(2024) 24:505
Ong et al. BMC Pediatrics
https://doi.org/10.1186/s12887-024-04977-8

BMC Pediatrics

RESEARCH

Open Access

Impact of neonatal sepsis on neurocognitive
outcomes: a systematic review
and meta‑analysis
Wei Jie Ong1† , Jun Jie Benjamin Seng1,2,3*† , Beijun Yap1, George He4, Nooriyah Aliasgar Moochhala4,Chen Lin Ng1, Rehena Ganguly5 , Jan Hau Lee6   and Shu‑Ling Chong7   

Abstract
Introduction Sepsis is associated with neurocognitive impairment among preterm neonates but less is known
about term neonates with sepsis. This systematic review and meta-analysis aims to provide an update of neurocognitive outcomes including cognitive delay, visual impairment, auditory impairment, and cerebral palsy, among neonateswith sepsis.
Methods We performed a systematic review of PubMed, Embase, CENTRAL and Web of Science for eligible studies published between January 2011 and March 2023. We included case–control, cohort studies and cross-sectional
studies. Case reports and articles not in English language were excluded. Using the adjusted estimates, we performed
random effects model meta-analysis to evaluate the risk of developing neurocognitive impairment among neonateswith sepsis.
Results Of 7,909 studies, 24 studies (n = 121,645) were included. Majority of studies were conducted in the UnitedStates (n = 7, 29.2%), and all studies were performed among neonates. 17 (70.8%) studies provided follow-up
till 30 months. Sepsis was associated with increased risk of cognitive delay [adjusted odds ratio, aOR 1.14 (95% CI:
1.01—1.28)], visual impairment [aOR 2.57 (95%CI: 1.14- 5.82)], hearing impairment [aOR 1.70 (95% CI: 1.02–2.81)]
and cerebral palsy [aOR 2.48 (95% CI: 1.03–5.99)].
Conclusion Neonates surviving sepsis are at a higher risk of poorer neurodevelopment. Current evidence is limitedby significant heterogeneity across studies, lack of data related to long-term neurodevelopmental outcomes and term
infants.
Keywords Sepsis, Neonatal sepsis, Infantile sepsis, Neurocognitive outcomes, Systematic review†

Wei Jie Ong and Jun Jie Benjamin Seng are co-first authors.

*Correspondence:
Jun Jie Benjamin Seng
benjamin.seng@mohh.com.sg
1
MOH Holdings, Singapore, 1 Maritime Square, Singapore 099253,
Singapore
2
SingHealth Regional Health System PULSES Centre, Singapore HealthServices, Outram Rd, Singapore 169608, Singapore
3
SingHealth Duke-NUS Family Medicine Academic Clinical Programme,
Singapore, Singapore
4Yong Loo Lin School of Medicine, 10 Medical Dr, Yong Loo Lin Schoolof Medicine, Singapore, Singapore

5Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore,
Singapore
6
Children’s Intensive Care Unit, KK Women’s and Children’s Hospital,
SingHealth Paediatrics Academic Clinical Programme, 100 Bukit Timah Rd,
Singapore 229899, Singapore
7
Department of Emergency Medicine, KK Women’s and Children’s
Hospital, SingHealth Paediatrics Academic Clinical Programme,
SingHealth Emergency Medicine Academic Clinical Programme, 100 Bukit
Timah Rd, Singapore 229899, Singapore© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise 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-nc-nd/4.0/.

Ong et al. BMC Pediatrics(2024) 24:505

Introduction
Sepsis is a major cause of mortality and morbidity among
neonates [1–4]. Young infants especially neonates,
defined by age < 28 days old, have a relatively immature immune system and are susceptible to sepsis [5, 6].
Annually, there are an estimated 1.3 to 3.9 million casesof infantile sepsis worldwide and up to 700,000 deaths[7]. Low-income and middle-income countries bear a disproportionate burden of neonatal sepsis cases and deaths[7, 8]. While advances in medical care over the past decade have reduced mortality, neonates who survive sepsis
are at risk of developing neurocognitive complications,which affect the quality of life for these children and theircaregivers [9].
Previous reviews evaluating neurocognitive outcomesin neonates with infections or sepsis have focused on
specific types of pathogens (e.g., Group B streptococcus
or nosocomial infections [10]), or are limited to specificpopulations such as very low birth weight or very preterm neonates [11], and there remains paucity of data
regarding neurocognitive outcomes among term andpost-term neonates. There remains a gap for an updated
comprehensive review which is not limited by type of
pathogen or gestation. In this systematic review, we aim
to provide a comprehensive update to the current literature on the association between sepsis and the following
adverse neurocognitive outcomes (1) mental and psychomotor delay (cognitive delay (CD)), (2) visual impairment, (3) auditory impairment and (4) cerebral palsy(CP) among neonates [11].

Page 2 of 38

Methods
We performed a systematic review using the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [12]. This study protocol
was registered with Open Science Framework (https://​doi.​org/​10.​17605/​OSF.​IO/​B54SE).

Campaign guidelines definitions [17], or if they fulfilled
clinical, microbiological and/or biochemical criteria forsepsis as defined by study authors. The primary outcomeof interest was impaired neurocognitive outcome definedby the following domains of neurodevelopmental impairment (NDI) [11]: (1) CD, (2) visual impairment, (3) auditory impairment and (4) CP. We selected these domains
because they were highlighted as key neurocognitive
sequelae after intrauterine insults in a landmark review
by Mwaniki et al. [18]. The authors’ definitions of theseoutcomes and their assessment tools were captured,
including the use of common validated instruments (e.g.,
a common scale used for CD is the Bayley Scales of Infant
Development (BSID) [19] while a common instrumentused for CP was the Gross Motor Function Classification
System (GMFCS) [20]. Specifically for BSID, its two summative indices score – Mental Development Index (MDI)
and Psychomotor Development Index (PDI) were collected. The MDI assesses both the non-verbal cognitiveand language skills, while PDI assess the combination offine and gross motor skills. The cut-off points for mild,moderate and severe delay for MDI and PDI were < 85or < 80, < 70 and < 55 respectively [21]. There were no
restrictions on duration of follow-up or time of assessment of neurocognitive outcomes to allow capturing ofboth short- and long-term neurocognitive outcomes.
Case–control, cohort studies and cross-sectional studies published between January 2011 and March 2023
were included. Because the definition and management of sepsis has evolved over the years [22], we choseto include studies published from 2011 onwards. Case
reports, animal studies, laboratory studies and publications that were not in English language were excluded.
Hand-searching of previous systematic reviews were performed to ensure all relevant articles were included. To
avoid small study effects, we also excluded studies with asample size of less than 50 [23].

Eligibility criteria

Information sources and search strategy

We identified studies which evaluated neurocognitive
outcomes in neonates less than 90 days old (regardless ofgestational age) with sepsis. While the neonatal period istraditionally defined to be either the first 28 days postnatally for term and post-term infants, or 27 days after
the expected date of delivery for preterm infants [13],serious late onset infections in the young infant population can present beyond the neonatal period [14], hence
we defined the upper age limit as 90 days old to obtaina more complete picture of the burden of young infantile sepsis [15]. Post-term neonates was defined as aneonate delivered at >  = 42 weeks of gestational age inthis study [16]. We included studies that either follow
international sepsis definitions such as Surviving Sepsis

Four databases (PubMed, Cochrane Central, Embase andWeb of Science) were used to identify eligible studies.
The search strategy was developed in consultation witha research librarian. The first search was conducted on 4
December 2021 and an updated search was conducted on
3 April 2023. The detailed search strategy can be found in
Supplementary Tables 1A and B.
Study selection process

Covidence systematic review software (Veritas HealthInnovation, Melbourne, Australia) [24] was utilized during this review. Five reviewers (WJO, BJY, NM, CLN andGH) independently conducted the database search andscreened the title and abstracts for relevance. Following

Ong et al. BMC Pediatrics(2024) 24:505

training on inclusion and exclusion eligibility, 4 reviewers (WJO, NM, CLN and GH) subsequently assessed thefull text of shortlisted articles for eligibility. All full texts
were independently assessed by at least 2 reviewers. Any
conflict related to study eligibility were resolved in discussion with the senior author (S-LC). We recorded thereason(s) for exclusion of each non-eligible article.
Data collection process and data items

Four reviewers (WJO, NM, CLN and GH) independently
carried out the data extraction using a standardized datacollection form, and any conflict was resolved by discussion, or with input from the senior author (S-LC). A
pilot search was performed for the first 200 citations toevaluate concordance among reviewers and showed goodconcordance among reviewers of 94%. For studies withmissing data required for data collection or meta-analyses, we contacted the corresponding authors of articles toseek related information. If there was no reply from theauthors, the data were labelled as missing.
Study risk of bias assessment

Three reviewers (BJY, GH and WJO) independently carried out the assessment of risk of bias using the Newcastle–Ottawa Scale (NOS) for all observational studies [25].
Studies were graded based on three domains namely,
selection, comparability and outcomes. Studies wereassigned as low, moderate and high risk of bias if they
were rated 0–2 points, 3–5 points and 6–9 points respectively. Any conflict was resolved by discussion or with
input from the senior author (S-LC).
Statistical analysis

All outcomes (i.e. CD, visual impairment, auditory
impairment and CP) were analysed as categorical data.
Analyses were done for each NDI domain separately. To
ensure comparability across scales, results from different
studies were only pooled if the same measurement tools
were used to assess the outcomes and hence sub-group
analyses were based on different scales and/or different
definitions of neurocognitive outcomes used by authors.
Both unadjusted and adjusted odds ratios (aOR) and/or
relative risk (RR) for each NDI domain were recorded.
Where source data were present, we calculated the unadjusted OR if the authors did not report one, together with
the 95% confidence interval (CI). For adjusted odds ratio,these were extracted from individual studies and variables used for adjustment were determined at the individual study level.
Meta-analysis was conducted for all outcomes that werereported by at least 2 independent studies or cohorts.
Studies were included in the meta-analysis only if theyreported outcomes for individual NDI domains within

Page 3 of 38

30 months from sepsis occurrence. For each domain, allselected studies were pooled using DerSimonian-Laird
random effects model due to expected heterogeneity.
Studies were pooled based on adjusted and unadjusted
analyses. Case–control and cohort studies were pooled
separately. The pooled results were expressed as unadjusted odds ratio (OR) or adjusted odds ratio (aOR) withcorresponding 95% confidence interval (95% CI). If there
was more than 1 study that utilized the same population,
we only analysed data from the most recent publication
or from the larger sample size, to avoid double counting. Standard error (SE) from studies with multiple arms
with same control group were adjusted using SE = √(K/2),
where K refers to number of treatment arms including
control [26]. Heterogeneity across studies was evaluatedusing the I^2 statistic, for which ≥ 50% is indicative of significant heterogeneity. With regards to publication bias,
this was performed using Egger’s test and funnel plots
only if the number of studies pooled were 10 or more foreach outcome.
For neurocognitive related outcomes, subgroup analyses were performed based on the severity of the NDI
domain outcomes and distinct, non-overlapping populations of septic infants (such as late onset vs early onset
sepsis, culture positive sepsis vs clinically diagnosed sepsis, term and post term patients).
All analyses were done using ‘meta’ library from R
software (version 4.2.2) [27]. The statistical significancethreshold was a two tailed P-value < 0.05.
Certainty of evidence

The certainty of evidence for outcomes in this review was
performed during the GRADE criteria [28] which is centred on the study design, risk of bias, inconsistency, indirectness, imprecision, and other considerations.

Results
Study selection

From 7,909 studies identified, a total of 24 articles were
included (Fig. 1) [29–52]. A total of 101,657 and 19,988
preterm and term infants were included in this review.
Study characteristics

There were 2 case–control studies and 22 cohort studies, with a total of 121,645 infants (Table 1). Studies wereconducted in 16 different countries (Fig. 2), with themost studies conducted in the United States of America(USA) (7 studies, n = 92,358 patients) [30, 33, 37, 41, 42,
47, 52]. There were no studies that were conducted solely
on term infants. 5 studies reported data specifically on
ELBW infants (27,078 infants) and 6 studies on VLBW
infants (3,322 infants). All studies were performed among
neonates.

Ong et al. BMC Pediatrics(2024) 24:505

Page 4 of 38

Fig. 1 PRISMA flowchart of the study selection process for search

Risk of bias

Overall, all 24 studies were classified as low risk (Supplementary Table 2). 5 papers scored high risk for outcome
bias for having greater than 10% of initial population
being lost to follow-up [29, 32, 40–42].
Outcome measures reported by domain

As the number of studies pooled for each outcome wasless than 10, publication bias was not analysed in themeta-analyses.
Cognitive delay (CD)Among 24 studies that assessed for CD, 16 studies
reported either the incidence of CD among young infants
with sepsis compared to those without, and/or the odds
ratio (adjusted and/or unadjusted) comparing the two
populations [29, 31–38, 40–42, 45, 46, 48, 49]. The scales
used, authors’ definition of CD, incidence of CD among
those with sepsis and those without are described inTable 2. The most common tools used for assessment of
CD were the Bayley Scales of Infant Development (BSID)(n = 13) and Denver Development Screening Test II(n = 2).
Infantile sepsis was associated with increased risk ofoverall CD delays [aOR 1.14 (95%CI: 1.01, 1.28)], overall
PDI delay (aOR 1.73 (95%CI: 1.16, 2.58)) and moderate
PDI delay [aOR 1.85 (95%CI: 1.01, 3.36)]. Conversely,

infantile sepsis was not associated with increased risk
for severe PDI delay nor overall MDI delay [aOR 1.30
(95%CI: 0.99, 1.71)] or its subgroups. There were no
significant differences in outcomes between different
subgroups of infections as well as culture-proven or
clinically defined sepsis for either MDI or PDI (Table 8,
Fig. 3A and B).
Visual impairment

Seven studies reported data on visual impairment(Table 3) [31, 33, 41, 42, 47, 49]. The most common definition of visual impairment utilized was “visual acuityof < 20/200” (n = 4, 66.7%).
In the meta-analysis, infantile sepsis was associatedwith significantly increased risk of visual impairment[aOR 2.57 (95%CI: 1.14, 5.82)] but there were no statistically significant differences in visual impairment between
subgroups of early or late onset sepsis, and blood culture
negative conditions as compared to the non-septic population (Table 8, Fig. 3A and B).
Hearing impairment

Seven studies reported data on hearing impairment(Table 4) [31, 33, 41, 42, 47, 49]. Two studies definedhearing impairment as permanent hearing loss affecting
communication with or without amplification [42, 47].
Other definitions included “sensorineural hearing loss

Country

Switzerland

First author, Year

Schlapbach, 2011[29]

Table 1 Study characteristics

Extreme preterm,
ELBW

Population

Cohort study

Study design

Sepsis: 26.4
(25.7–27.1)
Suspected sepsis:26.6 (25.7–27.3)

Gestational Age

Sepsis: 820(700–959)
Suspected sepsis:
850 (740–995)

Birth weight541 (305)

Sample size,
total (sepsis)
21 to 25 months

Duration offollow-up
Gram positivebacteria (80%)
CONS (51%)
Staphylococcus
aureus (15%)

Causative
organisms

Composite
NDI?

Proven sepsis:
No
Positive result on 1
or more bacterial
or fungal cultures
obtained from bloodor cerebrospinal fluidin an infant with clinical signs of infection(temperature instability, irritability, apathia,
feeding difficulties,
prolonged capillary
refill, apnea, tachycardia, and tachypnea)
treated with antibiotics for 5 or more daysor until death
pathogens that may
represent contaminations were considered
as proven sepsis
only if laboratory
signs of infection
such as elevated CRP,
left shift, or leukopenia, were present
and if the sepsis
episode had beentreated for 5 or moredays or until deathSuspected sepsis:
an episode with clinical and/or laboratory
signs of infectionin the absenceof a positive bacterial
or fungal culture
from a normallysterile site in an infant
who received treatment with antibiotics
for 5 or more daysor until death

Sepsis definition

Ong et al. BMC Pediatrics(2024) 24:505
Page 5 of 38

Country

United states

Netherlands

FranceFirst author, Year

Adams-Chapman,2013 [30]de Haan, 2013 [31]Mitha, 2013 [32]Table 1 (continued)

Preterm

Preterm

ELBW

Population

Cohort study

Cohort study

Cohort study

Study designNR< 30 weeks gestation:
Neonatal candida
sepsis: 27.1 ± 1.4
Gram negative
sepsis: 27.0 ± 1.5

NR

Gestational Age

Sample size,
total (sepsis)

NR

NCS: 936.6 ± 208.2
GNS: 933.3 ± 197.8

2665 (955)

204 (84)

Birthweight < 750g: 1317 (1037)
257

Birth weight

60 months

24 months

18–22 months

Duration offollow-up

EOS (only 84% had
causative organisms identified)- GBS (34%)- E coli (33%)
LOS (only 75% had
causative organisms identified)- CoNS (46%)- Staph aureus(20%)

Candida sepsis:- C. albicans: 52%- C. parapsilosis:
48%
Gram negative
sepsis:- Klebsiella pneumonia: 24%- E. coli: 18%- Enterobactercloacae: 18%

CandidaCausative
organisms

Composite
NDI?

No

Early-onset sepsis
No(EOS) was definedas confirmed infection of maternal
origin (vertically transmitted), on the basisof medical records.
Late-onset sepsis(LOS) was defined
as a postnatallyacquired infection (horizontallyacquired) treatedwith antibiotics
for at least 7 days,
also on the basisof medical records.

1. Gram-negative
bacteria or candida
species foundin peripheral blood
cultures2. Clinical sepsis: At
least 2 of the following symptoms- Increase in frequency or durationof apnoea or bradycardia (not related
to feeding problems
or airway obstruction) necessitating
an increase in ventilatory support- Hypothermia
or hyperthermia- Circulatory compromise: Systolic bloodpressure < P5

Positive blood culture Yes
and antibiotic therapy
for >  = 5 days

Sepsis definition

Ong et al. BMC Pediatrics(2024) 24:505
Page 6 of 38

Country

United states

BrazilBrazilSouth Africa

United States

First author, Year

Alshaikh, 2014 [33]Ferreira, 2014 [34]Hentges, 2014 [35]Dangor, 2015 [36]Bright, 2017 [52]Table 1 (continued)

Preterm

Preterm and term

Preterm, VLBWPreterm, VLBWPreterm

Population

Cohort study

Case–control
study

Cohort study

Cohort study

Cohort study

Study design

23–24 weeks: 187
25–26 weeks: 399
27 weeks or more:
298

NR

29.06 ± 1.84

29.1 ± 2 weeks

25.9 ± 1.7

Gestational Age<  = 750g: 331
751-1000g: 382> 1000g: 171

NR

1024 ± 228

1015 ± 256

834 ± 211g

Birth weight894 (362)

384 (122)

411 (94)

194 (86)332 (105)

Sample size,
total (sepsis)

10 years

3 and 6 months

18 and 24 months

12 months

37.1 ± 2.1 months

Duration offollow-up

NR

Group B Streptococcus

Coagulase negative Staphylococcus
S. aureus
CandidaNA

Coagulase negative streptococcus

Causative
organisms

No

No

No

Composite
NDI?

Documented lateNobacteremia: Recoveryof an organism
from blood drawn
during week 2, 3, or 4.
Specific organisms
were not identified.
Suspected infections:Culture-negative,
but the infantsreceived
antibiotics for morethan 72 h.

1. > 90 days of age
Noin whom GBS was cultured from blood,
CSF or other normallysterile sites
2. GBS identified
in CSF by latex agglutination

Late onset sepsis:presence of positive blood cultures
over 72 h of life,
followed by clinicalsigns- changes in breathing pattern- hypothermia
or hyperthermia- circulatory symptoms- GIT symptoms

1. Presence of a positive blood culture
2. Presence of clinicaland laboratory signs
suggestive of infection

Combination of:- Suggestive clinicalsigns- Positive singleorganism sterile
body fluids culture
for coagulase-negative staphylococcus(CoNS)

Sepsis definition

Ong et al. BMC Pediatrics(2024) 24:505
Page 7 of 38

Country

United States

India

The Netherlands

First author, Year

Savioli, 2018 [37]Singh, 2018 [38]Zonnenberg, 2019[39]

Table 1 (continued)

Preterm, VLBWPreterm, VLBWPreterm and term

Population

Cohort study

Cohort study

Cohort study

Study design

28 + 0 (15 SD) days

< 32: 40 (50%)
32–36: 37 (46.3%)
34–36: 7 (8.8%)
36–38: 3 (3.8%)

NR

Gestational Age

1078 ± 322

1000–1200: 37(43.6%)
1201–1400: 29(36.3%)
1401–1500: 14(17.5%)

Over 2500g
Known sepsis: 97
Suspected sepsis:2858
1500-2499g
Known sepsis: 28
Suspected sepsis:455
1000-1499g
Known sepsis: 23
Suspected sepsis:109< 1000g
Known sepsis: 42
Suspected sepsis:
27

Birth weight

117 (85)

160 (80)

65,938 (3639)

Sample size,
total (sepsis)

24 months

6 months

Within 60 months

Duration offollow-up

Coagulase-negative staphylococci(82.3%)
Staphylococcus
aureus (16.4%)
Escherichia coli
(2.3%)

Composite
NDI?

Late-onset sepsisNo
was defined as a positive blood culture
after 72 h of life. If
the blood culture
did not turn positive
but clinical signs
implied antibiotic
treatment for 7 days,late-onset sepsis
was considered probable but not proven.
If in one of the episodes a causal microorganism was found,the infant was classified as proveninfection.

No

Criteria for sepNo
sis: documented
clinical symptoms,
five or more daysof antibiotic use,
and a positive laboratory screening test
(positive microbial
growth in the blood,urine, or CSF).
Suspected sepsis:
clinical symptomsof sepsis and fiveor more daysof antibiotic use without a positive laboratory screening test,
consistent with otherstudies’ definitionof suspected sepsis

Sepsis definition

Klebsiella pneumo- Postive blood culture
niae (33.8%)
Escherichia coli
(15%)
Candida species(13.8%)

NR

Causative
organisms

Ong et al. BMC Pediatrics(2024) 24:505
Page 8 of 38

CountrySouth Africa

United States

First author, Year

Nakwa, 2020 [40]Mukhopadhyay,2020 [42]Table 1 (continued)

Extreme preterm,
ELBW

Preterm and term

Population

Cohort study

Case–control
study

Study design

24.4 ± 1.1

NR

Gestational Age

713 ± 131NR

Birth weight

6565 (153)

571 (122)

Sample size,
total (sepsis)

18–22 months (forbirths before 1st
July 2012)
22–26 months (forbirths on or after
1st July 2012)

12 months

Duration offollow-up

Gram positive(27.5%)
Gram negative(65.4%)
Fungi (1.3%)

NR

Causative
organisms

Composite
NDI?

EOS was defined
as blood or cerebrospinal fluid (CSF)
culture obtained ≤ 72
h of age that grewpathogenic bacteria
or fungi, for which
the infant received
antibiotics ≥ 5 daysor died with intent
to receive antibiotics ≥ 5 days

No

GBS sepsisNo
was defined
as isolation of GBS
from blood culture
in infants < 90 daysof age. GBS meningitis was defined
through identificationof GBS in cerebrospinal fluid (CSF) by culture or latex agglutination (irrespectiveof whether GBS
was cultured
on blood); or in cases
where the CSF
was sterile
but the blood
culture was GBSpositive, a pleocytosisof ≥ 20 cells/mm
3 for < 28-day oldsand ≥ 10 cells/mm 3
for 29–89-day olds
(with no adjustment
made for traumatictaps) was taken
as evidence for GBS
meningitis.

Sepsis definition

Ong et al. BMC Pediatrics(2024) 24:505
Page 9 of 38

Country

Denmark

The Netherlands

United States

GermanyFirst author, Yeara) Horváth-Puhó,
2021 [43]b) Horváth-Puhó,
2021 [44]Mukhopadhyay,2021 [41]Ortgies, 2021 [45]Table 1 (continued)

Preterm, VLBWExtreme preterm,
ELBW

Preterm and term

Preterm and term

Population

Cohort study

Cohort study

Cohort study

Cohort study

Study designNR

24.7 ± 1.0

NR

NR

Gestational AgeNR

708 ± 135

NR

NR

Birth weight342 (54)3940 (2387)

7658 (697)

16,470 (1525)

Sample size,
total (sepsis)

21–27 months

18–22 months (forbirths before 1st
July 2012)
22–26 months (forbirths on or after
1st July 2012)

9 years (6–11)

14 years (7–18)

Duration offollow-up

Composite
NDI?

Exposed children
Yes
were defined as having a history of iGBS
disease (sepsis, meningitis, or pneumonia)
by the age of 89 days.
Sepsis was defined
as a positive blood
culture only.

Exposed children
Yes
were defined as having a history of iGBS
disease (sepsis,
meningitis, or pneumonia) by the ageof 89 days. GBS
meningitis, sepsis,and pneumonia were
defined on the basisof discharge diagnoses with the useof International Classification of Diseases(ICD)-10 codes

Sepsis definition

NR

Culture-provenNo
EOS was defined
as a positive resultof one or more bacterial or fungal blood
cultures obtained
from patientsand antimicrobial
treatment for at least
5 daysClinical EOS
was definedusing establishedlaboratory parametersand persistent clinicalpresentation

CoNS (52%)
Late onset sepsis
No
Staph aureus (13%) (LOS) defined as isolaE coli (7%)
tion of a pathogen
from blood or CSF
obtained > 72 hof age and appropriate therapy for ≥ 5days (≥ 7 days for CSF
growth) or death
before completed
treatment

GBS

GBS

Causative
organisms

Ong et al. BMC Pediatrics(2024) 24:505
Page 10 of 38

Country

Korea

United States

BrazilDenmark

First author, Year

Shim, 2021 [46]Brumbaugh, 2022
[47]

Golin, 2022 [48]a) Horváth-Puhó,
2022 [43]Table 1 (continued)

Preterm and term

Preterm

Extreme preterm

Preterm, VLBW

Population

Cohort study

Cohort study

Cohort study

Cohort study

Study designNR

31.22 (24–36)

25.0 (24.1–25.9)(27 + 2) ± (2 + 2)

Gestational AgeNR

1419 (550–2300)

700 (600–810)

927.3 ± 239.3

Birth weight

15,643 (1432)

100 (50)

13,372 (4731)

2098 (419)Sample size,
total (sepsis)

Up till 18 years

Corrected
gestational age
between 37 and 42
weeks

18—26 months

18–24 months

Duration offollow-up

GBS

Gram positive in 1
Streptococcus
b in1
Bacillus gramnegative + Klebsiella pneumoniae
in 1
Escherichia coli
in 3
E.coli + E faecalis
in 1
E. coli + Bacillus
in 1(hemoculture
only performed in 84%
and only positive
in 9%)

NR

Coagulase-negative Staphylococcus (48.8%)
Gram negative(19%)
Gram positivebacteria (79.5%)

Causative
organisms

Composite
NDI?

No

Having a history
of GBS sepsis
or meningitis by age
89 days as identified
based on International Classificationof Diseases. 10th revision (ICD-10) codesof discharge diagnosis from the Danish
National Patent
Registry

Yes

Neonatal sepsisNo
was consideredin the presenceof a positive blood
culture and/or clinicaland laboratory signs
suggestive of infection.

LOS was defined
as isolation of a bacterial or fungal
pathogen from bloodobtained morethan 72 h after birthand accompaniedby treatment
for at least 5 daysor death before completed treatment.

LOS was definedNo
as a postnatallyacquired infection
which occurred
after the third
postnatal day of life.
Only sepsis confirmedby blood culture
was considered.

Sepsis definition

Ong et al. BMC Pediatrics(2024) 24:505
Page 11 of 38

Extreme pretermand ELBW

Germany

KuwaitHumberg, 2022
[49]

Kartam, 2022 [50]Preterm

Preterm and term

The Netherlandsb) Horváth-Puhó,
2022 [44]Population

CountryFirst author, Year

Table 1 (continued)

Cohort study

Cohort study

Cohort study

Study design

No sepsis: 29.5
(28.1–31.4)
EOS: 27.0(25.8–28.7)
LOS: 25.9(25.0–27.7)

No LOS: 26.3
(25.1–27.4)
One LOS: 25.7
(24.4–26.9)
Recurrent LOS: 25.3
(24.1–26.6)
Total including no sepsis: 26.1
(25.0–27.3)

NR

Gestational Age

No sepsis: 1190
(1020–1380)
EOS: 1045(832–1335)
LOS: 840 (695–966)

No LOS: 780(640–900)
One LOS: 725(630–860)
Recurrent LOS: 660(575–790)
Total including no sepsis: 748(630–890)

NR

Birth weight203 (109)1343 (263)7658 (697)

Sample size,
total (sepsis)

36 months CA

5–6 years

Up to 12 years

Duration offollow-up

Klebsiella pneumonia (31.3%)
Streptococcus
agalactia (25.0%)
Escherichia coli
(18.8%)

S. hominis
S. agalactiae
VRE
ESBL-positive
Klebsiella spp
Enterobacter spp

GBS

Causative
organisms

No

Yes

Composite
NDI?

Neonatal sepsisNo
was confirmed
using a positive
culture, which
was defined as any
sample of bloodor cerebrospinal
fluid which tested
positive for bacterial growth. A blood
culture was considered contaminatedif the presenceof gram-positive cocci
in it was negatedby another culturedrawn 30-min apart.
Earlyonset sepsis(EOS) was describedby a positive blood
culture occurring ≤ 72
h after birth, and LOS
as an infection
contracted after thisperiod. A case of sepsis was consideredsevere if associatedwith hemodynamic
instability and disseminated intravascular coagulation (DIC)

Neonatal sepsis
was confirmed using
a positive culture,
which was defined
as any sampleof blood or cerebrospinal fluid which
tested positive
for bacterial growth

Having cerebrospinal
fluid and/or a blood
culture positive for
GBS, identified
through the Netherlands Reference
Laboratory
for Bacterial Meningitis

Sepsis definition

Ong et al. BMC Pediatrics(2024) 24:505
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LMIC (South Africa,
India, Mozambique, Kenya
and Argentina)

Paul, 2022[51]Preterm and term

Population
Cohort study

Study design
NR

Gestational Age
NR

Birth weight577 (159)

Sample size,
total (sepsis)
1–18 years

Duration offollow-up
NR

Causative
organisms

Composite
NDI?
GBS-meningitis
Yes
was diagnosed
by GBS-positive
cerebrospinal fluid(CSF) culture in mostcases (67¢4%),
but five cases defined
as meningitis had
suggestive CSF leucocyte count of > 20
£ 106/l plus GBSpositive blood
culture and nine had
GBS-positive blood
culture plus suggestive clinical symptomsof meningitis.

Sepsis definition

Foot note: Results from studies are specified as frequencies (percentages) unless not reported in the study

Preterm ≤ 37 gestational weeks, VLBW Very low birth weight (VLBW) < 1500 g, ELBW extremely low birth weight (ELBW) < 1000 g, EOS Early Onset Sepsis, LOS Late Onset Sepsis, NCS Neonatal Candida Sepsis, GBS Group B
Streptococcus, NR Not Reported, CONS Coagulase-negative Staphylococcus, VRE vancomycin-resistant enterococcus, ESBL extended spectrum beta-lactamase

CountryFirst author, Year

Table 1 (continued)

Ong et al. BMC Pediatrics(2024) 24:505
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Ong et al. BMC Pediatrics(2024) 24:505

Page 14 of 38

Fig. 2 World map depicting distribution of studies that evaluate neurocognitive outcomes in infantile and neonatal sepsis

requiring amplification” (n = 1), “bilateral hearing impairment with no functional hearing (with or without amplification)” (n = 1), “clinical hearing loss” (n = 1).
In the meta-analysis, sepsis was associated withincreased risk of hearing impairment [aOR 1.70 (95%
CI: 1.02–2.81)]. However, in the subgroup analyses,
there were no differences in risk of hearing impairment
between patients with late onset sepsis as compared to
the non-septic population (Table 8, Fig. 3A and B).

due to significant heterogeneity in definitions of sepsis,time of assessment of outcomes.
Differences in neurocognitive outcomes between termand post‑term neonates

There were no studies which evaluated neurocognitive
outcomes between term and post-term neonates andinfants.
Certainty of evidence

Cerebral palsy

Nine studies [29, 32, 33, 41, 42, 47–50] reported data on
CP (Table 5), of which 5 studies [41, 42, 45, 49, 50] used
the GMFCS scale. In the meta-analysis, infantile sepsis
was associated with significantly increased risk of CP[aOR 2.48 (95%CI: 1.03; 5.99)]. There was no difference
in rates of CP among patients with proven or suspected
sepsis, as compared with infants with no sepsis (Table 8,
Fig. 3A and B).
Differences in neurocognitive outcomes between neonateswith culture‑proven or clinically diagnosed sepsis as wellas early or late onset sepsis

Tables 6 and 7 showed data related to differences in neurocognitive outcomes between neonates with cultureproven or clinically diagnosed sepsis as well as early orlate onset sepsis. Meta-analyses were not be performed

We found that the certainty of evidence to be very low to
low for the four main neurocognitive outcomes selected.
(Supplementary File 3).
Discussion

In this review involving more than 121,000 infants, we
provide an update to the literature regarding young infant
sepsis and neurocognitive impairment. Current collective evidence demonstrate that young infant sepsis was
associated with increased risk of developing neurocognitive impairment in all domains of CD, visual impairment,
auditory impairment and cerebral palsy.
Cognitive delay

In this review, higher rates of cognitive delay werenoted among infants with sepsis [29, 31, 33–38, 40–42,
45, 46, 48, 49, 52]. We found that infants with sepsis
reported lower PDI scores (Table 8), which measures

de Haan, 2013 [31]Bayley Scales of Infant
Development (Second
Edition-Dutch version)

Bayley Scales of Infant
Development III(Evaluated after 1 October
2007)

Bayley Scales of Infant
MDI < 70 or PDI < 70
Development II(Evaluated prior to 1 October 2007)

Adams-Chapman, 2013[30]

Sepsis incidence- Mildly delayed:
MDI and PDI scores
between 70 to 84- Severely delayed: MDI
or PDI scores below 70

BSID-III cognitive < 70

Mildly abnormal
Neonatal Candida Sepsis(NCS) = 9/17 (53%)
Gram negative sepsis(GNS) = 8/33 (24%)
Severely abnormal
NCS = 1/17 (6%)
GNS = 7/33 (21%)

NR

MDI and/or PDI scores < 70 PDI < 70:
Proven sepsis: 32/128(25%)
Suspected sepsis: 38/164(23%)
MDI < 70:
Proven sepsis: 30/132(23%)
Suspected sepsis: 30/166(18%)
MDI or PDI scores
between 70 and 84:
Proven sepsis: 43/134(32%)
Suspected sepsis: 49/167(29%)

Bayley’s Scales of Infant
Development (BSID) II

Schlapbach, 2011 [29]Cognitve delay
definition

Scale used

First author, Year

Table 2 Cognitive delay assessment and definition

Mildly abnormal
Uncomplicated(UC) = 13/102 (13%)
Severely abnormal
UC = 2/102 (2%)

NR

PDI < 70:
Uninfected: 29/193 (15%)
MDI < 70:
Uninfected: 39/229 (17%)
MDI or PDI scores
between 70 and 84:
Uninfected: 68/232 (29%)

No sepsis incidence

NR

NR

Multivariable OR (95% CI)
for PDI < 70:
Proven sepsis vs uninfected: 1.80 (0.95–3.41),
P-value = 0.073
Suspected sepsis vs uninfected: 1.36 (0.72–2.59),
P-value = 0.341
Multivariable OR (95% CI)
for MDI < 70:
Proven sepsis vs uninfected: 1.37 (0.73–2.58),
P-value = 0.325
Suspected sepsis vs uninfected: 0.70 (0.36–1.35),
P-value = 0.286
Multivariable OR (95% CI)
for MDI or PDI between 70
and 84:
Proven sepsis vs uninfected: 0.96 (0.57–1.59),
P-value = 0.863
Suspected sepsis vs uninfected: 1.23 (0.75–2.01),
P-value = 0.419

RatiosNA

NA

Center, year of birth, gender,
gestational age, birthweight, brain injury, BPD,
ROP, socioeconomic status,and postnatal growth.

Adjusted for (if any)

Ong et al. BMC Pediatrics(2024) 24:505
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Scale used

Kaufman Assessment Battery for Children

First author, Year

Mitha, 2013 [32]Table 2 (continued)

Mental processing composite (MPC) score < 70

Cognitve delay
definition
NR

Sepsis incidenceNR

No sepsis incidence
Adjusted OR (95% CI)
EOS: 0.98 (0.47–2.04),
P-value = 0.95
LOS: 0.79 (0.50–1.24),
P-value = 0.31

RatiosFor cerebral palsy, models
were adjusted for maternal
and neonatal variables
selected in the univariate
analysis (preterm ruptureof membranes, spontaneous preterm labor, gender,
gestational age, and small
for gestational age)and other factors previously
reported to be associatedwith short- and long-term
outcomes (eg, antenatal
corticosteroid therapy)
For cognitive impairment,
models were adjusted
for maternal and neonatal variables selectedin the univariate analysis(maternal age at birth,maternal level of education, parity, preterm
rupture of membranes,
gender, gestational age,small for gestational age,and duration of central
venous catheter use)
and other factors previously
reported to be associatedwith short- and long-term
outcomes (eg, antenatal
corticosteroid therapy)

Adjusted for (if any)

Ong et al. BMC Pediatrics(2024) 24:505
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Altered: MDI or PDI
scores < 85
- Mildly delayed:
MDI and PDI scores
between 70 to 84- Severely delayed: MDI
or PDI scores below 70
Changes associatedwith one or moreof several body segments at clinical/neurological evaluation, suchas: change in muscle
tone, abnormal posture,abnormal spontaneous
movements, alteredneurological examination,and motor developmental
delay
Did not reach age-appropriate motor milestones

Bayley Scale of Infant
Development (Second
edition)Amiel-Tison and Grenier
protocolMotor development
milestones

Ferreira, 2014 [34]Sepsis incidence

Altered PDI at 12 months:
48/86 (55.8%)
Neuromotor impairment
at 12 months: 29/86(33.7%)
Neuromotor impairment and/or altered
PDI at 12 months: 51/86(59.3%)
Altered MDI at 12 months:
41/86 (47.7%)> 2 standard deviation
NR
below the mean on standardized assessment- Wechsler Preschool
and Primary Scaleof Intelligence-Revised- Bayley Scales of Infant
Development II- Stanford-Binet IV

AL Shaikh, 2014 [33]Cognitve delay
definition

Scale used

First author, Year

Table 2 (continued)
Adjusted for (if any)NA

Adjusted OR (95% CI): 2.23 Because of small event(1.01–4.9), P-value = 0.048 numbers in deafness
and blindness, their association with CoNS sepsis were
adjusted for GA only
For CP, cognitive delay
and major disabilities,
which had a greaternumber of outcome
events, the associations
were adjusted for GA,
chorioamnionitis, severe
intraventricular hemorrhage and use of postnatal
steroids

RatiosAltered PDI at 12 months: NR
25/108 (23.1%)
Neuromotor impairment
at 12 months: 10/108(9.3%)
Neuromotor impairment and/or altered PDI
at 12 months: 28/108(25.9%)
Altered MDI at 12 months:
35/108 (32.4%)

NR

No sepsis incidence

Ong et al. BMC Pediatrics(2024) 24:505
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Scale used

Bayley Scales of Infant
and Toddler Development II

First author, Year

Hentges, 2014 [35]Table 2 (continued)

Mildly delayed:
MDI and PDI scores
between 70 to 84
Severely delayed: MDI
or PDI scores below 70

Cognitve delay
definition
Cognitive Impairment:
Coagulase negative
Staphylococcus: 17/36(47.2%)
Gram Positive: 12/16(75.0%)
Gram negative and fungi:
5/10 (50%)
Motor deficit:
Coagulase negative
Staphylococcus: 6/36
(16.7%)
Gram Positive: 11/16(68.8%)
Gram negative and fungi:
4/10 (40.0%)

Sepsis incidence
Cognitive Impairment:
Non-Septic: 76/164(46.3%)
Motor deficit
Non-Septic: 48/164(29.3%)

No sepsis incidence
Severe motor deficit
adjusted OR (CI)
Coagulase negative Staphylococcus: 0.6 (0.1–4.1),
P-value = 0.68
Other gram positive: 4.1(0.88–19), P-value = 0.071
Gram negative bacteria
and fungi: 1.3 (0.2–8),
P-value = 0.74
Severe and moderate
motor deficit adjusted
OR (CI)
Coagulase negative Staphylococcus: 0.5 (0.1–1.6),
P-value = 0.24
Other gram positive: 6(1.6–21), P-value = 0.006
Gram negative bacteria
and fungi: 0.8 (0.1–3.9),
P-value = 0.8
Severe cognitive impairment adjusted OR (CI)
Coagulase negative Staphylococcus: 0.9 (0.1–5.6),
P-value = 0.99
Other gram positive: 1.9(0.4–8.9), P-value = 0.39
Gram negative bacteria
and fungi: 1.5 (0.2–10.2),
P-value = 0.67
Severe and moderatecognitive impairment
adjusted OR (CI)
Coagulase negative Staphylococcus: 0.9 (0.3–2.4),
P-value = 0.91
Other gram positive: 3.9(0.96–16), P-value = 0.06
Gram negative bacteria
and fungi: 0.3 (0.03–3),
P-value = 0.33

Ratios
Logistic regression adjusted
for type of delivery,
maternal preeclampsia, useof antenatal corticosteroids,
CHAD transfusion, leukomalacia, retinopathy of prematurity, length of stay,
SNAPPE II, gestational Age

Adjusted for (if any)

Ong et al. BMC Pediatrics(2024) 24:505
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Scale used

Denver Development
Screening Test II- School-Age Differential
Ability Scales, Second Edition (DASII)- Verbal and Nonverbal
Reasoning scale- Oral and Written Language Scales (OWLS)- NEPSY-II (A Developmental NEuroPSYchological
Assessment, Second
Edition)- TheWechsler Individual
Achievement Test, Third
Edition (WIAT-III)- Gross Motor Function
Classification System- Manual Ability Classification System.

First author, Year

Dangor, 2015 [36]Bright, 2017 [52]Table 2 (continued)- Sensorimotor function
Manual Ability Classification system>  = 3- Gross motor function
classification system>  = 3- Processing speed
NEPSY-II Inhibition Naming(1) Z score =  < -2(2) Z score > -2, =  < -1
- Fine motor function
NEPSY-II Visuomotor
Precision(1) Z score =  < -2(2) Z score > -2, =  < -1

Abnormal test for anyof the four domains(gross motor, fine motor,
language and personalsocial) or hypertonia and/or hyperreflexia detected
on examination

Cognitve delay
definition

Sensorimotor function:- Suspected late onset
bacteremia: 12- Definite late onset bacteremia: 12
Gross motor function classification system:- Suspected late onset
bacteremia: 5- Definite late onset bacteremia: 6
Processing speed:(1) Z score =  < -2
- Suspected late onset
bacteremia: 33- Definite late onset bacteremia: 35(2) Z score > -2, =  < -1
- Suspected late onset
bacteremia: 21- Definite late onset bacteremia: 19
Fine motor function
NEPSY-II Visuomotor
Precision(1) Z score =  < -2
- Suspected late onset
bacteremia: 22- Definite late onset bacteremia: 22(2) Z score > -2, =  < -1
- Suspected late onset
bacteremia: 33- Definite late onset bacteremia: 35

Evaluated at 3 months
Overall: 9/68 (13.2%)- Abnormal Denver-II
assessment: 3/68 (4.4%)- Hypertonia/hyperreflexia: 6/68 (8.9%)
Evaluated at 6 months
Overall: 9/68 (13.2%)- Abnormal Denver-II
assessment: 5/68 (7.4%)- Hypertonia/hyperreflexia: 4/68 (5.9%)

Sepsis incidence
Gender, gestational age,birth weight < 2500 g, perinatal asphyxia, mechanicalventilation, infant HIV exposure status and previous
non-GBS related hospitalizations

Evaluated at 3 months:
Multivariate OR:
21.48 (2.58–179.15),
P-value = 0.005
Evaluated at 6 months:
Multivariate OR:
13.18 (1.44–120.95),
P-value = 0.023

NA

Adjusted for (if any)

RatiosSensorimotor function:
NR- No late onset bacteremia: 8
Gross motor function classification system:- No late onset bacteremia: 5
Processing speed:(1) Z score =  < -2
- No late onset bacteremia: 29(2) Z score > -2, =  < -1
- No late onset bacteremia: 20
Fine motor function
NEPSY-II Visuomotor
Precision(1) Z score =  < -2
- No late onset bacteremia: 20(2) Z score > -2, =  < -1
- No late onset bacteremia: 35

Evaluated at 3 months
Overall: 1/262 (0.4%)- Abnormal Denver-II
assessment: 1/262 (0.4%)- Hypertonia/hyperreflexia: 0/262 (0%)
Evaluated at 6 months
Overall: 1/232 (0.4%)- Abnormal Denver-II
assessment: 1/232 (0.4%)- Hypertonia/hyperreflexia: 0/232 (0%)

No sepsis incidence

Ong et al. BMC Pediatrics(2024) 24:505
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Scale used

The Agency for Healthcare
Quality and Research(AHQR) Clinical Classification System (CCS)

Differential Ability Scales,
Second Edition (DASII)- Bayley’s Scales of Infant
and Toddler Development
II (BSID-II)- Lexiquotient- Child Behavior Checklist(CBCL)

Denver II developmental
scale

First author, Year

Savioli, 2018 [37]Singh, 2018 [38]Zonnenberg, 2019 [39]Nakwa, 2020 [40]Table 2 (continued)

Known sepsis: 96/190(50.5%)
Suspected sepsis:971/3,449 (28.2%)

Sepsis incidence

Mild delay:
Delay (i.e. fail or refusalof the item) in 1 out of 4
domains (gross motor,
fine motor, language,
personal-social)
Moderate-to-severe delay:
Any of the following- Delay in > 1 domain- Blindness- Cerebral palsy

Overall delay: 15/65(23.1%)
Mild delay: 9/65 (13.9%)
Moderate to severe delay:
6/65 (9.2%)

No definition of impairNR
ment given. Meanscores were compared
between sepsis and nonsepsis groups for statisticalsignificance

Measurement of neurode- 11/47 (23.4%)
velopmental outcomes
Significantly delayeddevelopment: DASII
score < 70

Diagnosis within the following two CCS subcategories within the first
5 years of life
- ICD-9 diagnostic codefor developmental
disorders- ICD-9 diagnostic codefor disorders usually diagnosed in infancy, childhood, or adolescence

Cognitve delay
definition

Overall delay: 11/207(5.3%)
Mild delay: 11/207 (5.3%)
Moderate to severe delay:
0/207 (0%)

NR

2/66 (3%)

No sepsis: 13,802/62,299(22.2%)

No sepsis incidence

NA

NA

Preterm birth, low birthweight, retinopathyof prematurity, chroniclung disease, patent ductus
arteriosus, intra-ventricularhemorrhage, periventricular leukomalacia, hypoxic
ischemic encephalopathy,
and hearing loss

Adjusted for (if any)

Adjusted OR (95% CI):
Variables with a P < 0.2
Overall: 4.23 (1.65–10.83), in the univariable analysis
P-value = 0.003
Sepsis only: 3.51 (1.23–
10.04), P-value = 0.019
Meningitis only: 8.29
(0.88–78.3), P-value = 0.065

NRNR

OR (95% CI) for any developmental delay
Known sepsis: 3.59
(2.70–4.77)
Known sepsis – Preterm
infants: 1.80 (1.09–2.98)aKnown sepsis – Term
infants: 1.71 (1.10–2.65)a
Suspected sepsis: 1.38
(1.28–1.49)
Suspected sepsis –Preterm infants: 1.18
(1.00–1.40)a
Suspected sepsis – Term
infants: 1.08 (0.98–1.19)

RatiosOng et al. BMC Pediatrics(2024) 24:505
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Mild NDI: Children who
NR
received additional support in regular schools
Moderate or severe NDI:
Children who received
education in special needs
schools

NR

EOS: 38/90 (42.2%)b) Horváth-Puhó, 2021 [44] Special educational sup(The Netherlands)
port

Bayley-3 cognitive composite score < 85

Sepsis incidence

NDI: impairment in any
domainMultidomain NDI: impairment in more than one
domainBayley Scales of Infant
Development, Third
EditionMukhopadhyay, 2020 [42]Cognitve delay
definitiona) Horváth-Puhó, 2021 [43] ICD-10 codes for mental,(Denmark)
behavioural, and nervous
system disorders

Scale used

First author, Year

Table 2 (continued)

NR

NR

Unaffected infants
with prolonged antibiotics: 745/2,270 (33.1%)
Unaffected infants without prolonged antibiotics:
695/2,333 (30.0%)

No sepsis incidence
Maternal education, maternal insurance, maternal
race/ethnicity, maternal
hypertension, antepartum
hemorrhage, antenatal steroids, maternal antibiotics
received during the delivery
admission, clinical chorioamnionitis, membranerupture > 18 h, caesareandelivery, infant GA (categorical), BW (continuous), malesex, intubation at birth, temperature < 60 min of birth,
severe intraventricularhemorrhage ≤ 7 days
age and start of enteralfeeds ≤ 3 days age

Adjusted for (if any)

No ratios available for cog- NA
nitive delay alone

No ratios available for cog- NA
nitive delay alone

Adjusted RR (95% CI)
EOS vs prolonged antibiotics: 1.26 (0.98–1.63),
P-value = 0.07
EOS vs prolonged antibiotics: 1.34 (1.04–1.74),
P-value = 0.02

RatiosOng et al. BMC Pediatrics(2024) 24:505
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Both motor and cognitive
delay: Scores < 70
Both motor and cognitive
delay: Scores < 80

Bayley Scales of Infant
Development II (Germantranslation)

Bayley scales of infantdevelopment (BSID)
second edition

Bayley scales of infantdevelopment (BSID) third
editionOrtgies, 2021 [45]Shim, 2021 [46]

LOS: 35/579 (6.1%)
LOCNC: 130/1,395 (9.3%)

Sepsis incidence

HHNE: Hammersmith
Significant differInfant Neurological Exami- ences in the domains
nationof the HNNE

Golin, 2022 [48]

BSID-II MDI < 70
BSID cognitive composite
score < 85

BSID II and BSID III

Brumbaugh, 2022 [47]NR

NR

Motor delay: 111/347(32.0%)
Cognitive delay: 124/392(31.6%)

MDI and/or PDI scores < 70 PDI < 70: 6/31 (19.35%)
PDI < 85: 8/31 (25.81%)
MDI < 70: 3/31 (9.68%)
MDI < 85: 7/31 (23.58%)

Bayley-3 cognitive composite score < 85

Bayley Scales of Infant
Development, Third
EditionMukhopadhyay, 2021 [41]Cognitve delay
definition

Scale used

First author, Year

Table 2 (continued)

NR

NR

Motor delay: 308/1,751(17.6%)
Cognitive delay:
295/1,706 (17.3%)

PDI < 70: 3/135 (1.65%)
PDI < 85: 18/135 (13.33%)
MDI < 70: 6/135 (4.44%)
MDI < 85: 37/135 (27.41%)

Unaffected: 54/1,387(3.9%)

No sepsis incidence

OR (95% CI) for effectof neonatal sepsis on clinical neurological alterations: 7.08 (2.13–23.53)

NR

Adjusted OR (95% CI)
for cognitive delay: 1.48
(1.02–2.16), P-value = 0.042

OR (95% CI) for PDI < 70:
10.56 (2,476–45,035),
P-value = 0.001
OR (95% CI) for PDI < 85:
2.261 (0.879–5,818),
P-value = 0.091
OR (95% CI) for MDI < 70:
2.304 (0.543–9,771),
P-value = 0.318
OR (95% CI) for MDI < 85:
0.773 (0.307–1,944),
P-value = 0.584

Adjusted RR (95% CI)
LOS vs unaffected: 1.12
(0.96–1.31), P-value = 0.14
LOCNC vs unaffected: 1.15
(1.01–1.30), P-value = 0.03

RatiosNA

Variables showing significant differences in the univariate analysis: High CRIB
score for MDI < 70 and high
CRIB scores and chorioamnionitis for PDI < 70

Maternal education,
insurance, race/ethnicity, antenatal antibiotics, antenatal steroids,
antepartum haemorrhage,
infant GA, birth weight, sex,
temperature at <  = 60 minof birth, intubation at birth,maximum respiratory support <  = 24 h of age, enteralfeeds started <  = 3 daysof birth, receipt of antibiotics for >  = 5 days starting <  = 72 h of age, severe
IVH diagnosed <  = 7 daysof birth and centre

Adjusted for (if any)

Ong et al. BMC Pediatrics(2024) 24:505
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IQ < 85:
One LOS: 31 (19.7[14.1–26.5])
Recurrent LOS: 24 (38.7[27.3–51.1])a
Manual dexterity difficulties:
One LOS: 36 (34.6[26.0–44.1])
Recurrent LOS: 19 (48.7[33.6–64.0])a
Aim and catching difficulties:
One LOS: 39 (37.1[28.4–46.6])a
Recurrent LOS: 16 (40.0[25.9–55.4])a
Balance difficulties:
One LOS: 16 (15.2[9.3–23.0])a
Recurrent LOS: 15 (35.7[22.6–50.8])aNR

Humberg, 2022 [49]1. Wechsler Preschool
and Primary Scale of Intelligence– Third Edition (WPPSI I-III,
German)2. Movement Assessment
Battery for Children – Second Edition (MABC-2)

Mild NDI: Children who
NR
received additional support in regular schools
Moderate or severe NDI:
Children who received
education in special needs
schools

NR

Sepsis incidenceb) Horváth-Puhó, 2022 [44] Special educational sup(The Netherlands)
port recorded in national
school registries

Cognitve delay
definition
NR

Scale useda) Horváth-Puhó, 2022 [43] ICD-10 codes for mental,(Denmark)
behavioural, and nervous
system disorders

First author, Year

Table 2 (continued)

IQ < 85:
No LOS: 174 (19.0[16.6–21.7])
Manual dexterity difficulties:
No LOS: 226 (33.1[29.6–36.7])
Aim and catching difficulties:
No LOS: 183 (26.9[23.6–30.3])
Balance difficulties:
No LOS: 79 (11.7[9.4–14.3])

NR

NR

No sepsis incidence

Adjusted for (if any)NR

Gestational age, birthweight, female gender,
antenatal administrationof steroids, small for gestational age, any intra-cranial
hemmorhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia,
treatment of retinopathyof prematurity (operation,laser, or use of anti-vascularendothelial growth factor),and highest maternal education level

No ratios available for cog- NA
nitive delay alone

No ratios available for cog- NA
nitive delay alone

RatiosOng et al. BMC Pediatrics(2024) 24:505
Page 23 of 38

Various tools (Each siteused various neurodevelopmental assessments,
with 26 tools in total
across the 5 study sites.
Each site selected assessment tools for their setting
based on child’s age,
cultural appropriateness,
validation of instrument
for their population,and technical capacity.)

Paul, 2022 [51]NR

NR

Sepsis incidence

NR

NR

No sepsis incidenceNR

Adjusted beta coefficientvalues:Motor composite score:- EOS: –0.1 (–7.7 to 7.5),
P-value = 0.938- LOS: -9.5 (–16.4 to –2.7),
P-value = 0.007
Cognitive composite
score:- EOS: 2.0 (–5.0 to 9.1),
P-value = 0.569- LOS: –4.7 (–11.2 to 1.7),
P-value = 0.146
Language composite
score:- EOS: 3.9 (–7.8 to 15.6),
P-value = 0.507- LOS: 0.82 (–8.3 to 6.6),
P-value = 0.829

RatiosNA

Birth weight, gestational age, severe sepsis,and necrotizing enterocolitis

Adjusted for (if any)aStatistically significant

BSID III Bayley Scales of Infant and Toddler Development 3rd edition, BSID II Bayley Scales Of Infant and Toddler Development 2nd edition, GMFCS Gross Motor Function Classification System, NDI neurodevelopmental
impairment, MDI Mental Developmental Index, PDI Psychomotor Developmental Index, NR Not recorded

Scored 2 standard deviations (SD)below the standardized
reference mean in cognition AND/OR motor
composite measures

Bayley scales of infantModerate developmental
and toddler development- delay: Score of 70–84
III (BSID-III)in ≥ 1 of the 3 domains
Severe developmental
delay: Score < 70 for any
domain or unable
to assign score due
to severe mental deficiency or cerebral palsy

Kartam, 2022 [50]Cognitve delay
definition

Scale used

First author, Year

Table 2 (continued)

Ong et al. BMC Pediatrics(2024) 24:505
Page 24 of 38

Ong et al. BMC Pediatrics(2024) 24:505

Page 25 of 38

Fig. 3 A Forest plot on adjusted odds ratios for neurocognitive outcomes related to MDI, PDI, visual impairment, hearing impairment and cerebral
palsy. B Forest plot on unadjusted odds ratios for neurocognitive outcomes related to MDI, PDI, visual impairment, hearing impairment and cerebral
palsy. Legend: MDI: Mental Developmental Index; PDI: Psychomotor Developmental Index. Foot note: Mild MDI or PDI: < 85 or < 80; Moderate MDI
or PDI < 70; Severe MDI or PDI < 55

mainly neuromotor development. On the other hand,
young infant sepsis was not associated with lower MDI
scores (Table 8), which assesses cognitive and language
development. The pathophysiological mechanism of
young infant sepsis and its preferential impact on PDI
remains unclear. Postulated mechanisms include development of white matter lesions which may arise fromthe susceptibility of oligodendrocyte precursors to
inflammatory processes such as hypoxia and ischemia[53]. Future studies should look into evaluating thecauses of the above findings. A majority of included
studies focused on early CD outcomes while no studies evaluated long-term outcomes into adulthood. CD
is known to involve complex genetic and experiential
interactions [54] and may evolve overtime with brain
maturation. Delays in speech and language, intellectual
delay and borderline intellectual functioning are shown
to be associated with poorer academic or employment outcomes in adulthood [55, 56], and early assessment of CD may not fully reveal the extent of delays.
The only study with follow-up to the adolescent phaseshowed a progressive increase in NDI rate as the participants aged, which provides evidence of incremental
long-term negative outcomes associated with infantile
sepsis [44]. Moving forward, studies with longer followup may allow for further examination of the long-term
effects of neonatal sepsis on CD.
There were different versions of the BSID instrument (BSID-II and BSID-III) [19, 57, 58]. BSID-II
lacked subscales in PDI and MDI scores, leading to thedevelopment of BSID-III with the segregation of PDI
into fine and gross motor scales and MDI into cognitive, receptive language, and expressive language scales[59]. Although we pooled results of both BSID-II and
BSID-III in our study, we recognize that comparisons
between BSID-II and BSID-III are technically challenging due to differences in standardised scores [59, 60].
In addition, the BSID-IV was created in 2019 which
has fewer items, However, none of our studies utilized
this instrument. Future studies should consider this
instrument, as well as standardising the timepoints forassessment of CD.

Ong et al. BMC Pediatrics(2024) 24:505

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Table 3 Visual impairment assessment and definition
First author, year

Definition of visual impairment

Outcome

Variables adjusted forde Haan, 2013 [31]Visual Handicaps

Neonatal Candida Sepsis = 3/17 (18%)
Gram Negative Sepsis = 10/33 (30%)
Uncomplicated = 8/102 (8%)

NA

Alshaikh, 2014 [33]Visual acuity < 20/200 following refractive correction

Adjusted OR (95% CI): 0.35 (0.03–3.37),
P-value = 0.36

NABright, 2017 [52]Child is legally blind in both eyes

No late onset bacteremia:2
Suspected late onset bacteremia: 6
Definite late onset bacteremia: 7NAMukhopadhyay, 2020 [42] Corrected vision < 20/200 in both eyes

Adjusted RR (95% CI):
1. EOS vs prolonged antibiotics: -0.40
2. EOS vs no prolonged antibiotics:
-0.62

NA

Mukhopadhyay, 2021 [41] Corrected vision < 20/200 in both eyes

Adjusted RR (95% CI):LOS vs unaffected: 2.40 (0.84–6.80),
P-value = 0.14
LOCNC vs unaffected: 2.70 (1.14–6.41),
P-value = 0.03

Maternal education, insurance, race/
ethnicity, antenatal antibiotics, antenatal
steroids, antepartum haemorrhage,
infant GA, birth weight, sex, temperature
at <  = 60 min of birth, intubation at birth,maximum respiratory support <  = 24 hof age, enteral feeds started <  = 3 daysof birth, receipt of antibiotics
for >  = 5 days starting <  = 72 h of age,severe IVH diagnosed <  = 7 days of birthand centre

Brumbaugh, 2022 [47]Bilateral blindness (visual acuity < 20/200)

Infants with LOM: 4/97 (4%)
Infants with LOS and no LOM: 95/2893(3%)
Infants with no LOS or LOM: 62/5982
(1%)a

NA

Humberg, 2022 [49]Visus < 0.8 in the best-performing eye
without glasses

No LOS: 181 (18.2 [15.9–20.7])
One LOS: 38 (21.6 [16.0–28.1])
Recurrent LOS: 21 (31.8 [21.5–43.6])aNA

OR Odds Ratio, RR Risk Ratio, NCS Neonatal Candida Sepsis, GNS Gram-Negative Sepsis, UC Uncomplicated SepsisaStatistically significant

Visual impairment

Young infant sepsis was associated with increased risk ofdeveloping visual impairment. This was similar to results
noted by a previous systematic review published in 2014[61] and 2019 [62] which showed that neonatal sepsis was
associated with twofold risk of developing retinopathy ofprematurity in preterm infants. Specifically, meningitis
was associated with a greater risk of visual impairment
compared to just sepsis alone [47]. The mechanism ofvisual impairment has not been fully described althoughvarious theories have been suggested, including sepsis mediated vascular endothelial damage, increased
body oxidative stress response as well as involvement ofinflammatory cytokines and mediators [63, 64].
Hearing impairment

Our meta-analysis showed an increased risk of hearing impairment for young infants with young infants
with sepsis. This is consistent with a previous reportthat found an association between neonatal meningitis and sensorineural hearing loss [65]. One potential

confounder which we were unable to account for may
have been the use of ototoxic antimicrobial agents suchas aminoglycosides. Additional confounders include very
low birth weight, patient’s clinical states (e.g. hyperbilirubinemia requiring exchange transfusion) and use of
mechanical ventilation or extracorporeal membrane
support. To allow for meaningful comparisons of results
across different study populations, it is imperative that astandardised definition of hearing impairment post neonatal sepsis be established for future studies.
Cerebral palsy

Our meta-analysis found an association between neonatal sepsis and an increased risk of developing CP. This isalso consistent with previous systematic reviews which
had found a significant association of sepsis and CP in
VLBW and early preterm infants [11]. One study foundthat infants born at full term and who experienced neonatal infections were at a higher risk of developing a
spastic triplegia or quadriplegia phenotype of CP [66].
The pathophysiology and mechanism of injury to whiteOng et al. BMC Pediatrics(2024) 24:505

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Table 4 Hearing impairment assessment and definition
First author, year

Definition of hearing impairment

Outcome

Variables adjusted forde Haan, 2013 [31]Clinical hearing loss

Neonatal Candida Sepsis = 4/17 (24%)
Gram Negative Sepsis = 6/33 (18%)
Uncomplicated = 1/102 (1%)

NA

Alshaikh, 2014 [33]Deafness: Sensorineural hearing loss
requiring amplification

Adjusted OR (95% CI): 2.24 (0.64–7.73),
P-value = 0.20

NABright, 2017 [52]Child has hearing aids or a cochlear
implant and/or receives special services for the hearing-impaired

No late onset bacteremia: 3
Suspected late onset bacteremia: 3
Definite late onset bacteremia: 7NAMukhopadhyay, 2020 [42] Permanent hearing loss affecting com- Adjusted RR (95% CI):
munication with or without amplifica- EOS vs prolonged antibiotics: 0.67
tion
(0.17–2.69), P-value = 0.77
EOS vs no prolonged antibiotics: 0.88
(0.22–3.54), P-value = 1.0

NA

Mukhopadhyay, 2021 [41] Permanent hearing loss with or without amplification

Adjusted RR (95% CI):LOS vs unaffected: 1.83 (0.96–3.47),
P-value = 0.07
LOCNC vs unaffected: 1.61 (0.94–2.76),
P-value = 0.10

Maternal education, insurance, race/
ethnicity, antenatal antibiotics, antenatal
steroids, antepartum haemorrhage,
infant GA, birth weight, sex, temperature
at <  = 60 min of birth, intubation at birth,maximum respiratory support <  = 24 hof age, enteral feeds started <  = 3 daysof birth, receipt of antibiotics
for >  = 5 days starting <  = 72 h of age,severe IVH diagnosed <  = 7 days of birthand centre

Brumbaugh, 2022 [47]Bilateral hearing impairmentwith no functional hearing (withor without amplification)

Infants with LOM: 8/96 (8%)
Infants with LOS and no LOM:
148/2880 (5%)
Infants with no LOS or LOM: 159/5940
(3%)a

NA

Humberg, 2022 [49]NR

No LOS: 501 (53.2 [50.0–56.4])
One LOS: 95 (56.5 [49.0–63.9])
Recurrent LOS: 44 (66.7 [54.8–77.1])aNA

OR Odds Ratio, RR Risk Ratio, NCS Neonatal Candida Sepsis, GNS Gram-Negative Sepsis, UC Uncomplicated SepsisaStatistically significant

matter resulting in increased motor dysfunction remains
unclear and more research is required in this area.
Limitations and recommendations for future research

The main limitation of this review lies in the heterogeneity in the definitions of sepsis, exposures and assessmentof outcomes across studies. This is likely attributed to thevarying definition of sepsis used in different countries aswell as lack of gold standard definitions or instruments
for assessment of each component of NDI. A recent
review of RCTs [67] also reported similar limitations
where 128 different varying definitions of neonatal sepsis
were used in literature. Notably, there is a critical needfor developing international standardized guidelines fordefining neonatal sepsis as well as assessment of NDI
such as hearing and visual impairment. Another important limitation relates to the inability to assess qualityof neonatal care delivered as well as temporal changes
in medical practices which could have affected neurocognitive outcomes for neonates with sepsis. Improving
quality of neonatal care has been shown to significantly

reduce mortality risk among neonates with sepsis, especially in resource-poor countries [68]. We performed acomprehensive search strategy (PubMed, Embase, Web
of Science and CENTRAL) coupled with hand searching of references within included systematic reviews, but
did not evaluate grey literature. Future studies should
include additional literature databases and grey literature. Another area of research gap lies in the paucity ofdata related to differences in neurocognitive outcomes
between term and post-term neonates with sepsis andfuture research is required to bridge this area of researchgap. Likewise, there are few studies which evaluated differences in neurocognitive outcomes between early orlate onset sepsis and outcomes assessed were significantly
heterogenous which limits meaningful meta-analyses.
Similarly, there was significant heterogeneity in study
outcomes, causative organisms and severity of disease.
We found a lack of long-term outcomes and recommend that future prospective cohorts include a longer
follow-up duration as part of the study design. This isimportant given the implication of NDI on development

Ong et al. BMC Pediatrics(2024) 24:505

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Table 5 Cerebral palsy assessment and definition
First author, year

Scale used

Definition of impairment

Outcome

Variables adjusted for

Schlapbach, 2011 [29]Palisano et al. classification

Non progressive motor disorder characterized by abnormal tone in at least 1 extremity
and abnormal control
of movement and posture

Incidence:
Proven sepsis: 14/136 (10%)
Suspected sepsis: 17/169 (10%)
No sepsis: 10/236 (4%)
OR (95% CI) comparing
proven sepsis and uninfected:
Univariable model: 2.90
(1.22–6.89), P-value = 0.016
Multivariable model: 3.23
(1.23–8.48), P-value = 0.017
OR (95% CI) comparing
suspected sepsis and uninfected:
Univariable model: 2.55
(1.10–5.93), P-value = 0.030
Multivariable model: 1.79
(0.61–5.25), P-value = 0.287

Center, year of birth, gender,
gestational age, birth weight,
brain injury, BPD, ROP, socioeconomic status, and postnatal
growth.

Mitha, 2013 [32]European Cerebral Palsy
Network

Presence of at least 2of the following:- Abnormal posture or movement- Increased tone
- Hyperreflexia

Adjusted OR (95% CI):
EOS alone: 1.70 (0.84–3.45),
P-value = 0.03
LOS alone: 1.71 (1.14–2.56),
P-value = 0.03
EOS & LOS: 2.33 (1.02–5.33),
P-value = 0.03

NA

Alshaikh, 2014 [33]NR

Non-progressive motor impair- Adjusted OR (95% CI): 0.63
ment characterized by abnor- (0.24—1.64), P-value = 0.34
mal muscle tone in at least
one extremity and decreased
range or control of movements

NA

Mukhopadhyay, 2020 [42]Gross motor function classifica- Mild: Level ≤ 1tion system (GMFCS)
Moderate: Level 2–3
Severe: Level 4–5

Adjusted RR (95% CI) for
GMFCS level: ≥ 2:
EOS vs prolonged antibiotics:
1.50 (0.91–2.46), P-value = 0.11
EOS vs no prolonged
antibiotics: 1.74 (1.05–2.88),
P-value = 0.03

NA

Mukhopadhyay, 2021 [41]Gross motor function classifica- Mild: Level ≤ 1tion system (GMFCS)
Moderate: Level 2–3
Severe: Level 4–5

Adjusted RR (95% CI) for
GMFCS level: ≥ 2:
LOS vs unaffected: 1.16
(0.77–1.76), P-value = 0.48
LOCNC vs unaffected: 1.91
(1.40–2.60), P-value =  < 0.001

NA

Ortgies, 2021 [45]Gross motor function classifica- NR
tion system (GMFCS)

Incidence:
EOS: 4/31 (12.09%)
No-EOS: 3/135 (1.65%)
P-value = 0.014
OR (95% CI): 6.519 (1379–
30,809), P-value: 0.018

NA

Brumbaugh, 2022 [47]

Palisano Gross Motor Function
Classification System

Infants with LOM: 13/97 (13%)
Infants with LOS and no LOM:
314/2887 (11%)
Infants with no LOS or LOM:
395/5981 (7%)aNA

Humberg, 2022 [49]Gross motor function classifica- GMFCS ≥ 1tion system (GMFCS)

No LOS: 82 (7.8 [6.3–9.5])
One LOS: 22 (12.0 [7.9–17.3])
Recurrent LOS: 10 (13.0[6.9–21.8])

NA

Kartam, 2022 [50]Gross motor function classifica- NR
tion system (GMFCS)

No sepsis: 8 (9.6)
EOS: 0 (0.0)a
LOS: 21 (28.0)aNA

Gross motor function level ≥ 2

GMFCS Gross Motor Function Classification System, OR Odds ratio, RR Risk ratio, NR Not reportedaStatistically significant

203 (109)

Kartam, 2022 [50]117 (85)

Zonnenberg, 2019 [39]Mukhopadhyay, 2021 [41] 3940 (2387)

411 (94)

Hentges, 2014 [35]Late onset sepsis

Mukhopadhyay, 2020 [42] 6565 (153)

Early onset sepsis

2665 (955)

Sample size

Mitha, 2013 [32]Late vs early onset sepsis

Authors, year of study

Late onset sepsis (LOS) defined as isolation of a pathogen from bloodor CSF obtained > 72 h of age and appropriate therapy for ≥ 5 days (≥ 7days for CSF growth) or death before completed treatment

Late-onset sepsis was defined as a positive blood culture after 72 hof life. If the blood culture did not turn positive but clinical signs implied
antibiotic treatment for 7 days, late-onset sepsis was considered probable but not proven. If in one of the episodes a causal microorganism
was found, the infant was classified as proven infection

Late onset sepsis: presence of positive blood cultures over 72 h of life, followed by clinical signs- changes in breathing pattern- hypothermia or hyperthermia- circulatory symptoms- GIT symptoms

EOS was defined as blood or cerebrospinal fluid (CSF) culture
obtained ≤ 72 h of age that grew pathogenic bacteria or fungi, for which
the infant received antibiotics ≥ 5 days or died with intent to receive
antibiotics ≥ 5 days.

Neonatal sepsis was confirmed using a positive culture, which was defined
as any sample of blood or cerebrospinal fluid which tested positive for bacterial growth. A blood culture was considered contaminated if the presence of gram-positive cocci in it was negated by another culture drawn
30-min apart.
Early onset sepsis (EOS) was described by a positive blood culture occurring ≤ 72 h after birth, and LOS as an infection contracted after this period.
A case of sepsis was considered severe if associated with hemodynamic
instability and disseminated intravascular coagulation (DIC)

Early-onset sepsis (EOS) was defined as confirmed infection of maternal
origin (vertically transmitted), on the basis of medical records.
Late-onset sepsis (LOS) was defined as a postnatally acquired infection (horizontally acquired) treated with antibiotics for at least 7 days,
also on the basis of medical records.

Definition of early or late onset sepsis

Table 6 Characteristics of study categorised by early vs late onset sepsis

1. Risk for NDI did not differ between late-onset sepsis (LOS) and late-onset,
antibiotic treated, blood culture-negative conditions (LOCNC)
2. Risk for NDI was higher for LOCNC infants compared with unaffected
infants (RR 1.17 (1.04–1.31))
3. Risk for NDI was not significantly higher for LOS compared with unaffected infants (might be due to smaller numbers of LOS)

1. No significant differences were found in cognitive, motor, and behavioral
scores or lexiquotient comparing patients with versus no proven infection
at 2 years correct age

1. VLBW infants with Gram-positive infection showed motor deficit
when compared to the non-septic group, 68.8% vs. 29.3%, respectively (OR 6; 1.6–21.8, p = 0.006); the cognitive development was similar
between the groups
2. However, no differences were observed in cognitive and motor scoresfor newborns who presented with late-onset sepsis by coagulase-negative
Staphylococcus (CNS)

1. Risk of NDI was higher for infants with early onset sepsis (EOS) comparedwith culture-negative infants who received prolonged early antibiotics
and compared with infants who did not receive prolonged early antibiotics
2. Among those without culture-confirmed EOS, the administrationof prolonged antibiotics was not associated with any significant differencein outcomes of death and/or NDI

1. The relationship between LOS and lower motor scores remained significant (adjusted β = –9.5, 95% CI: –16.4 to –2.7; p = 0.007), whereas the association with cognitive and language scores were no longer significant at 3
years of age after adjustment

1. There was no association between neonatal infection and cognitive
impairment
2. The frequency of cerebral palsy was higher in infants with isolated EOS(odds ratio [OR]: 1.70 [95% confidence interval (CI): 0.8423.45]) or isolated
LOS (OR: 1.71 [95% CI: 1.1422.56]) than in uninfected infants, and this risk
was even higher in cases of combined EOS and LOS (OR: 2.33 [95% CI:
1.0225.33])

OutcomesOng et al. BMC Pediatrics(2024) 24:505
Page 29 of 38

1. NDI was present in 42% (95%CI, 32%-52%) of children with LOM
and in 43% (95%CI, 41%-45%) of children with LOS without LOM comparedwith only 33% (95%CI, 32%-34%) of children with neither infection (P < .001)
2. The incidences of cerebral palsy (24%; 95% CI, 3%-14%), abnormal visualacuity (24%; 95%CI, 15%-32%), and bilateral hearing impairment (8%; 95%CI,
3%-14%) were highest among infants with a history of LOM

1. LOS had a significant association with cognitive delay (adjusted odds ratio,
1.48; 95% confidence interval, 1.02–2.16), but no association with motor
delay in VLBWIs at 18–24 months of correct age

Outcomes

CI confidence interval, EOS early onset sepsis, LOS late onset sepsis, LOCNC late-onset, antibiotic treated, blood culture-negative conditions, NDI neurodevelopmental impairment, OR odds ratio, RR Relative risk, VLBW very
low birth weight

13,372 (4731) LOS was defined as isolation of a bacterial or fungal pathogen from bloodobtained more than 72 h after birth and accompanied by treatment
for at least 5 days or death before completed treatment.

Brumbaugh, 2022 [47]

LOS was defined as a postnatally acquired infection which occurred
after the third postnatal day of life. Only sepsis confirmed by blood culture
was considered.

Definition of early or late onset sepsis

2098 (419)Sample size

Shim, 2021 [46]Authors, year of study

Table 6 (continued)

Ong et al. BMC Pediatrics(2024) 24:505
Page 30 of 38

Sample size

541 (305)

204 (84)

194 (86)894 (362)

Schlapbach, 2011 [29]de Haan, 2013 [31]Ferreira, 2014 [34]Bright, 2017 [52]

Culture positive vs culture negative sepsis

Authors, year of study

Documented late bacteremia: Recovery of an organism from blood drawn
during week 2, 3, or 4. Specific organisms were not identified.
Suspected infections: Culture-negative, but the infants received
antibiotics for more than 72 h

1. Presence of a positive blood culture
2. Presence of clinical and laboratory signs suggestive of infection

1. Gram-negative bacteria or candida species found in peripheral blood
cultures2. Clinical sepsis: At least 2 of the following symptoms- Increase in frequency or duration of apnoea or bradycardia (not related
to feeding problems or airway obstruction) necessitating an increasein ventilatory support- Hypothermia or hyperthermia- Circulatory compromise: Systolic blood pressure < P5

Proven sepsis:
Positive result on 1 or more bacterial or fungal cultures obtained
from blood or cerebrospinal fluid in an infant with clinical signs of infection (temperature instability, irritability, apathia, feeding difficulties,
prolonged capillary refill, apnea, tachycardia, and tachypnea) treatedwith antibiotics for 5 or more days or until death pathogens that may
represent contaminations were considered as proven sepsis only if laboratory signs of infection such as elevated CRP, left shift, or leukopenia, were
present and if the sepsis episode had been treated for 5 or more daysor until deathSuspected sepsis:
an episode with clinical and/or laboratory signs of infectionin the absence of a positive bacterial or fungal culture from a normallysterile site in an infant who received treatment with antibiotics for 5
or more days or until death

Definition of sepsis

Table 7 Characteristics of study categorised by culture positive vs clinical sepsis

1. Late-onset bacteremia was not associated with executive or motor
dysfunctions
2. Participants with bacteremia during the second
to fourth postnatal week of life were at increased risk for intellectual impairment (low IQ) at age 10 years
3. Children with either suspected or definite bacteremia were more likely
than their peers without bacteremia to be legally blind in both eyes. 4.
Children with definite bacteremia wereslightly more likely than other children to have a hearing impairment

1. Preterm infants with very low birthweight that had neonatal sepsis
are 2.5 times more likely to have altered neuromotor development at 12
months of corrected age, regardless of other risk factors

1. No difference in adverse outcome (death or severe NDI) between GNS
and NCS infants, and between NCS and uncomplicated group
2. Significantly adverse outcomes between GNS and UC group (OR 4.8(1.5–15.9))

1. Proven sepsis independently increased the risk of CP (OR: 3.23 [95% CI:
1.23– 8.48]; P = 0.017) and NDI (OR: 1.69 [95% CI: 0.96 –2.98]; P = 0.067)
2. Suspected sepsis was not associated with neurodevelopmental outcome(P > 0.05)

OutcomesOng et al. BMC Pediatrics(2024) 24:505
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Adams-Chapman, 2013 [30] 1317 (1037)

Culture positive

342 (54)

Ortgies, 2021 [45]Positive blood culture and antibiotic therapy for >  = 5 days

Culture-proven EOS was defined as a positive result of one or more bacterial or fungal blood cultures obtained from patients and antimicrobial
treatment for at least 5 days
Clinical EOS was defined using established laboratory parameters and persistent clinical presentation

Late-onset sepsis was defined as a positive blood culture after 72 hof life. If the blood culture did not turn positive but clinical signs implied
antibiotic treatment for 7 days, late-onset sepsis was considered probable but not proven. If in one of the episodes a causal microorganism
was found, the infant was classified as proven infection.

117 (85)

Zonnenberg, 2019 [39]Definition of sepsis

65,938 (3639) Criteria for sepsis: documented clinical symptoms, five or more daysof antibiotic use, and a positive laboratory screening test (positive microbial growth in the blood, urine, or CSF).
Suspected sepsis: clinical symptoms of sepsis and five or more daysof antibiotic use without a positive laboratory screening test, consistent
with other studies’ definition of suspected sepsis

Sample size

Savioli, 2018 [37]Authors, year of study

Table 7 (continued)

1. Candida infected had significantly higher odds of NDI comparedwith uninfected NRN registry infants with no history of suspected sepsis
or proven sepsis (OR (95% CI) = 1.83 (1.01,3.33, p = 0.047)
2. Survivors with systemic candidiasis had a similar risk of poor neurologic outcome as those infected with other pathogens, which suggeststhat the pathophysiologic pathways resulting in CNS injury in infected
preterm neonates may not be pathogen specific
3. Duration of positive cultures did not predict the risk for NDI

1. EOS among VLBW-infants significantly impaired the neurodevelopment
at 2 years corrected age
2. BSIDII examinations were carried out at a median of 24 months(Range 23 – 31 months) corrected age with no significant difference
between the study groups
3. MDI values were similar in both study groups, however PDI values weresignificantly lower in the EOS group- In particular, PDI values < 70 showed a significant association with infection while PDI values < 85 only showed a weak association
4. Occurrence of cerebral palsy was significantly higher in the EOS group

1. No significant differences were found in cognitive, motor, and behavioral
scores or lexiquotient comparing patients with versus no proven infection
at 2 years correct age

1. After adjustment for known developmental risk factors, sepsis and suspected sepsis were associated with increased risk for any developmental
delay, (1.48 (1.05–2.09) and 1.09 (1.01–1.18)), respectively, and multiple
developmental delay sub-types- Preterm infants with suspected sepsis: Significantly increased risks of communication and developmental delay- Preterm infants with known sepsis: Significantly increased risks of developmental delay- Term infants with suspected sepsis: Significantly increased risks of developmental, learning and pervasive developmental disorders (PDD) delay- Term infants with known sepsis: Significantly increased risks of communication, developmental, learning, motor and PDD delay
2. Suspected sepsis did not appear to confer as great a risk as known sepsis,
suspected sepsis was significantly associated with multiple categoriesof neurodevelopmental delay in unadjusted and adjusted models

OutcomesOng et al. BMC Pediatrics(2024) 24:505
Page 32 of 38

6565 (153)3940 (2387)

2098 (419)

13,372 (4731) LOS was defined as isolation of a bacterial or fungal pathogen from bloodobtained more than 72 h after birth and accompanied by treatment
for at least 5 days or death before completed treatment.

Mukhopadhyay, 2020 [42]Mukhopadhyay, 2021 [41]Shim, 2021 [46]Brumbaugh, 2022 [47]

1. Risk for NDI did not differ between late-onset sepsis (LOS) and late-onset,
antibiotic treated, blood culture-negative conditions (LOCNC)
2. Risk for NDI was higher for LOCNC infants compared with unaffected
infants (RR 1.17 (1.04–1.31))
3. Risk for NDI was not significantly higher for LOS compared with unaffected infants (might be due to smaller numbers of LOS)

1. Risk of NDI was higher for infants with early onset sepsis (EOS) comparedwith culture-negative infants who received prolonged early antibiotics
and compared with infants who did not receive prolonged early antibiotics
2. Among those without culture-confirmed EOS, the administrationof prolonged antibiotics was not associated with any significant differencein outcomes of death and/or NDI

1. At the six-month follow-up, there is a statistically significant difference(P = 0.001) in neurodevelopmental impairment (NDI) between the culturepositive infants and the controls
2. There is also a statistically significantly lower median developmental(P = 0.001), motor (P ≤ 0.001), and mental (P = 0.002) quotients in infants
with culture-positive sepsis compared to controls

1. VLBW infants with Gram-positive infection showed motor deficit
when compared to the non-septic group, 68.8% vs. 29.3%, respectively (OR 6; 1.6–21.8, p = 0.006); the cognitive development was similar
between the groups
2. However, no differences were observed in cognitive and motor scoresfor newborns who presented with late-onset sepsis by coagulase-negative
Staphylococcus (CNS)

Outcomes

1. NDI was present in 42% (95%CI, 32%-52%) of children with LOM
and in 43% (95%CI, 41%-45%) of children with LOS without LOM comparedwith only 33% (95%CI, 32%-34%) of children with neither infection (P < .001)
2. The incidences of cerebral palsy (24%; 95% CI, 3%-14%), abnormal visualacuity (24%; 95%CI, 15%-32%), and bilateral hearing impairment (8%; 95%CI,
3%-14%) were highest among infants with a history of LOM

1. LOS had a significant association with cognitive delay (adjusted
LOS was defined as a postnatally acquired infection which occurred
after the third postnatal day of life. Only sepsis confirmed by blood culture odds ratio, 1.48; 95% confidence interval, 1.02–2.16), but no association
was considered.
with motor delay in VLBWIs at 18–24 months of correct age

Late onset sepsis (LOS) defined as isolation of a pathogen from bloodor CSF obtained > 72 h of age and appropriate therapy for ≥ 5 days (≥ 7days for CSF growth) or death before completed treatment

EOS was defined as blood or cerebrospinal fluid (CSF) culture
obtained ≤ 72 h of age that grew pathogenic bacteria or fungi, for which
the infant received antibiotics ≥ 5 days or died with intent to receive
antibiotics ≥ 5 days.

Positive blood culture

160 (80)

Singh, 2018 [38]Late onset sepsis: presence of positive blood cultures over 72 h of life,
followed by clinical signs- changes in breathing pattern- hypothermia or hyperthermia- circulatory symptoms- GIT symptoms

Definition of sepsis

411 (94)

Sample size

Hentges, 2014 [35]Authors, year of study

Table 7 (continued)

Ong et al. BMC Pediatrics(2024) 24:505
Page 33 of 38

1343 (263)

203 (109)577 (159)

Humberg, 2022 [49]

Kartam, 2022 [50]Paul, 2022 [51]GBS-meningitis was diagnosed by GBS-positive cerebrospinal fluid (CSF)
culture in most cases (67¢4%), but five cases defined as meningitis had
suggestive CSF leucocyte count of > 20 £ 106/l plus GBS-positive blood
culture and nine had GBS-positive blood culture plus suggestive clinicalsymptoms of meningitis.

Neonatal sepsis was confirmed using a positive culture, which
was defined as any sample of blood or cerebrospinal fluid which tested
positive for bacterial growth. A blood culture was considered contaminated if the presence of gram-positive cocci in it was negated by anotherculture drawn 30-min apart.
Early onset sepsis (EOS) was described by a positive blood culture occurring ≤ 72 h after birth, and LOS as an infection contracted after this period.
A case of sepsis was considered severe if associated with hemodynamic
instability and disseminated intravascular coagulation (DIC)

Neonatal sepsis was confirmed using a positive culture, which
was defined as any sample of blood or cerebrospinal fluid which tested
positive for bacterial growth

Definition of sepsis

1. GBS disease is on average associated with a higher risk of moderate/
severe NDI (adjusted odds ratio: 1.27 (95% CI: 0.65, 2.45))
2. Mild impairment was also more frequent in GBS (27.6% (95% CI:
20.3 − 35.5%)) compared to non-GBS children (12.9% (95% CI: 9.7% -16.4%))
3. The risk of emotional-behavioural problems was similar irrespectiveof GBS exposure (aRR = 0.98 (95% CI: 0.55, 1.77))

1. The relationship between LOS and lower motor scores remained significant (adjusted β = –9.5, 95% CI: –16.4 to –2.7; p = 0.007), whereas the association with cognitive and language scores were no longer significant at 3
years of age after adjustment

1. Recurrent sepsis to be significantly associated with adverse motor development (critical MABC-2 testing: 3.3 [1.5–7.3], p = 0.003, pB = 0.012)
2. No significant impact of recurrent LOS was found on intelligence quotient and behavioral difficulties
3. Odds of having critical motor testing results for infants with recurrent LOS
were 1.7 times (95% confidence interval 1.4–2.3) that of infants with one
LOS
4. The study could not demonstrate that infants with single eventsor recurrent episodes of neonatal LOS had an higher likelihood for CP, intelligence, or behavioral difficulties when all cases were pooled and adjusted
for important neonatal risk factors

Outcomes

CI confidence interval, CP cerebral palsy, CSF cerebrospinal fluid, EOS early onset sepsis, GBS Group B streptococcus, GNB gram negative bacteremia, IQ intellectual quotient, LOS late onset sepsis, NDI neurodevelopmental
impairment, NCS neonatal candida sepsis, OR odds ratio, RR Relative risk, VLBW very low birth weight

Sample size

Authors, year of study

Table 7 (continued)

Ong et al. BMC Pediatrics(2024) 24:505
Page 34 of 38

Ong et al. BMC Pediatrics(2024) 24:505

Page 35 of 38

Table 8 Meta analysis related to neurocognitive outcomes among infants with sepsis
Parameter
MDI

Study

Subgroup by scale and cut-off

Ortgies, 2021 [45]

MDI < 70

0.45 [0.07; 2.84]-

MDI < 70

19.50 [0.59; 645.19]

25.56 [1.29; 506.04]

Schlapbach, 2011 [29]MDI < 70

1.47 [0.74; 2.92]

1.37 [0.63; 2.96]

Schlapbach, 2011 [29]MDI < 70

1.13 [0.57; 2.22]

0.70 [0.31; 1.58]

Subtotal

MDI < 70

1.26 [0.80; 2.00]

1.54 [0.42; 5.58]

Ferreira, 2014 [34]

MDI < 85

1.90 [1.05; 3.41]

1.05 [0.52; 2.12]

Hentges, 2014 [35]

MDI < 85

3.10 [0.54; 17.82]

3.90 [0.54; 28.32]

Hentges, 2014 [35]

MDI < 85

0.90 [0.29; 2.83]

0.90 [0.19; 4.26]

Hentges, 2014 [35]

MDI < 85

1.10 [0.18; 6.91]

0.30 [0.01; 7.79]

Ortgies, 2021 [45]

MDI < 85

0.77 [0.25; 2.35]-

Subtotal

MDI < 85

1.42 [0.87; 2.34]

1.11 [0.61; 2.02]

Shim, 2021 [46]

MDI < 80

2.21 [1.73; 2.82]

1.48 [1.02; 2.15]

1.57 [1.14; 2.16]

1.30 [0.99; 1.71]

PDI < 70

19.38 [0.58; 643.51]

14.62 [0.07; 3211.34]

Ortgies, 2021 [45]Ortgies, 2021 [45]

PDI < 70

6.55 [1.20; 35.71]

2.70 [0.19; 38.89]

Schlapbach, 2011 [29]

PDI < 70

2.10 [1.00; 4.39]

1.80 [0.82; 3.94]

Schlapbach, 2011 [29]

PDI < 70

1.71 [0.85; 3.42]

1.36 [0.62; 2.96]

Shim, 2021 [46]

PDI < 70

1.23 [0.75; 2.02]-

Subtotal

PDI < 70

1.74 [1.15; 2.63]

1.63 [0.95; 2.80]

Ferreira, 2014 [34]

PDI < 85

2.72 [1.27; 5.83]

1.99 [0.88; 4.51]

Ferreira, 2014 [34]

PDI < 85

2.99 [1.03; 8.70]

1.60 [0.48; 5.32]

Hentges, 2014 [35]

PDI < 85

4.81 [0.93; 24.90]

6.00 [0.93; 38.90]

Hentges, 2014 [35]

PDI < 85

0.40 [0.06; 2.83]

0.50 [0.05; 4.87]

Hentges, 2014 [35]

PDI < 85

1.60 [0.23; 11.36]

0.80 [0.04; 15.15]

Ortgies, 2021 [45]

PDI < 85

2.26 [0.71; 7.17]-

Subtotal

PDI < 85

2.43 [1.49; 3.94]

1.85 [1.01; 3.36]

1.98 [1.42; 2.74]

1.73 [1.16; 2.58]

MDI or PDI < 70

3.13 [0.16; 62.63]

-

Total
MDI or PDI

Visual impairment

Adjusted OR (95% CI)

Ortgies, 2021 [45]

Total
PDI

Unadjusted OR (95%CI)

de Haan, 2013 [31]de Haan, 2013 [31]MDI or PDI < 70

13.46 [1.83; 98.99]-

Subtotal

MDI or PDI < 70

8.60 [1.63; 45.26]-

de Haan, 2013 [31]MDI or PDI between 70 and 84

7.10 [1.55; 32.53]-

de Haan, 2013 [31]MDI or PDI between 70 and 84

2.01 [0.51; 8.03]-

Schlapbach, 2011 [29]MDI or PDI between 70 and 84

1.12 [0.63; 1.99]

0.96 [0.51; 1.82]

Schlapbach, 2011 [29]MDI or PDI between 70 and 84

1.05 [0.61; 1.82]

1.23 [0.67; 2.25]

Subtotal

MDI or PDI between 70 and 84

1.49 [0.81; 2.71]

1.09 [0.70; 1.70]

Mukhopadhyay, 2021 [41]MDI or PDI < 85

1.38 [1.06; 1.80]

1.12 [0.93; 1.35]

Mukhopadhyay, 2021 [41]MDI or PDI < 85

1.41 [1.15; 1.74]

1.15 [0.98; 1.35]

Subtotal

MDI or PDI < 85

1.40 [1.19; 1.65]

1.14 [1.01; 1.28]

Total

1.40 [1.20; 1.62]

1.13 [1.01; 1.28]

de Haan, 2013 [31]2.52 [0.43; 14.61]-

de Haan, 2013 [31]5.11 [1.43; 18.21]-

Mukhopadhyay, 2021 [41]2.41 [0.66; 8.76]

2.40 [0.66; 8.68]

Mukhopadhyay, 2021 [41]2.72 [0.94; 7.89]

2.70 [0.94; 7.76]

Brumbaugh, 2022 [47]4.11 [1.42; 11.89]-

Brumbaugh, 2022 [47]3.24 [2.15; 4.88]

-

Total

3.27 [2.35; 4.54]

2.57 [1.14; 5.82]

Ong et al. BMC Pediatrics(2024) 24:505

Page 36 of 38

Table 8 (continued)
Parameter

Study

Hearing impairment

de Haan, 2013 [31]

Cerebral palsy

Subgroup by scale and cut-off

Unadjusted OR (95%CI)

Adjusted OR (95% CI)

31.08 [1.93; 499.30]-

de Haan, 2013 [31]22.44 [1.59; 315.81]-

Mukhopadhyay, 2021 [41]1.85 [0.83; 4.13]

1.83 [0.83; 4.03]

Mukhopadhyay, 2021 [41]1.62 [0.83; 3.16]

1.61 [0.83; 3.11]

Brumbaugh, 2022 [47]3.28 [1.54; 6.99]-

Brumbaugh, 2022 [47]1.96 [1.48; 2.60]

-

Total

2.08 [1.65; 2.63]

1.70 [1.02; 2.81]

Mukhopadhyay, 2021 [41]1.59 [0.93; 2.71]-

Mukhopadhyay, 2021 [41]2.54 [1.70; 3.80]-

Ortgies, 2021 [45]6.52 [1.38; 30.81]-

Schlapbach, 2011 [29]2.90 [1.00; 8.37]

3.23 [0.99; 10.54]

Schlapbach, 2011 [29]2.55 [0.91; 7.14]

1.79 [0.48; 6.69]

Brumbaugh, 2022 [47]2.18 [1.20; 3.96]-

Brumbaugh, 2022 [47]1.72 [1.43; 2.07]

-

Total

2.02 [1.62; 2.52]

2.48 [1.03; 5.99]

Legend: MDI Mental Developmental Index, PDI Psychomotor Developmental Index
Foot note: Mild MDI or PDI: < 85 or < 80; Moderate MDI or PDI < 70; Severe MDI or PDI < 55

into adulthood. Most data were reported for preterm
infants with low birth weight, and there was a paucity ofdata for term infants in our literature review. Since prematurity itself is a significant cause of NDI [69], futurestudies should consider how gestational age and/or birthweight can be adequately adjusted for in the analysis.
Apart from the domains of NDI we chose to focus on inthis review, there are other cognitive domains classified
by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) [70] and/or recommended
by the Common Data Elements (CDE) workgroup [71].
Future studies may wish to look into the implications ofsepsis on other neuro-cognitive domains related to executive function, complex attention and societal cognition
which are studied for other types of acquired brain injury[71, 72].

Conclusion
Our systematic review and meta-analysis found thatneonates surviving sepsis are at a higher risk of poorer
neurodevelopment. However, the evidence is limited bysignificant heterogeneity and selection bias due to differing definitions used for NDI and for sepsis. There is alsoa lack of long-term follow-up data, as well as data specific for term and post-term infants. Future prospective
studies should be conducted with long-term follow-up
to assess the impact of neurodevelopmental impairment
among all populations of neonates with sepsis.

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12887-​024-​04977-8.
Supplementary Material 1.
Acknowledgements
We would like to thank Ms. Wong Suei Nee, senior librarian from the National
University of Singapore for helping us with the search strategy. We will also
like to thank Dr Ming Ying Gan, Dr Shu Ting Tammie Seethor, Dr Jen Heng Pek,
Dr Rachel Greenberg, Dr Christoph Hornik and Dr Bobby Tan, for their inputs in
the initial design of this study.
Conflict of interest
No financial or non-financial benefits have been received or will be received
from any party related directly or indirectly to the subject of this article.
Authors’ contribution
SLC and JHL were the study’s principal investigators and were responsible forthe conception and design of the study. WJO, JJBS, BY, GE, NAM and CLN werethe co-investigators. WJO, JJBS, BY, GE, NAM and CLN were responsible for thescreening and inclusion of articles and data extraction. All authors contributed
to the data analyses and interpretation of data. WJO, JJBS, BY, GE, NAM and
CLN prepared the initial draft of the manuscript. All authors revised the draft
critically for important intellectual content and agreed to the final submission.
All authors had access to all study data, revised the draft critically for important intellectual content and agreed to the final submission.
Funding
Nil.
Availability of data and materials
All data generated or analyzed in the study are found in the tables and supplementary materials.

Ong et al. BMC Pediatrics(2024) 24:505

Declarations
Ethics approval and consent to participate
As this was a systematic review with no access to patient data, ethicalapproval from the institutional review board was exempted.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 11 May 2024 Accepted: 26 July 2024

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