whether main known risk fac-
tors explain the possible changes in bronchiolitis severity.
Methods
The IRIDE (“Investigating bRonchiolitis epidemiology
During the pandemic Emergency”) study is a multicenter
observational cohort study conducted in 27 hospitals in
Lombardy, Italy. These hospitals, whose list is given in
the supplementary online material (TableS1), account
for > 80% of hospital bed capacity for pediatric patients
in Lombardy. Eligible for the study were infants
aged < 24months, hospitalized for at least 12h with a
diagnosis of bronchiolitis and discharged by one of the
hospitals participating in the study during the follow-
ing four periods: July 2018—March 2019 (pre-pandemic
period), July 2020—March 2021, July 2021—March 2022,
and July 2022—March 2023. Since the outbreak of SARS-
CoV-2 and the first restrictive measures to limit its spread
occurred in Lombardy at the beginning of 2020, the period
2019–2020 was not considered. On the other hand, the
three pandemic periods considered in this study were char-
acterized by a gradual decrease in preventive and hygiene
measures against viral circulation [16, 17]. Bronchiolitis
cases not requiring hospitalization were excluded. To pre-
vent patients transferred from one hospital to another from
being enrolled twice, each center could recruit only those
patients who had been discharged from their own facility.
The following ICD-9 codes were initially used: 46,611
(respiratory syncytial virus bronchiolitis), 46,619 (bronchi-
olitis caused by other infectious agents), 4801 (pneumonia
due to respiratory syncytial virus), 0796 (respiratory syn-
cytial virus infection), 51,881 (respiratory failure in chil-
dren), 77,084 and 77,089 (respiratory failure in neonates).
Subsequently, the clinical charts were retrieved, and only
subjects with a history of acute respiratory tract infection
of the upper airways in the previous days, followed by an
acute onset of cough, diffuse crackles, and respiratory dis-
tress, were retained [4, 18]. For included subjects, the fol-
lowing data were retrospectively extracted from the clinical
records: age at admission, sex, neonatal gestational age and
body weight, any breastfeeding and duration of exclusive
breastfeeding, number of older siblings, underlying chronic
diseases that predispose to severe bronchiolitis (including
bronchopulmonary dysplasia and severe congenital heart
disease), occurrence of radiologically confirmed diagnosis
of pneumonia during the bronchiolitis episode, infectious
agent detected by nasopharyngeal aspirate, need and dura-
tion of O2-supplementation, use of non-invasive ventilation
support (including Bi-PAP and C-PAP), need and duration
of intensive care, need for invasive ventilation support, use
of extracorporeal membrane oxygenation (ECMO), length
of the whole hospital stay. Furthermore, fatal cases were also
considered. All data were gathered and de-identified at each
study center. They were then collected using REDCap tools
hosted at the Ospedale Maggiore, Policlinico, Milan, Italy.
The study was approved by the Ethical Committee of the
coordinating center (Comitato Etico Milano Area2, Milan,
code 186796, date of approval April 26, 2023) and by the
other participating centers.
Statistical analysis
The distribution of continuous variables was visually tested
using histograms and density plots. Parametric data were pre-
sented as mean and standard deviations and non-parametric
data as median and interquartile range [IQR]. Categorical data
were presented as absolute and relative frequencies. ANOVA
and Kruskal-Wallis test were used to compare continuous
variables, and Fisher exact test or Chi-squared test were used
to compare categorical variables, as appropriate. The Bonfer-
roni correction was used for multiple comparisons.

European Journal of Pediatrics
Mixed effect regression models were used to study differ-
ences in outcomes between the study periods, with the hospital
as a random effect. Models’ results are expressed as linear coef-
ficients or odds ratios for continuous and categorical outcomes,
respectively, with 95% CI and p-values. Categorical outcomes
included the need for O2-supplementation, use of non-invasive
or invasive ventilation and the need for intensive care. Con-
tinuous outcomes included the length of O2-supplementation,
intensive care stay and overall hospitalization. The four study
periods (2018–19, 2020–21, 2021–22 and 2022–23) were tested
as predictive variable. All models were adjusted for typical
(age, sex, gestational age at birth, underlying chronic disease
and positive testing for respiratory syncytial virus) and recently
recognized (history of breastfeeding and number of older sib-
lings) confounders of bronchiolitis severity. The models were
performed both including all patients and then including only
patients 12months of age or less. Statistical significance was
set at p < 0.05. The R software (R Foundation for Statistical
Computing, Vienna, Austria) was used for the analysis.
Results
A total of 5330 patients hospitalized for bronchiolitis were
included in the study. The median age of the included sub-
jects was 2.3 [IQR 1.0–5.0] months, and 57% were males.
The mean neonatal gestational age was 38.2 (± 2.7) weeks,
and 957 (76%) had a history of breastfeeding. A total of
2479 (47%) patients had at least one older sibling, while
371 (6.9%) had an underlying chronic disease. A pneumonia
was diagnosed in 905 (17%) infants. Respiratory syncytial
virus was detected in 3292 (62%) cases. During hospitali-
zation, 3712 (70%) patients required O2-supplementation,
2293 (43%) received non-invasive ventilation support, 78
(1.6%) required invasive ventilation support, and 6 (0.1%)
were treated with ECMO. Three patients died in 2018–19
and one in 2021–22.
Data divided for the four study periods are reported in
Table1. The results of comparison between 2018–19 and the
other periods are detailed in the online Supplementary Material.
Table 1 Demographics, clinical and microbiological characteristics of included infants in the four study periods
Data are presented as median [IQR], mean (± SD) or absolute frequency (percentage). ANOVA or Kruskal-Wallis test for continuous variables,
and Fisher exact test or Chi-squared test for categorical variables were used for comparison
a July–September
2018–2019 2020–2021 2021–2022 2022–2023 p
N 1618 121 1577 2014
Age, months 3.0 [1.0–5.0] 5.6 [1.5–9.0] 2.0 [1.0–4.3] 2.5 [1.0–5.5] < 0.001
Age > 12months 96 (5.9) 23 (19) 77 (4.9) 140 (7.0) < 0.001
Sex
  Female 683 (42) 36 (30) 707 (45) 849 (42) 0.009
  Male 935 (58) 85 (70) 870 (55) 1165 (58)
Cases before autumn–winter seasona24 (1.5) 25 (20) 25 (1.6) 38 (1.9) < 0.001
Number of older siblings 1 [1-1] 1 [0–1] 1 [1-1] 1[1-1] 0.012
Maternal COVID-19 during pregnancy 0 (0.0) 2 (2.3) 20 (1.8) 63 (5.8) < 0.001
Neonatal gestational age, weeks 38.2 (± 2.7) 37.6 (± 3.2) 38.2 (± 2.7) 38.2 (± 2.6) 0.124
Neonatal body weight, grams 3101 (± 656) 2957 (± 779) 3137 (± 657) 3117 (± 635) 0.043
Breastfeeding 970 (76) 64 (69) 1040 (76) 1261 (78) 0.099
  Length of exclusive breastfeeding, months 2.0 [1.0–4.0] 1.5 [0.0–5.0] 1.5 [1.0–3.1] 2.0 [1.0–4.0] 0.057
Chronic disease 105 (6.5) 16 (13) 126 (8.0) 124 (6.2) 0.006
  Bronchopulmonary dysplasia 20 (1.2) 5 (4.1) 21 (1.3) 25 (1.2) 0.059
  Congenital heart disease 11 (0.7) 2 (1.7) 27 (1.7) 19 (0.9) 0.032
  Further 74 (4.6) 9 (7.4) 78 (4.9) 80 (4.0) 0.201
Radiologically confirmed pneumonia
  Yes 292 (18) 14 (12) 277 (18) 322 (16) 0.152
  No 509 (32) 50 (41) 495 (31) 480 (24)
  Rx not performed 814 (50) 57 (47) 805 (51) 1180 (60)
Etiologic agent
  Respiratory syncytial virus 897 (56) 8 (6.6) 1120 (71) 1267 (63) < 0.001
  Other infectious agents 271 (17) 63 (52) 184 (12) 321 (16)
  No agent identified 450 (28) 50 (41) 273 (17) 426 (21)

European Journal of Pediatrics
Considering the main outcomes of the analysis, differ-
ences among the four periods were observed for the need
and length of O2-supplementation, the need for and length
of intensive care, and the length of the whole hospitalization.
No difference was observed in the need for invasive ventila-
tion support or ECMO (Table2).
The results of the multiple models investigating the rela-
tion between bronchiolitis course and the pandemic peri-
ods after adjusting for typical and more recently recognized
confounders are reported in Tables3 and 4, respectively.
The periods 2021–22 and 2022–23 were significantly associ-
ated with a higher need and length of O2-supplementation,
increased use of non-invasive ventilation, and a longer hos-
pitalization. No association among periods and the use of
invasive ventilation support, and the need or length of inten-
sive care was observed. The results of the models includ-
ing exclusively patients 12months of age or less (n = 4914)
provided similar results (data are given in the online sup-
plementary material, TablesS2 and S3).
Discussion
The IRIDE study investigated the epidemiology and clini-
cal course of bronchiolitis in hospitalized infants during
the pre-pandemic and pandemic periods. The study reveals
a relevant reduction in bronchiolitis cases during the sea-
son 2020–21. More interestingly, it shows an increase in
Table 3 Results of the mixed effect regression models: oxygen supplementation, non-invasive ventilation support, invasive ventilation support,
intensive care admission were the dependent variables. Study periods (reference 2018–19) were the predictive variables
Models were adjusted for age, sex, gestational age at birth, underlying chronic disease (yes vs no), history of breastfeeding, number of older sib-
lings (no older sibling vs one or more older siblings) and testing positive for respiratory syncytial virus
Outcome Study periods Odds ratio Lower 95%
confidence interval Upper 95%
confidence interval p
Need for oxygen supplementation 2020–21 0.701 0.390 1.258 0.233
2021–22 1.649 1.289 2.109 < 0.001
2022–23 2.205 1.685 2.885 < 0.001
Need for non-invasive ventilation support 2020–21 1.642 0.858 3.145 0.134
2021–22 2.185 1.687 2.831 < 0.001
2022–23 3.643 2.752 4.824 < 0.001
Need for invasive ventilation support 2020–21 2.175 0.241 19.618 0.489
2021–22 0.592 0.225 1.555 0.287
2022–23 1.514 0.651 3.523 0.336
Need for intensive care unit admission 2020–21 1.461 0.565 3.781 0.434
2021–22 1.331 0.931 1.903 0.117
2022–23 1.306 0.883 1.931 0.181
Table 2 Bronchiolitis course and outcome in the four different study
periodsData are presented as median [IQR] or absolute frequency
(percentage). ANOVA or Kruskal-Wallis test for continuous varia-
bles, and Fisher exact test or Chi-squared test for categorical variables
were used for comparison
Data are presented as median [IQR] or absolute frequency (percentage). ANOVA or Kruskal-Wallis test for continuous variables, and Fisher
exact test or Chi-squared test for categorical variables were used for comparison
2018–2019 2020–2021 2021–2022 2022–2023 p
N 1618 121 1577 2014
Oxygen supplementation 959 (59) 69 (57) 1157 (73) 1527 (76) < 0.001
Length of oxygen supplementation, days 0 [0–4] 1 [0–3] 2 [0–5] 2 [0–5] < 0.001
Non-invasive ventilation support 470 (29) 42 (35) 726 (46) 1055 (52) < 0.001
Invasive ventilation support 20 (1.2) 1 (0.8) 18 (1.1) 39 (1.9) 0.159
Intensive care unit admission 178 (11) 13 (11) 239 (15) 320 (16) < 0.001
Length of intensive care stay, days 5 [3-7] 3 [2-6] 5 [3-7] 5 [4-8] < 0.001
Length of intensive care stay ≥ 3, days 143 (80) 8 (62) 192 (80) 285 (89) 0.001
Extracorporeal membrane oxygenation 3 (0.2) 0 (0.0) 1 (0.1) 2 (0.1) 0.735
Length of the whole hospitalization, days 6 [4-8] 5 [4-6] 6 [4-8] 6 [4-8] < 0.001
Length of the whole hospitalization ≥ 4days 1352 (84) 91 (75) 1343 (85) 1758 (87) < 0.001

European Journal of Pediatrics
the number of hospitalizations, in the need and length of
O2-supplementation, in the use of non-invasive ventilation,
and a longer hospital stay in 2021–22 and, especially, in
2022–23 as compared to the pre-pandemic season. This ten-
dency persists after adjusting for both typical risk factors
for severe bronchiolitis such as young age, male sex, low
neonatal gestational age, underlying chronic disease and the
positivity for respiratory syncytial virus, and more recently
recognized risk factors such as a decrease in breastfeeding
and the presence of older siblings. Moreover, the number
of patients requiring intensive care increased in 2021–22
and 2022–23. Nonetheless, the number of patients requiring
invasive ventilation support and the length of intensive care
stay did not change.
The drastic reduction in bronchiolitis during the season
2020–21 has been described in previous studies and con-
firms the efficacy of various preventive measures, such as
social distancing, reduction of day care attendance, hand-
washing, and the use of masks [19, 20]. After the relaxa-
tion of pandemic-related measures, there was a significant
increase in bronchiolitis burden in 2021–22 and 2022–23.
Our data are supported by the literature, which confirms that
the typical risk factors for severe bronchiolitis do not account
for the observed tendency [13, 21, 22]. Decrease in breast-
feeding and the presence of older siblings might also be new
potential modulators of bronchiolitis severity [13, 21]. This
comprehensive large-scale study shows for the first time that
neither the main typical nor the newly recognized risk fac-
tors fully explain the higher burden of bronchiolitis observed
in the pediatric wards during 2021–22 and 2022–23. It might
be argued that the increased percentage of infants requiring
O2-supplementation or non-invasive ventilation depends on
a change in clinical practice over time (e.g., a higher thresh-
old for hospitalization and a higher availability of devices for
ventilation, respectively). However, the dramatic increase in
the absolute number of infants requiring O2-supplementation
from 2018–19 to 2012–22 (+ 21%) and 2022–23 (+ 60%)
and of infants requiring intensive care (+ 54% and + 80%,
respectively) does not support the latter hypothesis. Fur-
thermore, recommendations for hospitalization and manage-
ment did not vary during the study period in Italy [23]. This
unexplained greater impact of bronchiolitis compared to the
pre-pandemic period suggests the existence of higher vulner-
ability among infants. Notably, this vulnerability appears to
persist for at least two bronchiolitis seasons. This hypothesis
is in line with the findings of another study with a similar
sample size including children affected with RSV infection
in Spain [24].
The bronchiolitis burden was stronger in 2022–23 than in
2021–22. We have no clear-cut explanation for this finding. It is
tempting to assume that a further relaxation of restrictive meas-
ures in 2022–23 accounts, at least in part, for this observation.
The number of patients requiring intensive care increased in
2021–22 and in 2022–23 compared to that of the pre-pandemic
period. Nonetheless, the number of patients requiring inva-
sive ventilation support and the length of intensive care stay
remained stable. The results of the regression analysis suggest
that low neonatal gestational age and underlying chronic dis-
eases played a crucial role in the increased need for intensive
care [25, 26].
This study has some limitations. It relied on retrospec-
tive design. ICD-10 codes were not used as they are not yet
implemented for discharge diagnosis coding in Italy. Addi-
tionally, the use of ICD codes for case identification might
not have captured all cases accurately. To counterbalance
this risk, we used a wide range of codes and, then, all diag-
noses were reviewed according to well-established criteria.
Furthermore, our analysis focused uniquely on hospitalized
infants. This decision was made because during the first two
pandemic years, many infants with mild diseases that were
previously managed uniquely by primary care physicians
were directed to the emergency units. This redirection was
Table 4 Results of the mixed
effect regression models: length
of intensive care unit stay,
oxygen supplementation, and
overall hospitalization were
the dependent variables. Study
periods (reference 2018–19)
were the predictive variables
Models were adjusted for age, sex, gestational age at birth, underlying chronic disease (yes vs no), history
of breastfeeding, number of older siblings (no older sibling vs one or more older siblings) and testing posi-
tive for respiratory syncytial virus
Outcome Study periods ß Lower 95%
confidence
interval
Upper 95%
confidence
interval
p
Length of intensive care unit stay 2020–21 0.194 -0.468 0.856 0.565
2021–22 0.035 -0.224 0.293 0.793
2022–23 0.101 -0.175 0.377 0.474
Length of oxygen supplementation 2020–21 -0.637 -1.429 0.155 0.115
2021–22 0.750 0.441 1.059 < 0.001
2022–23 1.121 0.793 1.450 < 0.001
Whole duration of hospital stay 2020–21 -0.110 -1.068 0.849 0.822
2021–22 -0.060 -0.440 0.319 0.754
2022–23 0.637 0.233 1.042 0.002

European Journal of Pediatrics
partly due to organizational challenges in providing care to
infants with a potential SARS-CoV-2 infection outside the
hospital setting [27, 28]. Therefore, including infants who
were not hospitalized might overestimate cases requiring
emergency care during the first pandemic phases. The man-
agement of bronchiolitis may differ among centers. Mixed
effects models were employed to reduce the potential for
this issue. The study strengths lie in its large sample size,
the high number of involved centers, and the collection of
individual clinical and laboratory data. Furthermore, the
main risk factors for severe bronchiolitis were considered.
Finally, we did not have data on the immunological profile
(e.g., levels of immunoglobulins) or changes in the respira-
tory microbiome over the four study periods. Therefore, the
hypothesis of higher vulnerability remains only speculative.
Conclusions
Compared to adults, COVID-19 in infants is often asympto-
matic or mildly symptomatic and rarely results in hospitali-
zation [28, 29]. The IRIDE study indicates that the pandemic
has indirectly induced an increased prevalence and severity
of bronchiolitis requiring hospitalization. This shift, which
is not explained by the main typical or newly recognized
risk factors for severe bronchiolitis, suggests the existence
of higher infant vulnerability during the last two seasons.
Supplementary Information The online version contains supplemen-
tary material available at https:// doi. org/ 10. 1007/ s00431- 023- 05395-1.
Acknowledgements None.
IRIDE study group Roberta Barachetti, Ospedale Sant’Anna di Como,
Como, Italy; Claudia Pagliotta, Ospedale Sant’Anna di Como, Como,
Italy; Silvia Gulden, Ospedale Sant’Anna di Como, Como, Italy; Francesco
Maria Risso, Neonatal intensive care unit, Ospedali Civili di Brescia,
Brescia, Italy; Michael Colpani, Neonatal intensive care unit, Ospedali
Civili di Brescia, Brescia, Italy; Salvatore Aversa, Neonatal intensive
care unit, Ospedali Civili di Brescia, Brescia, Italy; Paolo Tagliabue,
S.C. Neonatologia e Terapia Intensiva Neonatale, IRCCS Fondazione
San Gerardo dei Tintori, Monza, Italy; Federico Cattaneo, S.C. Neona-
tologia e Terapia Intensiva Neonatale, IRCCS Fondazione San Gerardo
dei Tintori, Monza, Italy; Roberta Corbetta, S.C. Neonatologia e Tera-
pia Intensiva Neonatale, IRCCS Fondazione San Gerardo dei Tintori,
Monza, Italy; Maria Luisa Ventura, S.C. Neonatologia e Terapia Inten-
siva Neonatale, IRCCS Fondazione San Gerardo dei Tintori, Monza,
Italy; Stefano Ghirardello, S.C. Neonatologia e Terapia Intensiva Neo-
natale, Fondazione IRCCS Policlinico San Matteo; Ilaria De Lucia,
S.C. Neonatologia e Terapia Intensiva Neonatale, Fondazione IRCCS
Policlinico San Matteo; Francesca Garofoli, S.C. Neonatologia e Terapia
Intensiva Neonatale, Fondazione IRCCS Policlinico San Matteo; Luca
Mancini, Pediatria, Asst Grande Ospedale Metropolitano Niguarda di
Milano, Milan, Italy; Giulia Angela Carla Pattarino, Pediatria, Asst
Grande Ospedale Metropolitano Niguarda di Milano, Milan, Italy; Cos-
tantino De Giacomo, Pediatria, Asst Grande Ospedale Metropolitano
Niguarda di Milano, Milan, Italy; Salvatore Barberi, ASST Rhodense
Rho and Garbagnate Milanese, Italy; Mario Vernich, ASST Rhodense
Rho and Garbagnate Milanese, Italy; Elisabetta Veronelli, ASST Rho-
dense Rho and Garbagnate Milanese, Italy; Emanuela Brazzoduro,
ASST Rhodense Rho and Garbagnate Milanese, Italy; Ilaria Bottino,
ASST Brianza—Ospedale Pio XI Desio, Italy; Tiziana Varisco, ASST
Brianza—Ospedale Pio XI Desio, Italy; Patrizia Calzi, ASST Brianza—
Ospedale Pio XI Desio, Italy; Alessandro Porta, ASST Ovest Milanese,
Ospedale Fornaroli di Magenta, Italy; Paola Alga, ASST Ovest Milan-
ese, Ospedale Fornaroli di Magenta, Italy; Laura Cozzi, ASST Ovest
Milanese, Ospedale Fornaroli di Magenta, Italy; Francesca Lizzoli,
ASST Ovest Milanese, Ospedale Fornaroli di Magenta, Italy; Lorenzo
D'Antiga, SS Pediatria Internistica, SC Pediatria generale, ASST Papa
Giovanni XXIII, Bergamo, Italy; Angelo Mazza, SS Pediatria Internis-
tica, SC Pediatria generale, ASST Papa Giovanni XXIII, Bergamo, Italy;
Fabiana Di Stasio, SS Pediatria Internistica, SC Pediatria generale, ASST
Papa Giovanni XXIII, Bergamo, Italy; Giovanna Mangili,UOC Patolo-
gia Neonatale,Giovanni XXIII, Bergamo, Italy;Gian Luigi Marseglia,
Pediatria, Fondazione IRCCS Policlinico San Matteo, Pavia,Italy;
Mascolo Amelia, Pediatria, Fondazione IRCCS Policlinico San Matteo,
Pavia, Italy; Matea Jankovic, Pediatria, Fondazione IRCCS Policlinico
San Matteo, Pavia, Italy; Lidia Decembrino, ASST Pavia, Ospedale Civ-
ile di Vigevano, Italy; Dario Pantaleo, ASST Pavia, Ospedale Civile di
Vigevano, Italy; Chiara Vimercati, UO Pediatria, Ospedale San Gerardo
Di Monza, Italy; Martha Caterina Faraguna, UO Pediatria, Ospedale San
Gerardo Di Monza, Italy; Francesca Cattaneo, UO Pediatria, Ospedale
San Gerardo Di Monza, Italy; Irene Lepri, UO Pediatria, Ospedale San
Gerardo Di Monza, Italy; Laura Pogliani, ASST OVEST MI Ospedale
di Legnano; Liana Bevilacqua, ASST OVEST MI Ospedale di Legnano;
Luca Bernardo, ASST FateBeneFratelli Macedonio Melloni—Presidio
Ospedaliero Macedonio Melloni di Milano, Italy; Sergio Arrigoni,
ASST FateBeneFratelli Macedonio Melloni—Presidio Ospedaliero
Macedonio Melloni di Milano, Italy; Giuseppe Mercurio, ASST Fate-
BeneFratelli Macedonio Melloni—Presidio Ospedaliero Macedonio
Melloni di Milano;Paolo Del Barba,IRCCS Ospedale San Raffaele,
Milan, Italy;Graziano Barera,IRCCS Ospedale San Raffaele, Milan,
Italy;Claudia Aracu,IRCCS Ospedale San Raffaele, Milan, Italy
Authors’ contributions GPM, AR, CA, PM, GC, NP, LP, FM developed
the concept of the IRIDE study. AB, MC, RC, CP and the investigators
of the IRIDE study group performed data extraction. GPM, AR, CA,
PM, GC, NP, AB, MC, RC, CP and the investigators of the IRIDE
study group participated in data extraction,verification and interpretation. NP
was responsible for data cleaning and analyses. PM, FM supervised
all aspects of the study. GPM wrote the first draft and all authors con-
tributed to redrafting the manuscript. All authors critically reviewed
the manuscript for important intellectual content. All authors approved
the final manuscript as submitted.
Funding Open access funding provided by Università degli Studi di
Milano within the CRUI-CARE Agreement. The study was partially
supported by a grant of the Italian ministry of Health (Ricerca Cor-
rente 2022).
Availability of data and material Upon reasonable request to the cor-
responding author.
Code availability Not applicable.
Declarations
Disclaimer The funding agencies had no role in study design, data col-
lection, analysis or interpretation, or writing of the report.
Ethics approval The study was approved by the Ethical committee of
Milan Area2 and was conducted in accordance with the Declaration
of Helsinki.

European Journal of Pediatrics
Consent to participate Not required for this study.
Consent for publication All authors gave their consent for publication.
No further consent is required.
Conflicts of interest The authors declare no competing interests.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
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jurisdictional claims in published maps and institutional affiliations.

European Journal of Pediatrics
Authors and Affiliations
GregorioPaoloMilani1,2· AndreaRonchi3· CarloAgostoni1,2· PaolaMarchisio1,4· GiovannaChidini5·
NicolaPesenti3· AnitaBellotti2· MarcoCugliari2· RiccardoCrimi2· ValentinaFabiano6,7· CarloPietrasanta2,3·
LorenzaPugni3· FabioMosca2,3· IRIDE study group
* Paola Marchisio
paola.marchisio@unimi.it
1 Pediatric Unit, Fondazione IRCCS Ca’ Granda Ospedale
Maggiore Policlinico, Milan, Italy
2 Department ofClinical Sciences andCommunity Health,
Università Degli Studi Di Milano, Via Della Commenda 9,
20122Milan, Italy
3 Neonatal Intensive Care Unit, Fondazione IRCCS Ca’
Granda Ospedale Maggiore Policlinico, Milan, Italy
4 Department ofPathophysiology andTransplantation,
University ofMilan, Milan, Italy
5 Department ofAnaesthesia, Intensive Care andEmergency,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore
Policlinico, Milan, Italy
6 Pediatric Department, “Vittore Buzzi” Children’s Hospital,
Milan, Italy
7 Department ofBiomedical andClinical Science, University
ofMilan, Milan, Italy