Disease burden of neonatal invasive Group B Streptococcus infection in the Netherlands
Disease burden of neonatal invasive Group B Streptococcus infection in the Netherlands
Brechje de GierID 0 1
Merel N. van KasselID 1
Elisabeth A. M. Sanders 0 1
Diederik van de Beek 1
Susan J. M. Hahn e? 0 1
Arie van der Ende 1
Merijn W. Bijlsma 1
0 Centre for Infectious Disease Control, National Institute for Public Health and the Environment, Bilthoven, the Netherlands, 2 Department of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centre , Amsterdam , The Netherlands , 3 Department of Medical Microbiology and the Netherlands Reference Laboratory for Bacterial Meningitis , Amsterdam UMC , University of Amsterdam , Amsterdam , the Netherlands
1 Editor: Umberto Simeoni, Centre Hospitalier Universitaire Vaudois , FRANCE
Group B Streptococcus (GBS) is the leading cause of neonatal sepsis and meningitis worldwide. We aimed to estimate the current burden of neonatal invasive GBS disease in the Netherlands, as a first step in providing an evidence base for policy makers on the potential benefits of a future maternal GBS vaccine.
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: The authors received no specific funding
for this work.
Competing interests: The authors have declared
that no competing interests exist.
Surveillance of neonatal invasive GBS occurs at the National Reference Laboratory for
Bacterial Meningitis, where culture isolates from cerebrospinal fluid and blood are sent by
diagnostic laboratories. From the number of cultures we estimated the incidence of neonatal
(age 0?90 days) GBS meningitis and sepsis. We constructed a disease progression model
informed by literature and expert consultation to estimate the disease burden of neonatal
invasive GBS infection. As many neonates with a probable GBS sepsis are never confirmed
by blood culture, we further estimated the disease burden of unconfirmed cases of probable
GBS sepsis in sensitivity analyses.
An estimated 97 cases and 6.5 deaths occurred in the Netherlands in 2017 due to culture
positive neonatal invasive GBS infection. This incidence comprised 15 cases of meningitis
and 42 cases of sepsis per 100.000 births, with an estimated mortality of 3.8 per 100.000
live births. A disease burden of 780 disability-adjusted life years (DALY) (95% CI 650?910)
or 460 DALY per 100.000 live births was attributed to neonatal invasive GBS infection. In
the sensitivity analysis including probable neonatal GBS sepsis the disease burden
increased to 71 cases and 550 DALY (95% CI 460?650) per 100.000 live births.
In conclusion, neonatal invasive GBS infection currently causes a substantial disease
burden in the Netherlands. However, important evidence gaps are yet to be filled. Furthermore,
cases of GBS sepsis lacking a positive blood culture may contribute considerably to this
burden potentially preventable by a future GBS vaccine.
Streptococcus agalactiae or group B Streptococcus (GBS) is the leading cause of neonatal sepsis
and meningitis. GBS is part of the microbiome of the intestinal and urogenital tract, with a
carriage rate of around 20% [
]. However, after perinatal acquisition of GBS, neonates may
present with signs of pneumonia, meningitis and/or sepsis. Invasive infections presenting within
the first 7 days of life are categorized as ?early-onset GBS?. Infections presenting after one
week, up to three months of age, are termed ?late-onset GBS?. Early onset disease results from
vertical transmission from the colonised mother, in late onset disease the pathogen may also
be transmitted by nosocomial or community sources [
Many industrialised countries, such as the United States, Canada and most of Europe, have
adopted a GBS prevention strategy based on universal screening of pregnant women for GBS
carriage, and providing intrapartum antibiotic prophylaxis when positive [
]. Other countries,
including the United Kingdom and the Netherlands, do not actively screen for GBS but offer
intrapartum antibiotic prophylaxis to certain risk groups, e.g. women with premature and
prolonged rupture of membranes, intrapartum fever, or when GBS is cultured from urine during
]. Antibiotic prophylaxis has important disadvantages: it exposes many women
and their children to antibiotics, while only a few of the neonates would have developed
invasive GBS disease . Unnecessary use of antibiotics increases risks for antimicrobial resistance
]. In addition, it can affect colonisation patterns of the neonate, which may in turn affect
immunological development and body composition [
]. Moreover, although intrapartum
antibiotics may prevent cases of early-onset GBS, it is not effective against late-onset disease
A maternal vaccine against invasive GBS could overcome these disadvantages, by reducing
the use of antibiotics, with likely little effect on the overall microbiome of mother and child
]. Moreover, maternally derived vaccine-induced antibodies can remain in the child for
several months, and might prevent both early and late-onset GBS disease. Several GBS vaccines
are in development, but not yet on the market [
]. To prepare for future introduction of
GBS vaccines during pregnancy, it is important to study the current burden of neonatal GBS
Recently, results were published of a comprehensive project estimating the global burden of
GBS disease. This project estimated over 300.000 neonatal and infant cases of GBS disease per
year worldwide, mostly occurring in low- and middle-income countries [
]. Building upon
this work, supplemented by national surveillance data and studies, we aimed to estimate the
burden in disability-adjusted life years (DALY) of neonatal invasive GBS infection in the
Netherlands in 2017 and trends over time in 2000?2017, to serve as a baseline for future vaccine
effect estimates and for prioritization of future vaccine introduction.
Incidence of neonatal invasive GBS infection was estimated using data from the Netherlands
Reference Laboratory for Bacterial Meningitis (NRLBM). The NRLBM receives isolates of
cerebrospinal fluid (CSF) culture-confirmed cases of bacterial meningitis in the Netherlands,
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and collects isolates from blood cultures of patients under 1 year of age. Yearly counts of GBS
isolates from patients age 0?90 days were obtained from the NRLBM register for 2000?2017.
Cases were classified as sepsis (GBS cultured from blood only) or meningitis (GBS cultured
from CSF only or from both CSF and blood). To estimate the coverage of this surveillance
system, we used data from a previous study on neonatal GBS disease in the Netherlands, which
compared the NRLBM data to a temporary enhanced surveillance system among all
paediatricians nationwide in the period 1997?2001 [
]. In this study, 96 cases of proven GBS
meningitis were reported by the paediatric surveillance system, and 86 were sent in to the NRLBM. As
the number of received E. coli isolates from neonatal blood or CSF cultures has not changed
considerably since that period, we assumed the NRLBM coverage has remained stable [
Therefore we used a multiplication factor of 1.12 (95% CI 1.06?1.22) to correct for the
underestimation of the NRLBM data. The total number of live births per year in the period 2000?
2017 was retrieved from the Statistics Netherlands open data website [
We followed the European Centre for Disease Prevention and Control (ECDC) Burden of
Communicable Disease in Europe (BCoDE) methodology, and constructed an
incidencebased disease progression model [
]. As a template, the BCoDE ?healthcare-associated
neonatal sepsis? model was used [
]. We simplified the ?outcome tree? by setting transition
parameters to zero for unused health outcomes. Fig 1 shows the outcome tree of our neonatal invasive
GBS disease model. Model structure and parameters were adjusted to the Dutch situation,
informed by published and unpublished literature and expert consultations. Two practicing
paediatricians with specific expertise on bacterial meningitis (authors MWB and EAMS) were
consulted on the available (un)published evidence and clinical reality of neonatal GBS disease
in the Netherlands. Imprecision of parameters (multiplication factors for underestimation and
disease progression probabilities) was taken into account by modelling them as distributions
rather than point estimates. We mainly used Beta distributions for the model parameters,
however for clarification we here present the 95% confidence intervals of those distributions (Beta
parameters are presented in S1 File).
Fig 1. Structure of the neonatal invasive group B Streptococcus disease burden model.
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Acute invasive infection. The duration of the acute phase was derived from Schroeder
et al, with 3.8 days in intensive care (ICU) and a further hospital stay of 14.7 days [
Case fatality. We applied case fatality rates from a recently performed retrospective
clinical study of all neonatal GBS cases reported to the NRLBM in a 22-year period. This
unpublished study by Van Kassel et al found a 3-week mortality rate of 8.3% for meningitis and 6.1%
for sepsis (personal communication, authors MNvK and MWB) (Table 2). These findings are
in line with the estimated European GBS mortality rate of 7% [
] and with the global case
fatality rate of 8.4% [
Long-term neurodevelopmental impairment. Within the global GBS burden project,
Kohli-Lynch et al performed a meta-analysis of neurodevelopmental impairment (NDI) after
neonatal GBS disease. Of the neonatal GBS meningitis survivors, 32% (95% CI 25%?38%)
showed NDI at 18 months of follow-up, including 18% (95% CI, 13%?22%) with moderate to
severe NDI. This study also included preliminary data from an unpublished study by Heath
et al, of GBS sepsis survivors. Of the neonatal GBS sepsis survivors, 5 out of 61 had any NDI
and 1 of them had moderate to severe NDI. In absence of published estimates, we based the
probability of NDI after both proven and probable GBS sepsis on these numbers from Heath
et al (Table 1).
For estimation of the years lived with disability (YLD), disability weights by Haagsma et al
were applied [
]. The standard GBD2010 life expectancy table was used to estimate years of
life lost (YLL) . The models were run for the year 2017 with 10,000 iterations in BCoDE
toolkit version 1.4, without discounting (except for sensitivity analysis, see below) [
Summation of DALY over the different models (GBS meningitis and sepsis) was done in R
statistical software by simulating random draws with the assumption of normal DALY distributions.
Model results were rounded to two significant digits to avoid false precision.
Model estimates of the YLD and YLL per case, estimated incidence per year from the
NRLBM surveillance data and numbers of live births per year were used to estimate the DALY
per 100.000 live births attributable to neonatal invasive GBS infection for the period 2000?
The number of isolates cultured from blood or CSF will be an underestimation of the total
incidence of neonatal invasive GBS, as not all GBS infections will be culture-confirmed. A
previous Dutch study found that including probable GBS sepsis, defined as a neonate with clinical
and laboratory signs of sepsis and with GBS isolated from various sites but not from blood or
CSF, would more than double the incidence of neonatal GBS sepsis [
]. Indeed, in many
cases of neonates with clinical and laboratory signs of sepsis, blood cultures remain negative.
0.644 (ICU admission)
0.125 (infectious disease episode, severe)
(motor + cognitive impairments, mild)
(motor + cognitive impairments, moderate?severe)
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14% (95% CI 12?18%)
18% (95% CI 13?22%)
8.3% (95% CI 5.6?11.5%)
6.6% (95% CI 2.7?15.9%)
1.6% (95% CI 0.4?8.6%)
6.1% (95% CI 4.4?8.1%)
Van Kassel et al unpublished
This can be due to several reasons; first, blood volumes from venepuncture in neonates may be
insufficient for a positive blood culture. Second, blood culture may lack sensitivity for GBS: in
a recent study, of 24 GBS PCR-positive blood samples only 13 had a positive blood culture
]. Furthermore, it is recognised that intrapartum antibiotic treatment may lead to negative
cultures despite invasive disease [
]. However, culture is still the golden standard for
diagnosis of invasive GBS infection, and PCR testing is not routinely performed nor are PCR
results systematically collected. For these reasons, incidence and disease burden estimates for
probable GBS sepsis (i.e. unconfirmed by blood culture but with clinical and laboratory signs
of sepsis and GBS cultured from normally non-sterile sites) were included as sensitivity
analysis. In the first sensitivity analysis, all probable GBS sepsis cases were assumed to be true cases
of GBS sepsis. The number of received blood cultures was multiplied by 2.19 (95% CI 2.04?
2.35); derived from 430 proven GBS sepsis cases of a total of 942 (proven + probable) GBS
sepsis cases in Trijbels-Smeulders et al 2007 . In the second sensitivity analysis, we assumed
that a proportion of the probable GBS sepsis cases are true cases of GBS sepsis. To estimate
this proportion, the case fatality rates of proven and probable GBS sepsis from
TrijbelsSmeulders et al were compared. Because the case fatality rate of probable GBS cases was 26%
(95% CI 12?51%) of the case fatality of the proven sepsis cases, we assumed 26% of probable
GBS sepsis cases to be true GBS sepsis cases. Lastly, a sensitivity analysis was conducted with
3% per year discounting of DALY, with incidence based only on proven sepsis and meningitis.
Incidence and disease burden, 2017
An overview of model results is presented in Table 3. The incidence of neonatal invasive GBS
infection in the Netherlands in 2017 was estimated at 57 per 100.000 live births, or 97 cases in
total in 2017. The estimated mortality of neonatal invasive GBS infection was 6.5 in total in
2017, with 1.2 deaths per 100.000 live births for GBS meningitis and 2.6 deaths per 100.000 live
births for GBS sepsis. A total of 780 DALY (95% CI 650?910) was attributed to neonatal
invasive GBS infection in the Netherlands in 2017; 550 years of life lost due to neonatal mortality
(YLL) and 230 years lived with disability (YLD).
Trends over time, 2000?2017
Fig 2 shows that the number of GBS isolates received by the NRLBM from children 90 days old
increased over time, particularly for blood cultures. Fig 3 shows the DALY per 100.000 live births
attributable to neonatal invasive GBS infection in the period 2000?2017. An increasing trend is
visible, which is mostly an increase in YLL as fewer YLD are attributed to sepsis cases (estimated
from blood cultures) than to meningitis (estimated from CSF or both CSF and blood cultures).
Fig 4 shows the total neonatal invasive GBS infection YLL and YLD per 100.000 live births
as function of the included proportion of neonatal sepsis cases without blood culture
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confirmation but with GBS isolated from normally nonsterile sites (probable GBS sepsis).
When all probable GBS sepsis cases are assumed to present true GBS sepsis cases, the disease
Fig 2. Number of GBS isolates from neonates (age 0?90 days) received by the NRLBM, by culture specimen type. CSF:
cerebrospinal fluid; GBS: group B Streptococcus; NRLBM: Netherlands Reference laboratory for Bacterial Meningitis.
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Fig 3. Estimated disease burden of neonatal invasive GBS infection per 100.000 live births in the Netherlands, 2000?2017, undiscounted.
YLL: years of life lost; YLD: years lived with disability; DALY: disability-adjusted life year.
burden increases to 1300 DALY for the Netherlands in 2017 (Table 3). When a proportion of
26% of the probable GBS sepsis cases is assumed to be attributable to GBS, the total neonatal
invasive GBS burden amounts to 940 DALY. When a 3% per year time discount rate is applied,
290 (95% CI 240?340) DALY are estimated for proven neonatal invasive GBS disease in the
Netherlands in 2017 (Table 3).
We present the first estimate of the disease burden of neonatal invasive GBS infection in the
Netherlands, at 780 DALY (95% CI 650?910) for the year 2017, or 460 DALY (95% CI 380?
540) per 100.000 live births. This estimate is based on an estimated incidence of neonatal
invasive GBS infection of 57 per 100.000 live births (95% CI 55?59), with an estimated mortality of
3.8 per 100.000 live births (95% CI 3.2?4.5). When a proportion (26%) of neonatal sepsis cases
unconfirmed by blood culture but with proven GBS colonisation is included in the estimate,
940 DALY (95% CI 770?1100) or 550 DALY (95% CI 460?650) per 100.000 live births are
attributable to neonatal invasive GBS infection. Surveillance data show an increasing trend of
neonatal invasive GBS infections, as reported before in the Netherlands and the UK [
The current risk factor-based GBS prevention strategy appears inadequate to halt the increase
of neonatal GBS sepsis.
Our results allow for comparison of the neonatal invasive GBS disease burden with other
potentially vaccine-preventable diseases in the Netherlands before introduction of a vaccine.
Van Lier et al recently estimated the burden in DALY of several diseases in the year before
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Fig 4. Estimated disease burden of neonatal invasive GBS infection per 100.000 live births in the Netherlands, 2017, per proportion of
probable GBS sepsis cases classified as true GBS sepsis. YLL: years of life lost; YLD: years lived with disability; DALY: disability-adjusted
life year; GBS: Group B Streptococcus.
introduction into the Dutch National Immunisation Programme (NIP), plus the 2017 disease
burden for several candidate NIP target diseases [
]. The neonatal invasive GBS disease
burden of 780 DALY is comparable to the 2017 population burden of meningococcal B (620
DALY, not included in NIP) and W disease (410 DALY, vaccine introduced in NIP in 2018),
and measles (560 DALY) before the vaccine was introduced in the NIP in 1976 (S1 Fig).
Our burden estimate was restricted to neonatal invasive GBS disease only. The recent global
GBS burden study included maternal disease and stillbirth [
]. We do not have national data
to estimate GBS disease burden in pregnancy or the puerperium, or its impact on pregnancy
outcome. Applying the incidence of maternal GBS sepsis in developed countries of 0.23 per
1000 live births, an estimated 39 cases of maternal GBS sepsis would have occurred in the
Netherlands in 2017 [
]. Further, neonatal GBS pneumonia likely causes an additional
substantial disease burden in the Netherlands. As cultures from sites other than blood and CSF
are not routinely collected by the NRLBM, we did not have data to include pneumonia, or rare
presentations such as soft tissue infections, in our estimates. A study from the UK, with a
comparable incidence and ratio of GBS sepsis to meningitis, reported a further 20% of neonatal
GBS disease presenting as pneumonia [
]. In addition, GBS can cause invasive disease in
non-pregnant adults, which adds on to the GBS burden in the Netherlands [
There are some important evidence gaps on the neonatal GBS disease burden. The risk
estimates of NDI after neonatal GBS disease are uncertain. NDI is a very heterogeneous outcome,
which can manifest as e.g. poor academic outcomes or severe visual or hearing impairment. In
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a cohort of Dutch childhood meningitis survivors, 39 / 93 (42%) had academic or behavioural
]. Although this cohort included only 2?3% GBS meningitis and the age at
infection was generally quite high (2?3 yo), these outcomes seem generally in line with the
32% estimated by Kohli-Lynch et al in the global GBS burden project [
]. However, the risk
of NDI after sepsis without meningitis is more uncertain. From Kohli-Lynch et al., reporting
preliminary results from Heath et al, we applied the 6.6% risk of mild NDI after GBS sepsis,
plus 1.6% moderate to severe NDI. However, Haller et al estimated the risk of a low mental
development index after neonatal sepsis in very low birth weight infants at 13%, cerebral palsy
at 8%, visual impairment at 9% and hearing impairment at 4% [
]. More data is needed to
quantify the risk of NDI attributable to neonatal GBS sepsis. Further, we applied the GBS
meningitis model with its high NDI risk to CSF culture-positive neonates only. However, in clinical
practice a lumbar puncture is not routinely performed in early onset disease. As a
consequence, we will have misclassified a number of early-onset meningitis patients as sepsis
patients or missed the infection altogether.
Our disease burden estimate focuses only on illness and outcomes for the child itself.
However, each case of neonatal GBS disease can be expected to pose a substantial burden on
families as well. Even when a case fully recovers, parents experience substantial stress and anxiety
during NICU admission of their newborn [
]. In the longer term, grief after the loss of a child
or worries about child development can also be expected to cause substantial distress.
In conclusion, neonatal invasive GBS infection poses a substantial disease burden in the
Netherlands. The neonatal GBS disease burden is likely to be underestimated when including
only cases with GBS cultured from normally sterile sites. More research is needed to quantify
risk of long-term sequelae after neonatal GBS sepsis. Especially with the prospect of a maternal
vaccine becoming available in the near future, a solid evidence base is needed to inform public
health policy on GBS prevention.
S1 Fig. Ranking of vaccine-preventable diseases by estimated disease burden (expressed in
DALYs) at population and individual level. Adapted from: Van Lier A, De Gier B,
McDonald SA, Mangen MJJ, Van Wijhe M, Sanders EAM, Kretzschmar ME, Van Vliet H, De Melker
HE. Disease burden of varicella versus other vaccine-preventable diseases before introduction
of vaccination into the National Immunisation Programme in the Netherlands.
Eurosurveillance. 2019; 24(18).
S1 File. Model parameters.
S2 File. Neonatal GBS sepsis model import file for BCoDE toolkit version 1.4.
S3 File. Neonatal GBS meningitis model import file for BCoDE toolkit version 1.4.
Conceptualization: Brechje de Gier, Elisabeth A. M. Sanders, Merijn W. Bijlsma.
Data curation: Merel N. van Kassel, Merijn W. Bijlsma.
Formal analysis: Brechje de Gier, Merel N. van Kassel.
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Methodology: Brechje de Gier.
Project administration: Diederik van de Beek, Susan J. M. Hahne?.
Resources: Arie van der Ende.
Supervision: Elisabeth A. M. Sanders, Diederik van de Beek, Susan J. M. Hahne?, Arie van der
Validation: Merijn W. Bijlsma.
Visualization: Brechje de Gier.
Writing ? original draft: Brechje de Gier, Merijn W. Bijlsma.
Writing ? review & editing: Brechje de Gier, Merel N. van Kassel, Elisabeth A. M. Sanders,
Diederik van de Beek, Susan J. M. Hahne?, Arie van der Ende, Merijn W. Bijlsma.
10 / 12
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