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DOI: 10.1111/1471-0528.

16085 Systematic review


www.bjog.org

Universal screening versus risk-based protocols


for antibiotic prophylaxis during childbirth to
prevent early-onset group B streptococcal
disease: a systematic review and meta-analysis
GF Hasperhoven,a S Al-Nasiry,b V Bekker,c E Villamor,d BWW Kramerd
a
Faculty of Health Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands b Department of Gyneacology and
Obstetrics, Maastricht University Medical Centre, Maastricht, the Netherlands c Department of Paediatrics, Leiden University Medical Centre,
Leiden, the Netherlands d Department of Paediatrics, Maastricht University Medical Centre, Maastricht, the Netherlands
Correspondence: Prof. Dr BWW Kramer, Department of Paediatrics, Maastricht University Medical Centre, P. Debyelaan 25, 6229 HX
Maastricht, the Netherlands. Email: b.kramer@mumc.nl

Accepted 2 January 2020. Published Online 4 February 2020.

Background Early-onset group B streptococcal (EOGBS) disease studies, RR 0.43, 95% CI 0.32–0.56) or with no policy (four
(including sepsis, meningitis, and pneumonia) causes significant studies, RR 0.31, 95% CI 0.11–0.84). Meta-analysis could not
morbidity and mortality in newborn infants worldwide. Antibiotic demonstrate a significant effect of risk-based protocols versus no
prophylaxis can prevent vertical streptococcal transmission, yet no policy (seven studies, RR 0.86, 95% CI 0.61–1.20). In studies
uniform criteria exist to identify eligible women for prophylaxis. reporting on the use of antibiotics, screening was not associated
Some guidelines recommend universal GBS screening to pregnant with higher antibiotic administration rates (31 versus 29%).
women in their third trimester (screening-based protocol),
Conclusions Screening-based protocols were associated with lower
whereas others employ risk-based protocols.
incidences of EOGBS disease compared with risk-based protocols,
Objectives To compare the effectiveness of screening-based versus while not clearly overexposing women to antibiotics. This
risk-based protocols in preventing EOGBS disease. information is of relevance for future policymaking.
Search strategy Key words for the database searches included Keywords Antibiotic prophylaxis, early-onset neonatal sepsis,
GBS, Streptococcus agalactiae, pregnancy, screening, culture-based, group B streptococcus, meta-analysis, newborn infant, risk-based,
risk-based. screening, sepsis, streptococcal infections, Streptococcus agalactiae,
Selection criteria Studies were included if they investigated systematic review, vertical transmission.
EOGBS disease incidence in newborn infants and compared Tweetable abstract Meta-analysis: general screening is associated
screening or risk-based protocols with each other or with controls. with lower rates of early-onset group B strep. neonatal sepsis
Data collection and analysis Risk ratios (RR) and 95% confidence compared with risk-based protocols.
intervals (CI) were determined using Mantel-Haenszel analyses Linked article This article is commented on by MA Turrentine,
with random effects. p. 692 in this issue. To view this mini commentary visit
Main results Seventeen eligible studies were included. In this https://doi.org/10.1111/1471-0528.16097. This article is also
meta-analysis, screening was associated with a reduced risk for commented on by KF Walker et al., p. 693 in this issue. To view this
EOGBS disease compared either with risk-based protocols (ten mini commentary visit https://doi.org/10.1111/1471-0528.16116.

Please cite this paper as: Hasperhoven GF, Al-Nasiry S, Bekker V, Villamor E, Kramer BWW. Universal screening versus risk-based protocols for antibiotic
prophylaxis during childbirth to prevent early-onset group B streptococcal disease: a systematic review and meta-analysis. BJOG 2020;127:680–691.

cases annually.1,2 Group B streptococcus (GBS) is a gram-


Introduction
positive commensal micro-organism of the human intestinal
Early-onset group B streptococcal (EOGBS) disease, includ- tract. Vaginal colonisation was estimated in a large meta-
ing sepsis, meningitis, and pneumonia, is a leading cause of analysis to occur transiently in 18% (95% confidence inter-
infant morbidity and mortality, even with a limited inci- val [CI] 17-19%) of pregnant women worldwide.3 The bac-
dence of 0.41 cases per 1000 live births (0.32 in Asia to 0.71 teria are transmitted vertically at delivery or earlier by
in Africa), and a corresponding estimated total of 205 000 ascending from the vagina into the uterus, or in some cases

680 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
Screening versus risk-based protocols to prevent EOGBS, a meta-analysis

by invading through the intact membranes.4 Intravenous policies: universal culture-based maternal GBS screening
antibiotics for at least 4 hours during labour was introduced and risk-based protocols. Studies with concurrent as well as
around 19805 as intrapartum antibiotic prophylaxis (IAP), with historical controls were considered.
and has successfully reduced vertical transmission.6
Women eligible for IAP are generally identified through Types of participants
two strategies: universal culture-based screening for GBS The participants were all pregnant women. Outcomes were
colonisation, or presence of clinical risk factors for GBS measured in all live newborn infants. No exclusion criteria
transmission.7–9 The Centers for Disease Control (CDC) were employed.
recommend universal screening for maternal colonisation
between 36 and 38 weeks of pregnancy.9 In contrast, guide- Types of interventions
lines in the UK, the Netherlands, and New Zealand recom- Screening-based protocols versus risk-based protocols used
mend risk-based protocols.7,10,11 These clinical indicators by clinicians to determine for each individual pregnant
include prolonged rupture of membranes, bacteriuria, an woman whether intrapartum prophylaxis is indicated. ‘No
earlier child with EOGBS, and maternal fever. The inci- policy’ was defined as a situation in which no consistent
dence of EOGBS disease has increased in both the Nether- protocol was used but IAP could have been administered
lands and the UK in recent years.12,13 on an individual basis. Therefore, all groups included the
Missed opportunities for EOGBS prevention exist in administration of IAP, defined as intravenous antibiotic
both protocols and lead to preventable infant morbidity, treatment intended to commence at least 4 hours before
while overtreatment, undesirable in the light of rising birth. All antibiotic agents (penicillin, clindamycin, etc.)
antibiotic resistance and potential effects on the micro- used in this way and for this purpose were accepted as
biome, occurs, too.14–17 Although technical developments IAP.
such as vaccines or polymerase chain reaction quick tests
are promising for EOGBS prevention, they have not been Types of outcome measures
widely implemented.18–20 The outcome measure was the incidence of EOGBS disease
Improving efficacy of IAP through either of the targeting in newborn infants as determined by positive bacterial cul-
protocols will help reduce the incidence of EOGBS disease, ture from blood or cerebrospinal fluid.24
and may reduce overtreatment. No international consensus
on the best protocol currently exists and a future strategy Information sources
is under debate.21 As no randomised studies on the topic Records were obtained through literature searches in MED-
have been carried out, policy-making remains a challenge. LINE (using PubMed), CINAHL, and Embase databases.
Additional publications were obtained manually by search-
Objectives ing reference lists and relevant reviews.
The objective of this systematic review and meta-analysis was
to determine the relative success of screening-based and risk- Search strategy
based protocols in preventing EOGBS disease in newborn An overview of the search terms and the syntax used in
infants. It is, to the best of our knowledge, the only meta- MEDLINE is presented in Tables S1 and S2. Articles in
analysis comparing available data on these two policies. English and Dutch with publication dates until 2019 were
included in the final search. Last queries were run in
March 2019.
Methods
Protocol and registration Study selection
The PRISMA statement for reporting systematic reviews was The study selection process was performed by a primary
used to conduct and report this systematic review.22 The investigator (G.H.) and critically reviewed by a second
protocol was made public in advance in the International (B.K.). Records obtained from the various databases were
Prospective Register of Systematic Reviews (PROSPERO entered in ENDNOTE X8 (Clarivate Analytics, Boston,
CRD42019127633).23 This study had no patient involvement MA, USA; 2018)25 to deduplicate automatically the dataset.
as the review is based completely on data from the literature. Remaining studies were identified by titles and abstracts
and were excluded if they did not fit the eligibility criteria.
Eligibility criteria Remaining records were assessed by full-text analysis, and a
final selection of relevant publications was constructed.
Types of studies Potential disagreements between reviewers were solved
Randomised or non-randomised studies, performed in any through discussion and re-evaluation. Reviewers were not
country, on the effect of either of the two GBS prevention blinded.

2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of 681
Royal College of Obstetricians and Gynaecologists
Hasperhoven et al.

Data collection process heterogeneity beyond chance.30,31 Heterogeneity was con-


Information from the studies was extracted to a pre-de- sidered high if the I2 was above 50%. We carried out publi-
fined data extraction form. Three authors of selected arti- cation bias analyses (visual inspection of the funnel plot
cles were contacted to obtain additional data.13,26,27 and Egger’s regression test) for meta-analyses including at
least 10 studies.32 The pooled number needed to screen
Data items and weighted IAP rates were calculated post hoc, using
The studies were indexed in the data extraction form to Microsoft EXCEL (Microsoft, Seattle, WA, USA). 33
obtain information on four different aspects: general infor-
mation on the article, data of the study population, inter-
Results
ventions, and information on the outcomes.
Study selection
Risk of bias in individual studies The selection process is presented visually in flow diagram
To determine the risk of bias per study, the Cochrane Risk Figure S1. The various database searches together provided
of Bias in Non-randomized Studies of Interventions 934 citations. Three additional titles were identified from
(ROBINS-I) tool was used, as this is the most up-to-date reference lists of relevant literature sources. Titles and
and elaborate risk of bias tool for non-randomised studies, abstracts were reviewed for 878 records, after automatically
evaluating also the bias in historical controls.28 In short, removing 59 articles. After exclusion of articles that did not
seven domains of bias divided in three different time- meet inclusion criteria (n = 845), 33 articles were reviewed
points in each study were scored: in detail. Sixteen articles were then excluded for reasons
pre-intervention—bias due to confounding; bias in selec- shown in Table S3. A total of 17 observational studies
tion of participants of the study; could be included in the systematic review. Data for the
at intervention—bias in classification of interventions; meta-analysis could be extracted from 14 studies12,34–46.
post-intervention—bias due to deviations from intended Additional data for the meta-analysis were kindly provided
interventions; due to missing data; in measurement of out- by the authors of one study.13 No randomised controlled
comes; in selection of the reported results. trials (RCTs) on this subject were found.
Each domain was scored Low Risk, Moderate Risk, Seri-
ous Risk, Critical Risk or No Information. To aid the Study characteristics
judgement on the domain of ‘bias due to confounding’, Eleven studies27,34,35,39–43,45–47 provided a direct comparison
common confounding factors were identified before risk of of screening-based versus risk-based protocols (analysis 1),
bias assessment was performed. of which three also studied incidences during ‘no policy’
periods.35,43,45 In analysis 2 (any policy versus no policy)
Summary measures the introduction of universal screening26,35,38,43,45 was inves-
To determine the effects of the interventions, risk ratios tigated in five studies and the introduction of risk-based
(RR) were calculated from the respective incidence rates in protocols in seven.12,13,35–37,43,45 (Tables 1 and 2).
the individual studies. Incidence rates were calculated for
the cases of EOGBS disease relative to the population of Types of methods
live births. They were expressed as cases per 1000 live All studies included in this review were performed accord-
births and were extracted from the studies or calculated ing to a non-randomised design. Most studies used national
using the data provided in the studies. If both incidence or regional microbiological data to identify cases of EOGBS
rates and absolute numbers were given, calculations were disease retrospectively. Some studies included an additional
reproduced to check for incongruences. exploration of the reported cases. One employed a prospec-
tive design in which medical professionals were asked to
Methods of analysis report suspected cases to the researchers36 in addition to
Studies were combined and analysed using THE COCHRANE confirmed cases. Some used a surveillance approach com-
COLLABORATION REVIEW MANAGER ( The Nordic bined with one period of closer observation of a sample.43
Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark).29 Participants
Due to anticipated heterogeneity, summary statistics In all studies combined, 3798 cases of EOGBS disease were
were calculated with a random-effect model. The Mantel- identified in a total population of 11 million live births.
Haenszel risk ratios with 95% confidence intervals (CI) Most studies aimed to include all pregnant women, but
were calculated from the data provided in the studies. Sta- one study34 actively excluded women with previous GBS-
tistical heterogeneity was assessed by the I2 statistic, which affected children. One study41 excluded preterm births to
describes the proportion of total variation that is due to prevent risk of confounding.

682 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists
Table 1. Study characteristics of analysis 1 (studies comparing screening-based protocols with risk-based protocols, using either historical or concurrent controls) and primary outcomes:
incidences of EOGBS disease under different policies

Authors study design Controls Country Setting/data EOGBS disease Screening-based: Risk-based: Antibiotic agent EOGBS disease incidence per 1000 live births
source definition criteria for IAP criteria for IAP [95% confidence interval]

No policy Risk policy Screening

Angstetra et al. Retrospective historical Australia One tertiary Blood culture ++ 34–37 weeks. NI benzylpenicillin IV n/a 0.84 [0.57– 0
(2007) cohort study obstetric unit and necessity for Culture = pos or 1.2 g- 600 mg/h 1.2]
admission to N(I) risk factor: previous OR clindamycin
CU with GBS, GBS IV 600 mg/8 h
ABs + ventilation bacteriuria, OR cephalothin
<7 days. preterm labour IV 2 g - 1 g/h

Royal College of Obstetricians and Gynaecologists


<37 weeks,
temp.>38°C,
prolonged ROM
>18 h (if GBS
status unknown) ->
IAP
Chen et al. (2005) Retrospective historical USA One tertiary care Positive blood 35–37 weeks, Preterm birth Ampicillin or 2.0 [1.5–2.6] 1.1 [0.80–1.5] 0.36 [0.24–
cohort study centre culture <7 days vaginal and rectal (threat), fever clindamycin; 0.55]
positive culture - (non-specified), later penicillin G
>IAP prolonged OR erythromycin
rupture of
membranes -
>IAP
Edwards et al. Retrospective historical US (Florida) One general Positive blood CDC guidelines of NI Ampicillin until n/a 1.7 [1.0–2.9] 1.0 [0.52 –1.9]
(2003) cohort study hospital culture <7 days 1996 1995, then
penicillin
Eisenberg et al. Retrospective concurrent US (Tennessee) All acute care Positive blood or CDC guidelines Risk group = not NI n/a 0.85 [0.58– 0.40 [0.21–
(2005) cohort study hospitals in four CSF culture (retrosp. selection: screened. 1.3] 0.74]
major counties <7 days found any GBS Preterm <37,
of Tennessee status in record, ROM> 18 h,
taken at least temp. >38C,
2 days before birth GBS bacteriuria,
-> screening group) previous GBS
Gilson et al. Retrospective Concurrent US (New One hospital Positive culture Women with known Rom> 18 h, temp. Ampicilin n/a 1.49 [0.56– 0
(2000) cohort study Mexico) from blood, CSF GBS + status, and >38 C, GBS 2 g + 2 g/6 h IV 4.0]
or other fluid. unknown status -> bacteriuria, before 1995;
risk factors previous GBS Penicillin G IV 5
(NB: preterm ml units + 2.5

2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
infants excluded) ml units/4 h
Gopal Rao et al. Retrospective historical London, UK One general Positive blood or Screening offered to previous GBS Benzylpenicillin n/a 1.1 [0.8–1.6] 0.33 [0.11–1.0]
(2017)* observational hospital CSF culture all women in the child; GBS 3 g IV – 1.5 g/h
study <7 days population. bacteriuria; OR clindamycin
According to CDC temp. > 38 C; 900 mg IV/8 h
(35–37 weeks). chorioamnionitis
Not screened ->
risk group
Screening versus risk-based protocols to prevent EOGBS, a meta-analysis

683
684
Table 1. (Continued)

Authors study design Controls Country Setting/data EOGBS disease Screening-based: Risk-based: Antibiotic agent EOGBS disease incidence per 1000 live births
source definition criteria for IAP criteria for IAP [95% confidence interval]
Hasperhoven et al.

No policy Risk policy Screening

Ma et al. (2018) Retrospective historical Hong Kong The eight Positive blood or 35–37 weeks GA, A previous NI n/a 1 (not 0.24 (not
cohort study hospitals of CSF culture later or at delivery with available) available)
Hong Kong <7 days admission. 2 EOGBS; GBS
separate swabs: bacteriuria; ROM
vagina and rectum. 18 h or more;
Non-screened -> GA <37 weeks;
risk-based. (women Intrapartum
with previous GBS fever
child excluded)
Main & Slagle Retrospective historical US (California) A primary practice + tertiary Positive blood or 35–37 weeks preterm <37, ROM> 18 h, Ampicilin
(2000) cohort & prosp. obstetric referral centre CSF culture vaginal and temp. >38 2 g + 1 g/4 h
Observational <7 days rectal culture C, GBS IV OR
study (+IAP for bacteriuria, clindamycin
preterm) previous GBS 900 mg/8 h
1.1 [0.58–2.3] 1.1 [0.68–1.9] 0.071
[0.010–
5.0)
Schrag et al. Retrospective concurrent USA Multiple hospitals Pos. blood Retrospective preterm <37, NI n/a 0.68 [0.59– 0.33 [0.27–
(2002) cohort study of the Emerging culture, CSF or selection: found rupture> 18 h, 0.77] 0.40]
Infections other ‘normally any GBS status in temp. >38C,
Program sterile fluid’. record, taken at GBS bacteriuria,
Network Days unclear. least 2 days before previous GBS
birth -> screening
group
Vergani et al. Retrospective Historical Italy One tertiary care Positive blood or <’97 Vaginal culture Preterm <37; Rom Ampiccilin 0.93 [0.47– 0.78 [0.39– 0.44 [0.20–
(2002) cohort study centre (university CSF culture between 26– >12 h; temp. 2 g + 1 g/4 h IV 1.9] 1.6] 0.97]
hospital) <7 days 28 week GA. >’97 >37.5C, GBS OR Erythromycin
between 35– bacteriuria; 500 mg/6 h
37 week GA previous child
GBS
Yu
€ cesoy et al. Prospective, quasi- concurrent Turkey One antenatal Positive blood Between 35– PPROM, Ampiccilin n/a 3.3 [1.0–10] 5.0 [0.71–35]
(2004) experimental clinic (in- and culture <72 h 37 weeks (note: prolonged ROM, 2 g + 1 g/4 h IV
out-patient) risk factor + neg. temp. >38C,
culture -> no IAP) preterm (but
individualised,
tocolytics etc.)

CSF, cerebrospinal fluid; EOGBS, Early-onset Group B streptococcal infection; IAP, intrapartum antibiotic prophylaxis; IV, intravenously; NI, no information; ROM, rupture of membranes.
*Pre-screening and post-screening periods are taken together (cross-over design).

2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists
Table 2. Study characteristics analysis 2 (introduction of any policy versus no policy) and primary outcomes: incidences of EOGBS disease under different policies

Author study design Controls country Setting/data source EOGBS disease Screening-based Risk-based criteria for Antibiotic EOGBS disease incidence (per 1000 live
definition criteria for IAP I IAP agent births)

No policy Risk policy Screening

Bekker et al Surveillance study Historical NL Netherlands Reference Positive blood or CSF n/a Previous GBS child or Penicillin/ 0.11 [0.10– 0.18 [0.16– n/a
(2014) (retrospective) Laboratory for culture <7 days bacteriuria -> IAP. amoxicillin 0.13] 0.20]
Bacterial Meningitis Confirmed GBS or
(all hospitals) threat preterm ->
consider IAP.

Royal College of Obstetricians and Gynaecologists


PROM + threat preterm
-> consider GBS test
Darlow et al. Prospective and Historical New New Zealand Clinical presentation + positive n/a Previous GBS
(2016) retrospective Zealand Paediatric Surveillance blood or CSF child,
surveillance Unit (all hospitals) culture + laboratory bacteriuria,
study indication of sepsis (CRP preterm,
or leucopenia etc.). temp.
Only cases <48 h are >38C,
reported. membrane
rupture> 18 h -> NI 0.5 [0.38 0.23 [0.16–0.33] n/a
IAP –0.65]
akansson
H Retrospective Historical Sweden National registers (all Positive blood or CSF n/a ROM> 18 h; NI 0.40 [0.34 – 0.30 [0.25 – n/a
et al. (2017) cohort study hospitals included) culture <7 days. temp.>38C; preterm 0.48] 0.36]
<37 week; GBS
bacteriuria; previous
infant with EOGBS
Hung et al Retrospective Historical Taiwan National Health <7 days, GBS disease CDC guidelines (35– n/a NI 1.0 (not n/a 0.2 (not
(2018) cohort study Insurance database is mentioned in 37 weeks) available) available)
(all hospitals) medical record
O’Sullivan Retrospective Historical UK Active surveillance (all <7 days, positive n/a Previous GBS child or Penicillin/ 0.48 [0.43– 0.57 [0.52– n/a
et al. (2019) cohort study paediatricians) and culture from blood or bacteriuria -> IAP. ampicillin 0.53] 0.62]
laboratory databases CSF or joint fluid Preterm <37, fever> 38,
(all) PPROM, prolonged
ROM> 18 h -> consider
IAP
Phares et al. Retrospective Historical USA All laboratories part of <7 days, positive CDC guidelines n/a NI 0.47 [0.44– n/a 0.34 [0.31–
(2008) cohort study the Emerging culture from blood or 0.51] 0.37]
Infections Program CSF

2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Network

CSF, cerebrospinal fluid; EOGBS, Early-onset Group B streptococcal disease; IAP, intrapartum antibiotic prophylaxis; IV, intravenously; NI, no information; ROM, rupture of membranes.
Screening versus risk-based protocols to prevent EOGBS, a meta-analysis

685
Hasperhoven et al.

Interventions impossible to define in one study (Figure S2, Tables S4


All studies used IAP to prevent GBS vertical transmission. and S5).
Despite discrepancies in risk factors across protocols, most Risk of bias during selection of participants was moder-
guidelines regarded an earlier child affected by GBS and ate in most studies, as problems arising from retrospective
GBS bacteriuria as a direct indication for IAP. Screening- selection etc. were mostly controlled for. In one study,44
based protocols generally followed the 2010 CDC guideli- women were included in the screening group if their
nes, consisting of a bacterial culture of a recto-vaginal swab screening results were available at least 2 days before deliv-
taken between a gestational age of 35 and 37 weeks. When ery. When authors controlled for availability of prenatal
maternal GBS status was unknown at labour, a risk-based care, preterm birth etc. results remained mostly
protocol was used: in the case of preterm delivery unchanged.40,44 Risk of confounding and risk of bias at
(<37 weeks GA), rupture of membranes >18 hours or intervention, e.g. bias due to classification of interventions,
maternal fever (>38°C), IAP was offered anyway. In risk- were moderate in most studies. Bias post-intervention was
based protocols these factors were used to determine the low or moderate in most studies. All studies with historical
indication for IAP. Different antibiotics were given across controls,12,13,26,27,34–39,42,43,45 except one using a cross-over
studies, although most studies used penicillin and ampi- design,42 suffered from bias due to healthcare improvement
cillin. Alternatively, erythromycin or clindamycin was given over time: ‘performance bias’. All studies had possible
to women allergic to penicillin. problems due to missing data, resulting from underre-
ported cases. In most studies this bias implied an actual
Outcomes greater effect of interventions.13
In 14 of the 17 studies, the incidence of EOGBS disease in
newborn infants was the primary outcome. Two studies Results of studies
had a primary focus on bacterial resistance35,39 but Incidence rates of EOGBS disease ranged from 0.0 to 5.0
included EOGBS disease as a secondary outcome. One per 1000 live births, with a weighted average of 0.33/1000.
study analysed incidences in different age groups and pop- The incidences are depicted in Tables 1 and 2.
ulations.38 EOGBS disease was defined by most studies as Risk ratios were calculated from available data in 15
the presence of GBS in a blood or cerebrospinal fluid cul- studies. In two studies26,27 the data could not be included
ture and thus included both sepsis and meningitis. Two in the meta-analysis as absolute numbers of cases and pop-
studies37,41 investigated incidences of ‘clinical sepsis’, too, ulations could not be extracted from the record and its ref-
but those were not included as cases in our review. Second- erence list, nor were these provided upon request. Effects
ary outcomes in the studies included mortality 12,36,38,45,46 of interventions expressed as risk ratios are presented in
or an audit of adherence to policy 27,43,45 the forest plots in Figures 1–3.
The prevalence of GBS colonisation in all pregnant
Risk of bias within studies women in the various studies ranged between 7 and 29%
Overall risk of bias was moderate in ten studies; moderate (weighted mean 23%, Table S7). The pooled number
to serious in two; serious in three, critical in one, and needed to screen (using a pooled baseline incidence in the

Figure 1. Forest plot of risk ratio (with 95% confidence intervals) of EOGBS disease (defined as positive GBS culture from a normally sterile site
<7 days of age) in universal screening policy groups versus risk-based policy groups. CI, confidence interval; M-H, Mantel-Haenszel.

686 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists
Screening versus risk-based protocols to prevent EOGBS, a meta-analysis

Figure 2. Forest plot of risk ratio (with 95% confidence intervals) of EOGBS disease (defined as positive GBS culture from a normally sterile site
<7 days of age) in universal screening policy groups versus no policy groups. CI, confidence interval; M-H, Mantel-Haenszel.

Figure 3. Forest plot of risk ratio (with 95% confidence intervals) of EOGBS disease (defined as positive GBS culture from a normally sterile site
<7 days of age) in risk-based policy groups versus no policy groups. CI, confidence interval; M-H, Mantel-Haenszel.

risk-based group of 0.94/1000 infants) for screening versus could not demonstrate a significant effect of risk-based
risk-based protocols was 1874 (Table S6). The percentage protocols versus no policy (seven studies, RR 0.86, 95% CI
of births during which IAP was administered was reported 0.61–1.20; heterogeneity: I2 = 89%) (Figure 3). The funnel
in four studies. Weighted means were 31 and 29% in the plot for analysis 1 (universal screening versus risk-based
screening and risk-based groups, respectively (Table S7). protocols) showed slight asymmetry (Figure S3), suggesting
None of the studies reported GBS resistance to penicillin a low risk of publication bias. Egger’s regression test did
or ampicillin, whereas resistance to erythromycin and clin- not show statistically significant asymmetry of the funnel
damycin was reported by three studies (Table S7).12,35,38 plot (2-tailed P = 0.180). Publication bias was not investi-
Lastly, mothers of infants with EOGBS sepsis did not pre- gated for the other two analyses due to the low number of
sent any risk factors in times of risk-based protocols in studies.
41.3% of cases (weighted mean, Table S8). False negatives
(EOBGS children born to women with negative screening
Discussion
results) were present in 24.2% of cases during periods of
screening protocols (weighted mean, Table S8). Main findings
This systematic review summarised the available observa-
Synthesis of results tional data on the two most common EOGBS prevention
Meta-analysis showed that universal screening was associ- policies. Overall, our meta-analysis shows lower incidences
ated with a reduced risk of EOGBS disease when compared of EOGBS disease under screening-based policies than under
either with risk-based protocols (10 studies, RR 0.43, 95% risk-based policies. Additionally, the retrospective data show
CI 0.32–0.56; heterogeneity: I2 = 13%) (Figure 1) or with no significant EOGBS reductions resulting from the initial
no policy (four studies, RR 0.31 95% CI 0.11–0.84; hetero- introduction of risk-based policies, whereas studies on the
geneity: I2 = 91%) (Figure 2). In contrast, meta-analysis introduction of universal screening do. Notably, two studies

2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of 687
Royal College of Obstetricians and Gynaecologists
Hasperhoven et al.

found higher incidences in ‘no policy’ groups compared with Interpretation


risk-based policies.12,13 The reported data on the use of A previously performed systematic review48 was limited to
antibiotics suggest similar rates of IAP under both policies. a smaller dataset, with the latest included study published
in 2005,40 and did not include data on the effect of the
Strengths and limitations policies compared with ‘no policy’. Our systematic review
The present meta-analysis offers an up-to-date, interna- includes a meta-analysis and presents data on eight addi-
tional perspective on EOGBS infection prevention. Seven- tional studies (up to 2019), while also using the most up-
teen studies from ten different countries were included. By to-date risk of bias assessment tool.28 Results were, how-
including studies in which either of two policies was intro- ever, similar. They further concur with a cost-effectiveness
duced after a ‘no policy’ situation, their respective effects Dutch study49 that suggested screening could protect most
could be assessed, too. infants from EOGBS infection and mortality in a hypothet-
Our study has several limitations. The limitations range ical cohort. The current Dutch guideline was estimated to
from lowered blood culture sensitivity in neonatal settings be poorest at preventing EOGBS in that model.49
per se21 to the different healthcare systems in which the In this analysis, clinical risk factors were poorly associ-
studies were conducted. Most importantly, as meta-analyses ated with vertical GBS transmission. The included studies
are dependent on the available data, the lack of randomised reported a significant number of missed cases (Table S8).
trials represents an important limitation. In studies with Up to 40% of the cases of EOGBS invasive infection did
consecutive intervention groups, there was a risk of perfor- not have maternal risk factors associated with them, and
mance bias, as the observed effect could have been inherent could therefore not be prevented under risk-based policies.
to secular improvement of healthcare. However, reporting Hakansson et al.37 further refuted the assumption that
of cases could have improved over time, leading to a GBS-infected infants born to mothers without risk factors
potentially even greater actual effect of screening.13,27 In had a better prognosis, as three of 11 deaths reported in
one study42 a period of screening was preceded and fol- their study occurred in such circumstances.
lowed by a period of risk-based management. Incidences of Homer et al.50 concluded in a review of EOGBS disease
EOGBS disease increased to initial high levels when risk- prevention guidelines that both risk-based and screening-
based policy was re-introduced. based guidelines were appropriate, but adherence to policy
Another limitation lies in the variation of policies that should be optimised to accomplish reduction of EOGBS
were employed by countries and states, although the 2010 disease. In this review, available data on adherence showed
CDC guidelines were the main screening policy. Risk fac- risk-based protocols were associated with lower adherence
tors such as fever or rupture of membranes >18 hours dif- compared with screening, which could have been a source
fered and were hard to identify, both during partum and of bias. Schrag et al.44 constructed a model with assump-
in a research setting, which is a drawback of this specific tions of perfect adherence in which screening outperformed
policy. Statistical heterogeneity in the direct comparison the risk-based protocols, suggesting the presence of an
was found to be limited. inherent advantage of screening protocols possibly owing
The incidence of EOGBS is generally low, and differ per to their limited complexity.
country. Still, on average the numbers correlate well with Importantly, concerns have been raised recently by See-
data reported elsewhere,3 and by comparing the changes in dat et al.21 that universal screening may lead to overtreat-
incidences, we could nonetheless analyse the independent ment with the consequent increase in adverse effects and
impacts of the two policies. resistance to antibiotics. Our findings do not support the
In this review, we included studies in English and Dutch concern that universal screening results in antibiotic
from three large online databases (MEDLINE, CINAHL, overtreatment. We found the same percentage of women
and Embase). Data from potentially relevant studies in receiving IAP in both protocols (Table S7). However, the
other databases or languages could have been missed, evidence we found is derived from observational data in an
despite additional manual searching of the literature. inherently heterogeneous set of studies with possible bias.
Of note, almost all studies controlled for possible con- Although the estimation of possible harm by antibiotic
founders, and studies with the highest impact on the meta- overtreatment by Seedat et al. is relevant, the conclusions
analysis12,13,38,44 suffered least from risk of bias. We did need to be verified by clinical data.21 We have to resign
not find evidence of publication bias. A last limitation of ourselves to the fact that an overtreatment may occur with
the reviewing process emerged, as risk of bias assessment both strategies. In this meta-analysis, the overall exposure
was performed successively by two non-blinded reviewers. to antibiotics does not appear to differ greatly between the
Standardised scoring of studies, however, increased the two protocols, whereas the rates of EOGBS disease do.
validity of the assessment. Lastly, GBS susceptibility to penicillin and ampicillin seems

688 2020 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of
Royal College of Obstetricians and Gynaecologists
Screening versus risk-based protocols to prevent EOGBS, a meta-analysis

unhindered in all studies in this review, even though some contributed to the statistical analyses and interpretation of
GBS strains with increasing minimum inhibitory concen- the results, and reviewed and revised the manuscript.
trations (MICs) for beta-lactam antibiotics have been
observed elsewhere.51 Funding
A point of concern in both strategies is how to approach The authors did not receive funding or other support for
GBS prevention in preterm deliveries. It was beyond the scope this publication.
of this article to compare subgroups of term and preterm
infants, mostly because the available studies generally did not
Supporting Information
provide data necessary to make a subdivision. As the recom-
mended timing for screening was between 35 and 37, and Additional supporting information may be found online in
now lies between 36 to 38 weeks of gestational age (GA), the Supporting Information section at the end of the
infants born at 35 weeks GA or less are not covered.9,52 Nota- article.
bly, these infants are at much higher risk of EOGBS disease as Figure S1. PRISMA6 flow diagram: a visual representa-
well as GBS-related mortality.53 For this reason, the CDC has tion of the systematic research process.
suggested that most preterm deliveries be accompanied by Figure S2. Visual representation of risk of bias assess-
IAP. However, more research towards best IAP management ment done using the risk of bias tool ‘ROBINS-I’ by
for women delivering preterm is needed, as long-term expo- Cochrane. + low risk of bias; +– moderate risk; – serious
sure to antibiotics poses a risk for preterm infants.54 Ideally, risk, – – critical risk, ? no information
immunisation of mothers should be introduced to prevent Figure S3. Funnel plot for meta-analysis of studies com-
EOGBS invasive infections, but although research in this field paring universal screening versus risk-based protocols.
has been going on for years, no effective GBS vaccine has been Egger’s regression test did not show statistically significant
made available so far.18 Until that time, it is recommended asymmetry of the funnel plot (2-tailed P = 0.180).
that the GBS prevention protocols are periodically re-evalu- Table S1. Search protocol, MeSH = Medical Subject
ated, and research aimed at accurate and fast detection meth- Headings
ods for all pregnant women is continued. Table S2. Search strategy used to identify records in
MEDLINE (final search March 2019). Similar queries were
run in CINAHL and Embase
Conclusion
Table S3. Articles excluded from analysis in the last step
In this systematic review and meta-analysis screening pro- of the reviewing process
tocols were associated with lower rates of EOGBS disease Table S4. Risk of bias assessment according to ROBINS-
compared with risk-based protocols. While there is insuffi- I, in studies comparing screening-based protocols and risk-
cient evidence to assume that risk-based policies reduce the based protocols (analysis 1). RoB, risk of bias; PB, perfor-
use of prophylactic intrapartum antibiotics, these protocols mance bias
might not be able to protect infants from EOGBS disease Table S5. Risk of bias assessment: studies assessing intro-
to the same extent as general screening does. These findings duction of either of the two protocols compared with a
can be of help to future policy-making and individual period/area of ‘no policy’ (analysis 2)
pregnancy counselling.55 Table S6. Numbers needed to screen (NNS) as calculated
from the data in the included studies
Disclosure of interests Table S7. Secondary outcomes with weighted means
VB was a co-author of one of the included studies in this Table S8. Missed cases in the included studies &
analysis. Other authors declare no competing interests.
Completed disclosure of interests forms are available to
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Royal College of Obstetricians and Gynaecologists

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