British Journal of Anaesthesia, 125 (4): 560e579 (2020)

doi: 10.1016/j.bja.2020.05.060
Advance Access Publication Date: 21 July 2020
Review Article

OBSTETRIC ANAESTHESIA

Comparative analgesic efficacy and safety of intermittent local

anaesthetic epidural bolus for labour: a systematic review and
meta-analysis
Nasir Hussain1, Christopher M. Lagnese1, Blair Hayes1, Nicolas Kumar1, Tristan E. Weaver1,
Michael K. Essandoh1, Joseph Reno1, Robert H. Small1 and Faraj W. Abdallah2,3,4,5,*
1
Department of Anesthesiology, Ohio State University, Wexner Medical Center, Columbus, OH, USA, 2Department of
Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada, 3The Ottawa Hospital Research Institute,
University of Ottawa, Ottawa, ON, Canada, 4The Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of
Toronto, Toronto, ON, Canada and 5Department of Anesthesiology and Pain Medicine, North York General Hospital,
University of Toronto, ON, Canada

*Corresponding author. E-mail: FAbdallah@toh.ca

Abstract
Background: Continuous epidural infusion (CEI) is commonly used for labour analgesia, but concerns over potential
motor block, second-stage labour complications, and ineffective analgesia in late labour have prompted examining
intermittent epidural bolus (IEB) as an alternative. However, evidence comparing these modalities is conflicting. The
meta-analysis evaluates the analgesic efficacy of CEI vs IEB.
Methods: Databases were searched for trials comparing CEI to IEB for labour analgesia. The two co-primary outcomes
were risk of breakthrough pain and difference in area under the curve (AUC) for pain scores during the first 4 h post-
epidural initiation. Local anaesthetic consumption, maternal outcomes (i.e. delivery mode, labour duration, and
maternal satisfaction), and side-effects of epidural analgesia were also evaluated. Results were pooled using random-
effects modelling. Trial sequential analysis (TSA) was used to evaluate evidence reliability.
Results: Twenty-seven studies (3133 patients) were analysed. Compared with CEI, IEB decreased risk of breakthrough
pain by 38% (risk ratio [95% confidence interval {CI}] of 0.62 [0.48, 0.81]; P¼0.0004; I2¼47%; 1164 patients) and reduced AUC
of pain during the 4 h interval by 32.9% (mean difference [95% CI] of e16.7 mm h1 [e18.9, e14.4]; P<0.0001; 1638 patients).
Intermittent epidural bolus enhanced maternal satisfaction, shortened labour duration, decreased motor block, and
reduced local anaesthetic consumption. The difference between the two groups was not statistically significant for
epidural side-effects or mode of delivery. The TSA indicated adequate power for reliable inferences.
Conclusions: Intermittent epidural bolus provides improved labour pain control during the first 4 h after epidural
initiation with less breakthrough pain. Moderate- to high-quality evidence of intermittent epidural bolus superiority
support its use as a safe and effective continuous epidural infusion alternative for labour analgesia.

Keywords: analgesia; breakthrough pain; epidural; labour analgesia; pain

Received: 26 January 2020; Accepted: 8 May 2020

© 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.
For Permissions, please email: permissions@elsevier.com

560

Editor’s key points
 The authors performed a meta-analysis of 27 studies
(3133 patients), examining the pain control provided by
intermittent epidural bolus and continuous epidural
infusion.
 The data suggest that intermittent epidural bolus pro-
vides superior pain control during the first 4 h of
epidural placement during labour and reduces the risk
of developing breakthrough pain.
 Intermittent epidural bolus also appears to reduce the
risk of motor weakness, but no difference was found
with other side-effects such as hypotension, nausea,
and pruritus.
Epidural analgesia has been shown to be the most effective
form of pain relief during labour.1 Nevertheless, the ideal
method of delivery remains under study.2 The traditional
mode of epidural delivery has been a continuous epidural
infusion (CEI), which delivers a constant rate of local anaes-
thetic throughout the duration of labour.3 The analgesic effi-
cacy of CEI is well established.3,4 However, the sustained
delivery of local anaesthetic places mothers at risk of motor
block and weakened pelvic muscle tone that may complicate
the second stage of labour.5,6 Further, delays in delivery in-
crease risks of shoulder dystocia and may necessitate instru-
mental delivery.7
The intermittent epidural bolus (IEB) technique, first
described by Wong and colleagues6 in 2006, has become
increasingly popular for labour analgesia. This method de-
livers a defined volume of local anaesthetic into the epidural
space at programmed intervals rather than a continuous
flow.6 As boluses are applied at a higher pressure, the local
anaesthetic can be more widely distributed.8 It is hypothesised
that local anaesthetic, when given by the IEB method, often
results in a lower cumulative dose, less motor block, and
improved pain control compared with CEI.9 However, the
transition to IEB would necessitate the implementation of
more sophisticated epidural pumps9 or the delegation of pro-
viders to manually infuse scheduled boluses, either of which
would incur greater institutional costs. Further, current evi-
dence has major limitations that prevent definitive recom-
mendations regarding the use of IEB for labour analgesia. First,
many small RCTs have yielded conflicting results, some of
which reported improved analgesia with IEB,10e12 whereas
others suggest no difference.13e16 Second, prior systematic
reviews (i) draw on limited evidence to suggest that the ben-
efits of IEB are modest, at best, when compared with CEI9,17,18;
(ii) have limited statistical pooling and imprecise estimates of
effect17; and (iii) are now largely outdated9,17,18 as there have
been many new RCTs2,6,8,10e16,19e35 published on the topic.
Finally, no review has yet to establish the extent to which IEB
affects clinically relevant parameters, such as pain control, in
labouring patients.9,17,18
The aim of this systematic review and meta-analysis was to
provide a comprehensive update to evidence comparing CEI
and IEB for labour analgesia.9,17,18 Based on the results of prior
evidence,9,17 we decided a priori that IEB is an effective anal-
gesic alternative to CEI if it (i) provided improved acute pain
control and (ii) reduced the incidence of breakthrough pain.
Thus, the primary objective of this review was to compare the
analgesic efficacy, as measured by pain severity and the
IEB vs CEI for labour analgesia - 561
incidence of breakthrough pain, of IEB vs CEI in labouring pa-
tients. As secondary outcomes, we aimed to compare addi-
tional maternal analgesic, maternal satisfaction, and safety
outcomes.
Methods
This article was prepared in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
guidelines.36 Randomised controlled trials that compared the
effects of IEB to CEI on labour analgesic and safety outcomes in
nulliparous or parous obstetric patients were sought. Studies
were evaluated using a predesigned protocol. The review
protocol was registered with the International Prospective
Register of Systematic Reviews under the number
CRD42019140388.
Eligibility criteria
All randomised or quasi-randomised studies that allocated
nulliparous and parous obstetric patients undergoing delivery
to receive either IEB or CEI for maintenance of labour analgesia
were considered for inclusion. We only included labouring
patients who had lumbar epidural catheters placed for
induced or spontaneous labour analgesia. We included both
manual and computerised pump-delivered IEB regimens,
provided that the manually delivered IEB had a consistent,
predefined delivery time (i.e. every 60 min). In addition, all
variations of intermittent bolus regimens were included (i.e.
bolus every 30 or 60 min). Studies were also included regard-
less of whether obstetric patients were provided combined
spinal and epidural (CSE) analgesia, a dural puncture epidural
(DPE), or an additional patient-controlled epidural analgesia
(PCEA) component. Studies were excluded if patients were
provided a combined low-dose continuous infusion in addi-
tion to IEB analgesia for labour. Trials of volunteers, those in
non-obstetric patients, and those not reporting analgesic
outcomes were excluded. No language restrictions were
placed on study inclusion; any non-English studies were
translated using an online translator.
Search methods
A systematic search strategy was created for the US National
Library of Medicine database (MEDLINE), the MEDLINE In-
Process and Other Non-Indexed Citations database, the
ExcerptaMedica database (EMBASE), and the Cochrane Data-
base of Systematic Reviews from inception to June 1, 2019. The
search strategy was created using Medical Subject Headings
and keywords relating to intermittent epidural, bolus epidural,
continuous epidural, analgesia, pain control, and labour. The
full search strategy for the MEDLINE database can be viewed in
Supplementary File 1. All subsequent search strategies were
based on the initial MEDLINE search strategy. The citations
and bibliographies of included articles and prior reviews were
hand searched to identify additional potentially relevant trials.
The proceedings of the following international conferences
also had their published abstracts electronically searched:
ASA 2011e8 and Society for Obstetric Anesthesia and Perina-
tology 2009e19. The clinical trial registry, ClinicalTrials.gov,37
was also searched for potentially relevant completed or
ongoing trials.
 562 - Hussain et al.
Selection of included studies
Two independent reviewers (CL and NK) initially assessed the
generated results from the literature search based on title and
abstract alone. After this, the full-text citations of potentially
eligible articles were subsequently retrieved and reviewed
independently by the same reviewers for inclusion. In the case
of disagreement between the two independent reviewers on
inclusion of a full-text citation, a discussion was initiated.
However, if a consensus could not be reached after the dis-
cussion, a third reviewer (NH) assessed the study in question
and made the final decision. The initial agreement between
the two independent reviewers on full-text citation inclusion
was assessed using an unweighted kappa (k).
Data extraction
A standardised data extraction form was created and piloted
before review initiation by an independent reviewer (NH). Af-
ter this, data extraction was carried out in duplicate by two
independent reviewers (NH and NK). In the case of discrep-
ancy in data extraction, a discussion was initiated. However, if
a consensus could not be reached after discussion, a third
reviewer (ME) assessed the data point in question and made
the final decision. The primary source of all data was numer-
ical data reported in figures/tables. A graph digitising software
(GraphClick; Arizona Software, Phoenix, AZ, USA) was used to
extract data from studies that reported data exclusively in
graphical form.
Extracted data included information regarding the year of
publication, the number of patients, parity of patients,
average age of patients, primary outcome investigated,
intervention and comparator groups, presence of neuraxial
anaesthesia at initiation of epidural, epidural analgesia
technique, and PCEA component regimen. Data with all
measures of variance at all reported follow-up times were
also extracted for pain scores at baseline and after placement
of epidural, incidence of breakthrough pain or need for
additional anaesthetic intervention, local anaesthetic con-
sumption (ml h1), degree of motor block, degree of sensory
blockade, duration of analgesia (i.e. time to first sensation of
pain or time to first supplemental analgesia request), labour
progression/duration of labour (min), time in Stage 1 of labour
(min), time in Stage 2 of labour (min), mode of delivery (i.e.
spontaneous vaginal, instrumental assisted, and Caesarean
delivery), level of maternal satisfaction with epidural regimen
technique, and epidural-related side-effects (hypotension,
nausea/vomiting, pruritus, shivering, pyrexia, urinary reten-
tion, oxygen desaturation, or bradycardia).
Assessment of methodological quality
The methodological quality of included randomised and
quasi-randomised trials was assessed using the Cochrane
Collaboration tool for risk-of-bias assessment.38 Each included
study was rated as having a low, unclear, or high risk of bias
for each item by two independent reviewers (NH and NK).
The overall methodological quality of evidence across
pooled estimates of effect for all outcomes was assessed using
the Grading of Recommendations Assessment, Development
and Evaluation (GRADE) guidelines.39,40 The GRADE guidelines
assist with decision-making by classifying evidence for pooled
outcomes based on predefined criteria for study quality, con-
sistency, directness, precision, and publication bias.40
Primary outcomes
The two co-primary outcomes of this meta-analysis were (i) the
incidence of breakthrough pain (i.e. need for additional
anaesthetic intervention) during the duration of labour anal-
gesia, and (ii) difference in the area under the curve (AUC) of the
weighted pooled pain scores in patients receiving IEB and CEI.
We chose to evaluate two co-primary outcomes because eval-
uation of each alone limits a definitive assessment of efficacy of
IEB or CEI for labour analgesia. For the AUC analysis, the
weighted pooled pain scores for 30 min and 1, 2, 3, and 4 h post-
epidural placement were used. We only evaluated AUC for up
to 4 h as our preliminary screen of the literature suggested that
severity of pain is rarely evaluated beyond this time point.
Further, the AUC analysis was selected because we anticipated
some variations in the analgesic effectiveness of IEB
throughout the duration of labour, given its presumed wider
local anaesthetic spread in the epidural space over time.41
Secondary outcomes
Secondary outcomes of this systematic review and meta-
analysis included pain severity (VAS pain scores) at 30 min
and 1, 2, 3, and 4 h post-epidural placement; local anaesthetic
consumption (ml h1) rate of maternal motor block; maternal
satisfaction with pain relief; duration of analgesia (min);
duration of labour (min); rate of instrumental delivery; and
rate of Caesarean delivery. Epidural safety was assessed by
analysing side-effects (hypotension, nausea/vomiting, pruri-
tus, shivering, pyrexia, urinary retention, oxygen desatura-
tion, or bradycardia).
Measurement of outcome data
A variety of standardised tools exist for the subjective
assessment of pain scores, including the VAS, numeric rating
scale, and the verbal rating scale.42e44 The VAS is a commonly
used instrument that quantifies pain on a 0e10 cm or a 0e100
mm pain scale, with higher scores being associated with
increased pain.43 For the purposes of this review, all pain
scores were converted to an equivalent score on the 0e100 mm
VAS.45 We chose to use this scale over the 0e10 cm VAS to
capture smaller changes in VAS pain scores between IEB and
CEI.
For secondary outcomes, local anaesthetic consumption
data were converted to an equivalent in millilitres of bupiva-
caine and expressed as millilitres per hour. All measures of
maternal satisfaction were converted to a VAS equivalent
score (0¼least satisfied and 100¼most satisfied).45 Further,
estimates of degree of motor block were obtained by pooling
the incidence of reported events of impaired motor function.
We anticipated the use of a variety of measures and tools to
evaluate motor function; thus, we pooled data according to the
following hierarchy: (i) partially or fully impaired motor
function on the Bromage scale,46 (ii) partially or fully impaired
motor function on the straight leg test, and (iii) impaired force
of isometric muscle contraction. Estimates of epidural side-
effects were obtained by pooling the incidence of all reported
side-effects. All time-to-event data (i.e. duration of labour and
duration of analgesia) were presented in minutes.
Statistical analyses
The mean and standard deviation (SD) were extracted for all
continuous outcomes. The median and inter-quartile range

were used to approximate these values in situations when
they were not reported.47 Where the mean and 95% confidence
interval (CI) were reported, statistical conversions were used
to estimate the mean and SD.48 When the mean could not be
approximated, the median was used to estimate the mean;
when the SD could not be approximated, the values were
imputed by the methods described by Furukawa and col-
leagues.49 If required for statistical pooling, all categorical data
(i.e. patient satisfaction) were statistically converted to
continuous form with a mean and SD using the methods
described by Moore and colleagues98 and Thorlund and col-
leagues.45 Finally, dichotomous outcomes (i.e. breakthrough
pain, degree of motor block, side-effects, and mode of delivery)
were converted to overall incidence numbers.
Meta-analysis
Statistical pooling was only performed if data were available
from three or more studies; a qualitative summary of data was
provided if it was available from less than three trials. As we
anticipated the presence of heterogeneity amongst the
included studies, we pooled continuous outcome data using
inverse variance methods with random-effects modelling. In
contrast, dichotomous outcome data were pooled using the
ManteleHaenszel approach with random-effects modelling.50
For the first primary outcome of this review (incidence of
breakthrough pain), a risk ratio (RR) with a 95% CI was calculated.
For the second primary outcome of this review (AUC of pooled
pain scores), a weighted mean difference (WMD) with 95% CI was
calculated. To reduce the risk of Type 1 error in the two co-
primary outcomes of this review, P<0.025 was considered to be
statistically significant for all the two-tailed tests performed.
For the continuous secondary outcomes of this review,
namely, VAS pain scores at 30 min and 1, 2, 3, and 4 h post-
epidural placement; local anaesthetic consumption (ml h1);
maternal satisfaction with pain relief; duration of analgesia
(min); and duration of labour (min), a WMD with 95% CI was
calculated. For the dichotomous secondary outcomes of this
review, namely, rate of motor block, rate of instrumental de-
livery, rate of Caesarean delivery, and side-effects, an RR with
a 95% CI was calculated. P-values <0.05 were considered to be
statistically significant for all of the two-tailed tests performed
on the secondary outcomes of this review.
Interpretation
The AUC of rest pain scores during the first 4 h after epidural
placement was calculated by first pooling the pain scores of
individual trials at the predetermined time points (30 min and
1, 2, 3, and 4 h) for the IEB and CEI comparisons. The weighted
pooled estimates were then used to estimate the AUC
(expressed in mm h1) of rest pain scores during the first 4 h
for each intervention, and a mean difference of the AUC was
calculated. We interpreted this mean difference in AUC in light
of a minimal clinically important difference (MCID)51 in pain of
30% (i.e. a mean difference 30% suggests a clinically mean-
ingful improvement).52,53 We used this approach as an MCID in
VAS pain scale score in the obstetric population, and specif-
ically for labour pain, has yet to be defined.54,55
Trial sequential analysis
We performed additional trial sequential analysis to evaluate
whether the data from the primary outcome (incidence of
IEB vs CEI for labour analgesia - 563
breakthrough pain) were sufficient to answer the research
question. Given that meta-analyses with small numbers of
patients/RCTs are at a greater risk of Type 1 error and multiple
testing bias,56,57 the trial sequential method calculates the
optimum information size,58 or the number of patients
required in a meta-analysis to make a reliable statistical
inference. For this analysis, boundaries are created that help
determine whether the evidence in a meta-analysis is reliable
and sufficient for the detection of an effect.58 We used a Type 1
error of 5%, a power of 80%, and two-sided testing to conduct
this analysis. The required information size was calculated for
the primary outcome based on the (i) incidence of break-
through pain in patients receiving CEI from the pooled meta-
analysis; and (ii) median RR reduction across all studies
included in the pooled meta-analysis, whilst incorporating
corrections for heterogeneity. We utilised CEI as the reference
point for this analysis given its long-standing use for epidural
analgesia in labouring patients. The O’BrieneFleming59 a-
spending function was then used to create boundaries for
concluding superiority, inferiority, or futility. Trial sequential
analysis was further used to guide sample size requirements
for future trials attempting to evaluate the effects of IEB and
CEI on labour analgesia.
Exploring heterogeneity
Heterogeneity in the primary outcomes of this review was
assessed through the calculation of an I2 statistic. Per the
Cochrane Collaboration, an I2 value >40% is suggestive of
moderate heterogeneity in the pooled estimate of effect.38 If
heterogeneity was above this threshold, then we conducted
additional meta-regression analysis using mixed random-
effects modelling to explore whether predefined predictors
explained the variation in the primary outcome estimate of
effect. We reported R2 values (coefficient of determination) to
quantify the extent to which covariate explained the vari-
ability in data. The R2 value could range between 0 and 1, with
a value of 1 suggesting that the covariate explains all the
variability and 0 suggesting that the covariate does not explain
any of the variability. Meta-regression was only conducted if
each group within a covariate included two or more trials, or
the variable was continuous in nature (i.e. local anaesthetic
dose). The following covariates were examined: (i) parity of
included patients (nulliparous only vs parous only vs com-
bined nulliparous and parous), (ii) use of additional neuraxial
anaesthesia (CSE vs DPE vs none),60,61 (iii) use of additional
PCEA component,62 (iv) local anaesthetic consumption (con-
verted to ml h1 of bupivacaine),63 (v) method of IEB admin-
istration (pump delivered vs manual), (vi) time frame of
intermittent bolus (i.e. every 30 or 60 min),64 and (vii) infusion
rate of intermittent bolus (i.e. 100 or 250 ml h1).65 We con-
ducted sensitivity analysis for those covariates that had less
than two studies per group. We also conducted additional
sensitivity analysis to examine the effect excluding studies
that were (i) published in non-indexed journals, (ii) available
only as abstracts, (iii) had a high risk of bias in one or more
domains of the Cochrane risk-of-bias assessment tool,66 and
(iv) had an unclear risk of bias in two or more domains of the
Cochrane risk-of-bias assessment tool.66
Separate sensitivity analysis was also performed on the co-
primary outcome of AUC of the weighted pooled rest pain
scores to explore the potential effects of epidural loading dose
on the results. By virtue of the cumulative nature of AUC, early
pain scores (i.e. 30 min and 1 h) may influence the overall
 564 - Hussain et al.
findings as these may relate to the actual loading dose of the
epidural and not the IEB infusion settings. As a result, we
conducted additional AUC analysis by removal of these early
time points.
Assessment of publication bias
Egger’s regression test was used to assess publication bias in
the primary outcomes of this review. We also created and
visually inspected a funnel plot for the assessment of publi-
cation bias; in situations of low risk of publication bias, the
funnel plot should resemble the shape of a symmetric, inver-
ted funnel.67
Data management
Random-effects meta-analysis and forest plots were con-
ducted and created using Review Manager software (RevMan,
version 5.2; Nordic Cochrane Centre, København, Denmark,
Cochrane Collaboration). Meta-regression was performed us-
ing Comprehensive Meta-Analysis 3.0 (Biostat, Englewood, NJ,
USA). Trial sequential analysis was performed using the TSA
software package (Copenhagen Trial Unit, København,
Denmark).58
Results
The primary search strategy identified 1449 unique citations.
Hand searching international conference proceedings yielded
an additional four potentially eligible studies. Thus, a total of
1453 unique citations were considered for inclusion, of which
1415 were excluded based on title and abstract screening
alone. The remaining 38 potentially eligible citations had their
full-length texts reviewed for eligibility. Of these, 16 were
excluded because of the following reasons: incorrect patient
population (n¼2),68,69 irrelevant comparator/intervention
group (n¼3),70e72 incorrect study design (n¼3),73e75 lack of
regularly scheduled intermittent bolus (n¼6),76e81 and abstract
published as full text (n¼2).82,83 Hand searching of reference
lists of included studies yielded an additional five stud-
ies26,30e33 that satisfied the inclusion criteria. Searching of
completed and ongoing trials registered at https://www.
clinicaltrials.gov/did not yield any potentially eligible trials.
Further, no quasi-randomised trials were identified. Thus, a
total of 27 randomised trials2,6,8,10e16,19e35 were included in
this systematic review and meta-analysis, including 25 full-
text manuscripts2,6,8,10e16,19e33 and two published ab-
stracts.34,35 Five26,30e33 of the trials were published in Chinese
and translated using an online translator. The unweighted k
for agreement on full-text eligibility between the two inde-
pendent reviewers was 0.80. Supplementary File 2 illustrates
the study selection flow diagram for this review. Additional
unpublished data were obtained through correspondence with
Nunes and colleagues15 and Fidkowski and colleagues.2
Study characteristics
The study characteristics and outcomes assessed for all
included studies are presented in Table 1. Eighteen
studies10e12,16,19e28,30,31,33,35 included only nulliparous women,
five studies6,8,15,29,32 included only parous women, and three
studies2,13,14 included both nulliparous and parous women;
one study34 did not specify the parity of women included.
Overall, the 27 studies2,6,8,10e16,19e35 involved a total of 3133
patients, of which 1396 received IEB and 1309 received CEI; the
allocation of 428 patients was unspecified34 as the published
abstract did not specify the number of patients randomised to
each group. Additionally, 18 studies6,8,10e15,21,23,25e28,30e33
provided patients with a supplemental PCEA component.
Before the initiation of epidural analgesia, eight
studies6,12,16,19,20,23,25,26 performed a spinal anaesthetic, and
one study performed a dural puncture35; the remaining 18
studies2,8,10,11,13e15,21,22,24,27e34 provided epidural analgesia
without any neuraxial anaesthesia (i.e. intrathecal or dural
puncture) at initiation. Of the included studies,
252,6,8,1016,1925,2734 reported to assess pain severity scores
after epidural placement (first co-primary outcome) and
182,6,8,10,1214,16,19,20,2225,27,29,31,35 reported to assess the inci-
dence of breakthrough pain or need for additional anaesthetic
intervention (second co-primary outcome). Finally, epidural
safety and side-effect events were assessed by 20
studies.8,12e16,19e25,29e35
The technical details of the epidural techniques and the
regimens used are presented in Table 2. Before epidural initi-
ation, eight studies6,12,16,19,20,23,25,26 performed a spinal
anaesthetic (i.e. CSE). Five of these studies6,12,16,23,25 performed
a spinal using a mixture of long-acting local anaesthetic
(ropivacaine or bupivacaine) and fentanyl narcotic; in
contrast, two studies19,20 exclusively used a fentanyl-based
mixture, and one study26 exclusively used a long-acting local
anaesthetic (bupivacaine)-based mixture. For epidural anal-
gesia, studies varied regarding the type of long-acting local
anaesthetic used and the type of opioid narcotic. Ropivacaine-
containing solutions were used by 20
studies,8,11,12,14e16,19,22,23,25e35 bupivacaine-containing solu-
tions were used by five studies,2,6,13,21,24 and levobupivacaine-
containing solutions were used by two studies.10,20 The
epidural local anaesthetic solution was further supplemented
with fentanyl by 14 studies2,6,12e14,16,20e25,28,29 and sufentanil
by 11 studies10,11,15,26,27,30e35; in contrast, two studies8,19 did
not supplement the epidural with opioid narcotics. In patients
randomised to receive CEI, the rate of continuous infusion
varied from 5 to 12 ml h1.2,6,8,10e16,19e35 In contrast, patients
randomised to receive IEB had a bolus regimen that ranged
from 2 to 10 ml2,6,8,1016,1935 every 10 min to every 1
h.2,6,8,10e16,19e35 The bolus infusion rate also varied from 60 to
400 ml h1.6,12e14,16,19,22,23,25,26,30e32 Finally, a computerised
pump was programmed to deliver the epidural bolus in 24
studies,2,6,8,10e16,19e23,25,26,28,30e35 whereas delivery was
manual (i.e. physician or nurse assisted) in two studies;27,29
one study24 did not specify the method of bolus
administration.
The risk-of-bias assessment for each included study is
presented in Figure 1.
Primary outcomes
Breakthrough pain
The need for additional anaesthetic intervention
(breakthrough pain) was reported by 15
trials,2,6,10,12e14,16,19,20,22e25,29,31 inclusive of 1164 patients (IEB:
590; CEI: 574). In total, 121 out of 590 patients in the IEB group
and 196 out of 574 patients in the CEI group experienced
breakthrough pain. In comparison with CEI, IEB significantly
reduced the risk of developing breakthrough pain by 38% or an
RR (95% CI) of 0.62 (0.48, 0.81) (P¼0.0004; I2¼47%) (Fig. 2). The
risk of publication bias was low for this outcome (P¼0.10)
Table 1 Study characteristics. CEI, continuous epidural infusion; CSE, combined spinal and epidural; DPE, dural puncture epidural; EA, epidural analgesia; IEB, intermittent epidural bolus;
LA, local anaesthetic; n, sample size; N/S, not specified; PCEA, patient-controlled epidural analgesia. *Defined as an assessment of need for additional physician/nurse-administered
analgesia before delivery.

Author Parity n Groups (n) Neuraxial Primary Rest Breakthrough LA Epidural- Duration Labour Mode of Degree Degree Patient
(yr) anaesthesia outcome pain pain* consumption related of progression delivery of of satis
at initiation scores side- analgesia motor sensory -faction
effects block blockade

Chua Nulliparous 42 (i) CEI (21) CSE Duration of       

and Sia19 (2004) (ii) IEB (21) analgesia
Lim and Nulliparous 60 (i) CEI (30) CSE Breakthrough         
colleagues20 (ii) IEB (30) pain
(2005)
Salim and Nulliparous 190 (i) CEIþPCEA EA Duration of       
colleagues21 (63) second
(2005) (ii) IEB (63) stage of
(iii) labour
Control
(64)
Fettes and Nulliparous 40 (i) CEI (20) EA Rest pain         
colleagues22 (ii) IEB (20) scores
(2006)
Wong and Parous 126 (i) CEIþPCEA CSE LA       
colleagues6 (63) consumption
(2006) (ii)
IEBþPCEA
(63)
Sia and Nulliparous 42 (i) CEIþPCEA CSE LA          
colleagues23 (21) consumption
(2007) (ii)
IEBþPCEA
(21)
Leo and Nulliparous 62 (i) CEIþPCEA CSE Breakthrough          
colleagues12 (31) pain
(2010) (ii
IEBþPCEA

IEB vs CEI for labour analgesia

(31)
Lim and Nulliparous 60 (i) CEI (21) CSE Breakthrough         
colleagues16 (ii) IEB (21) pain
(2010)
Capogna and Nulliparous 145 (i) CEIþPCEA EA Degree of      
colleagues10 (70) motor block
(2011) (ii)
IEBþPCEA
(75)
Mukherjee and Nulliparous 60 (i) CEI (30) EA Rest pain    
colleagues24 (ii) IEB (30) scores
(2013)
Nulliparous 102 (i) CEIþPCEA CSE Breakthrough          
(51) pain

-
565
Continued
Table 1 Continued

566
Author Parity n Groups (n) Neuraxial Primary Rest Breakthrough LA Epidural- Duration Labour Mode of Degree Degree Patient
(yr) anaesthesia outcome pain pain* consumption related of progression delivery of of satis
at initiation scores side- analgesia motor sensory -faction

-
effects block blockade

Hussain et al.
Sia and (ii)
colleagues25 IEBþPCEA
(2013) (51)
Zhao and Nulliparous 60 (i) CEIþPCEA CSE N/S     
colleagues26 (51)
(2013) (ii)
IEBþPCEA
(51)
Feng and Nulliparous 132 (i) CEIþPCEA EA Maternal        
colleagues27 (66) fever
(2014) (ii)
IEBþPCEA
(66)
Lin and Nulliparous 90 (i) CEIþPCEA EA N/S     
colleagues28 (30)
(2015) (ii)
IEBþPCEA
(30)
(iii)
Control
(30)
Patkar and Parous 60 (i) CEI (30) EA Number of        
colleagues29 (ii) IEB (30) additional
(2015) bolus doses
Fang and Nulliparous 100 (i) CEIþPCEA EA N/S        
colleagues30 (50)
(2016) (ii)
IEBþPCEA
(50)
Ji and Nulliparous 50 (i) CEIþPCEA EA N/S         
colleagues31 (25)
(2016) (ii)
IEBþPCEA
(25)
Lin and Nulliparous 200 (i) CEIþPCEA EA N/S     
colleagues11 (100)
(2016) (ii)
IEBþPCEA
(100)
Nunes and Parous 166 (i) CEIþPCEA EA Patient       
colleagues15 (78) satisfaction
(2016) (ii) IEB (41)
(iii) IEB (47)
Parous 200 (i) CEIþPCEA EA N/S        
(100)

Continued
Table 1 Continued

Author Parity n Groups (n) Neuraxial Primary Rest Breakthrough LA Epidural- Duration Labour Mode of Degree Degree Patient
(yr) anaesthesia outcome pain pain* consumption related of progression delivery of of satis
at initiation scores side- analgesia motor sensory -faction
effects block blockade

Wang and (ii)

colleagues32 IEBþPCEA
(2016) (100)
Ferrer and Nulliparous 132 (i) CEIþPCEA EA Breakthrough         
colleagues13 and parous (66) pain
(2017) (ii)
IEBþPCEA
(66)
Wang and Nulliparous 186 (i) CEIþPCEA EA N/S       
colleagues33 (62)
(2017) (ii)
IEBþPCEA
(62)
(iii)
IEBþPCEA
(62)
Fidkowski and Nulliparous 150 (i) CEI (50) EA Area under       
colleagues2 and parous (i) IEB (50) the curve
(2019) (iii) IEB (50) pain
Hu and N/S 428 (i) CEI (N/S) EA Rest pain      
colleagues34 (ii) IEB (N/ scores
(2019) S)
(iii) IEB (N/
S)
(iv) IEB (N/
S)
Ojo and Nulliparous 120 (i) CEIþPCEA EA LA         
colleagues14 and parous (60) consumption
(2019) (ii)
IEBþPCEA
(60)

IEB vs CEI for labour analgesia

Riazanova and Parous 84 (i) CEIþPCEA EA N/S       
colleagues8 (42)
(2019) (ii)
IEBþPCEA
(42)
Song and Nulliparous 116 (i) CEI (38) EA or DPE Time to       
colleagues35 (ii) adequate
(2019) CEIþDPE analgesia
(40)
(iii)
IEBþDPE
(38)

-
567
 568 - Hussain et al.
(Supplementary File 3), and the quality of evidence was mod-
erate as a result of heterogeneity in the pooled estimate.
This outcome was characterised by a moderate level of
heterogeneity; as a result, meta-regression analysis was per-
formed to examine potential sources of heterogeneity using
our predefined covariates. Analysis revealed that the risk of
developing breakthrough pain was not statistically different
for the following covariates: (i) parity of included patients
(nulliparous only vs parous only vs combined nulliparous and
parous) (R2¼0.00; I2¼55%; P¼0.96), (ii) use of additional neu-
raxial anaesthesia (CSE vs none) (R2¼0.20; I2¼44%; P¼0.17), (iii)
use of additional PCEA component (PCEA vs none) (R2¼0.32;
I2¼37%; P¼0.22), (iv) local anaesthetic consumption (R2¼0.29;
I2¼43%; P¼0.19), (v) time frame of intermittent bolus (R2¼0.00;
I2¼57%; P¼0.54), and (vi) infusion rate of intermittent bolus
(R2¼0.00; I2¼51%; P¼0.69) (Supplementary File 4). Sensitivity
analysis was carried out for the method of IEB administration
(pump delivered vs manual) as only one trial administered the
bolus manually; the exclusion of this trial29 from analysis did
not change the direction and magnitude of treatment effect.
Further, additional sensitivity analysis did not change the di-
rection and magnitude of treatment effect when studies that
were (i) published in non-indexed journals,24,31 (ii) had a high
risk of bias in one or more domains of the Cochrane risk-of-
bias assessment tool,14 and (iii) had an unclear of bias in two
or more domains of the Cochrane risk-of-bias assessment
tool2,19,24,29,31 were excluded from analysis. We did not
perform sensitivity analysis on studies available as abstracts
given that all studies included in this outcome were published
in full text.
AUC for pain severity
The pooled weighted pain scores were calculated at 30 min
and 1, 2, 3, and 4 h in labouring women in the IEB and CEI
groups. Each time point of the analysis included a different
number of patients. Specifically, 842 patients were included at
30 min (IEB: 417; CEI: 425),2,11,16,20,24,28e31 1192 patients at 1 h
(IEB: 596; CEI: 596),11,13,19,22,24,27e32 1402 patients at 2 h (IEB: 697;
CEI: 705),2,11,13,16,19,20,24,27e30,32,33 1141 patients at 3 h (IEB: 570;
CEI: 571),11,13,19,22,24,27e29,32,33 and 1246 patients at 4 h (IEB: 622;
CEI: 624).2,11e13,16,20,22,24,27e29,32,33 During the entire 4 h time
interval, the mean difference in AUC of the pooled rest pain
scores was e16.69 mm h1 (e18.91, e14.45) (P<0.0001) in favour
of IEB (Fig. 3). The percent mean difference in AUC pain scores
between IEB and CEI was 32.86%, which exceeded the a priori
MCID threshold of pain (30%),52,53 suggesting a clinically
meaningful improvement with IEB.
The results of the AUC analysis were robust to sensitivity
analysis when the potential effects of loading dose on pain
scores were assessed by removing the 30 min and 1 h time
point estimates. The mean difference in the adjusted AUC of
the pooled rest pain scores was e14.16 mm h1 (e16.26,
e12.06) (P<0.0001) in favour of IEB. The percent mean differ-
ence in AUC pain scores between IEB and CEI was 52.22%,
which exceeded the a priori MCID threshold of pain (30%),52,53
suggesting a clinically meaningful improvement with IEB.
Analgesic secondary outcomes
Pain severity at individual time points
Compared with CEI, IEB significantly improved pain control at
3 and 4 h post-epidural placement by a mean difference of
e5.82 mm (e11.62, e0.03) (P¼0.049; I2¼99%) and e8.96 mm
(e16.37, e1.54) (P¼0.02; I2¼100%). In contrast, CEI significantly
improved pain control at 1 h post-epidural placement by a
mean difference of 0.47 (0.07, 0.87) (P¼0.02; I2¼0%). The dif-
ference was not statistically significant at 30 min and 2 h post-
epidural placement (Table 3). The quality of evidence was
moderate as a result of heterogeneity in the pooled estimate.
Local anaesthetic consumption
Local anaesthetic consumption was reported by 19
trials,6,8,10e14,16,19e23,25e28,30,31 inclusive of 1843 patients (IEB:
928; CEI: 915). Compared with CEI, IEB significantly reduced
local anaesthetic consumption by a mean difference of e1.14
ml h1 (e1.60, e0.68) (P<0.00001; I2¼89%) (Table 3). The quality
of evidence was moderate as a result of heterogeneity in the
pooled estimate.
Duration of analgesia
Duration of analgesia (time to first supplemental analgesic
request or sensation of pain) was reported by nine
trials,10,12,16,19,20,23,25,30,31 inclusive of 666 patients (IEB: 331;
CEI: 335). The difference was not statistically significant be-
tween the two groups (Table 3). The quality of evidence was
moderate as a result of heterogeneity in the pooled estimate.
Degree of motor block
Degree of motor block was reported by 15
trials,2,6,8,10,13e15,19,22,23,27,29,31e33 inclusive of 1435 patients (IEB:
715; CEI: 720). Of these trials, degree of motor block was
assessed using the Bromage scale in 13
trials6,8,10,13e15,19,23,27,29,31e33 and the straight leg test in one
trial.22 In comparison with CEI, IEB significantly reduced the
risk of developing motor block after epidural placement by
48% or an RR of 0.52 (0.31, 0.87) (P¼0.01, I2¼38%) (Table 3). The
quality of evidence was high in the pooled estimate.
Maternal satisfaction
Maternal satisfaction with pain relief or epidural regimen was
reported by 15 trials,2,6,12,14e16,20,23,25,26,29e33 inclusive of 1428
patients (IEB: 707; CEI: 721). In comparison with CEI, patients
receiving IEB were more satisfied with their pain relief or
epidural regimen by a mean difference of 5.16 cm (0.15, 10.18)
(P<0.04; I2¼98%) (Table 3). The quality of evidence was mod-
erate as a result of heterogeneity in the pooled estimate.
Maternal delivery outcomes
Duration of labour
Duration of labour (i.e. progression of labour) was reported by
21 studies,2,6,8,11e16,20e23,25e28,30e33 inclusive of 2152 patients
(IEB: 1068; CEI: 1084). In comparison with CEI, IEB significantly
reduced the duration of labour by a mean difference of e15.45
min (e21.70, e9.21) (P<0.00001; I2¼7%) (Table 3). The quality of
evidence was high in the pooled estimate.
Mode of delivery
Twenty-one trials2,6,10e16,20e23,25e31,33 inclusive of 2075 pa-
tients (IEB: 1033; CEI: 1042) reported data on the rate of
instrumental delivery, and 20 trials2,6,10e16,20e23,25,26,28e31,33
inclusive of 1954 patients (IEB: 972; CEI: 982) reported data on
the rate of Caesarean delivery. The difference was not
Table 2 Details of epidural characteristics in included studies. CEI, continuous epidural analgesia; IEB, intermittent epidural bolus; N/S, not specified; PCEA, patient-controlled epidural
analgesia; q, every.

Authors (yr) Neuraxial Epidural solution CEI regimen IEB regimen

anaesthesia at
initiation Continuous PCEA Administrator Bolus rate Infusion PCEA
rate (ml h¡1) of bolus rate

Chua and Sia19 (2004) Fentanyl 25 mg Ropivacaine 0.1% 5 None Pump 5 ml q60min 100 ml None
h1
Lim and colleagues 20
Fentanyl 25 mg Levobupivacaine 0.1%þfentanyl 2 10 None Pump 5 ml q30min N/S None
(2005) mg ml1
Salim and colleagues21 None Bupivacaine 0.125%þfentanyl 2 mg 8 3 ml q20min Pump 10 ml q60min N/S None
(2005) ml1 (CEI); bupivacaine 0.25% (0.125%)
(IEB)
Fettes and colleagues22 None Ropivacaine 0.2%þfentanyl 2 mg 10 None Pump 10 ml q60min 120 ml None
(2006) ml1 h1
Wong and colleagues6 Bupivacaine Bupivacaine 0.0625%þfentanyl 2 12 5 ml q10min Pump 6 ml q30min 400 ml 5 ml q10min
(2006) 0.125%þ mg ml1 (max 15 ml h1 (max 15 ml
fentanyl 15 mg q60min) q60min)
Sia and colleagues23 Ropivacaine Ropivacaine 0.1%þfentanyl 2 mg 5 5 ml q10min Pump 5 ml q60min (or 150 ml 5 ml q10min
(2007) 0.2%þfentanyl ml1 (max 20 ml 60 min after h1 (max 20 ml
15 mg q60min) successful PCEA) q60min)
Leo and colleagues 12
Ropivacaine Ropivacaine 0.1%þfentanyl 2 mg 5 5 ml q10min Pump 5 ml q60min (or 150e300 5 ml q10min
(2010) 0.2%þfentanyl ml1 (max 20 ml 30 min after ml h1 (max 20 ml
15 mg q60min) successful PCEA) q60min)
Lim and colleagues16 Ropivacaine Ropivacaine 0.1%þfentanyl 2 mg 10 None Pump 2 ml q15min 75 ml None
(2010) 0.2%þfentanyl ml1 h1

15 mg
Capogna and None Levobupivacaine 0.0625%þ 10 5 ml q10min Pump 10 ml q60min N/S 5 ml q10min
colleagues10 (2011) sufentanil 0.5 mg ml1 (CEI/IEB); (max 15 ml (max 15 ml
levobupivacaine 0.125% (PCEA) q60min) q60min)
Mukherjee and None Bupivacaine 0.125%þfentanyl 2 mg 10 None N/S 10 ml q60min N/S None
colleagues24 (2013) ml1
Sia and colleagues25 Ropivacaine Ropivacaine 0.1%þfentanyl 2 mg 5 5 ml q10min Pump 5 ml q60min (or 100 ml 5 ml q10min
(2013) 0.2%þfentanyl ml1 (max 20 ml 15e30 min after h1 (max 20 ml

IEB vs CEI for labour analgesia

15 mg q60min) successful PCEA) q60min)
Zhao and colleagues26 Bupivacaine 0.3% Ropivacaine 0.1%þsufentanil 0.5 6 3 ml q15min Pump 3 ml q30min 60 ml 3 ml q15min
(2013) mg ml1 (max 15 ml h1 (max 15 ml
q60min) q60min)
Feng and colleagues27 None Ropivacaine 0.08%þsufentanil 0.4 10 5 ml q30min Manual 10 ml q60min N/A 5 ml q30min
(2014) mg ml1
Lin and colleagues28 None Ropivacaine 0.12%þfentanyl 2 mg 5 5 ml q20min Pump 5 ml q60min N/S 5 ml q20min
(2015) ml1 (max 15 ml (max 15 ml
q60min) q60min)
Patkar and colleagues29 None Ropivacaine 0.1%þfentanyl 2 mg 10 None Manual 10 ml q60min N/A None
(2015) ml1
Fang and colleagues30 None Ropivacaine 0.075%þsufentanil 8 6 ml q15min Pump 8 ml q60min 360 ml 6 ml q15min
(2016) 0.5 mg ml1 h1
Ji and colleagues31 None Ropivacaine 0.75%þsufentanil 0.3 8 5 ml q20min Pump 8 ml q60min 240 ml 5 ml q20min

-
(2016) mg ml1 (max 25 ml h1 (max 25 ml

569
q60min) q60min)

Continued
Table 2 Continued

570
Authors (yr) Neuraxial Epidural solution CEI regimen IEB regimen
anaesthesia at

-
initiation Continuous PCEA Administrator Bolus rate Infusion PCEA
rate (ml h¡1)

Hussain et al.
of bolus rate

Lin and colleagues11 None Ropivacaine 0.1%þsufentanil 0.3 5 5 ml q20min Pump 5 ml q60min N/S 5 ml q20min
(2016) mg ml1 (max 15 ml (max 15 ml
q60min) q60min)
Nunes and colleagues15 None Ropivacaine 0.15%þsufentanil 0.2 5 5 ml q20min Pump 10 ml q60min N/S As needed by
(2016) mg ml1 (CEI); ropivacaine 0.1% (max 15 ml nurse
or 0.15%þsufentanil 0.2 mg ml1 q60min)
(IEB)
Wang and colleagues32 None Ropivacaine 0.08%þsufentanil 0.4 10 5 ml q30min Pump 10 ml q60min 100 ml 5 ml q30min
(2016) mg ml1 (CEI/IEB); ropivacaine h1
0.1% (PCEA)
Ferrer and colleagues13 None Bupivacaine 0.1%þfentanyl 2 mg 10 10 ml (no limit) Pump 10 ml q60min 125 ml 10 ml (no limit)
(2017) ml1 h1
Wang and colleagues33 None Ropivacaine 0.08%þsufentanil 0.4 10 5 ml q30min Pump 5 ml q30min or 10 ml N/S 5 ml q30min
(2017) mg ml1 q60min
Fidkowski and None Bupivacaine 0.125%þfentanyl 2 mg 10 None Pump 5 ml q30min or 10 ml N/S None
colleagues2 (2019) ml1 q60min
Hu and colleagues34 None Ropivacaine 0.1%þsufentanil 0.3 8 Rate N/S Pump 5 ml q60min or 8 ml q60min N/S Rate N/S
(2019) mg ml1 or 10 ml q60min
Ojo and colleagues14 None Ropivacaine 0.1%þfentanyl 2 mg 8 8 ml q10min Pump 6 ml q45min (or 10 min 250 ml 8 ml q10min
(2019) ml1 (max 45 ml before or after successful h1 (max 45 ml
q60min) PCEA) q60min)
Riazanova and None Ropivacaine 0.08% 8 8 ml q30min Pump 8 ml q30min N/S 8 ml q30min
colleagues8 (2019)
Song and colleagues35 None Ropivacaine 0.1%þsufentanil 0.3 8 5 ml q20min Pump 8 ml q60min N/S 5 ml q20min
(2019) mg ml1

Fig 1. Risk-of-bias summary for included studies.
bias; , unclear risk of bias; , high risk of bias.
IEB vs CEI for labour analgesia - 571
statistically significant between the two groups for both
modes of delivery (Table 3). The quality of evidence was high
in both pooled estimates.
Epidural safety outcomes
Epidural side-effects
There was a wide range of epidural-related side-effects re-
ported across the 20 studies8,12e16,19e25,29e35 that assessed this
outcome; however, the difference in RR between the two
groups was not statistically significant in all analysed side-
effects (hypotension,12e16,19,20,22e26,28,29,31 nausea/
8,12,13,15,16,20,23e25,31
vomiting, pruritus,8,12,13,16,20,23e25
shivering,12,16,20,25 and pyrexia12,21,25,27) (Table 3). The quality
of evidence was high for all side-effect pooled estimates
except for risk of shivering, which was rated as being of
moderate quality as a result of heterogeneity.
Only one study24 reported instances of urinary retention
(IEB: one/30 patients; CEI: three/30 patients), bradycardia (IEB:
one/30 patients; CEI: two/30 patients), and desaturation (IEB:
four/30 patients; CEI: four/30 patients).
Trial sequential analysis
Trial sequential analysis on the incidence of breakthrough
pain (co-primary outcome) in patients receiving IEB vs CEI was
conducted based on an event rate reported in this meta-
analysis for the CEI group of 34% (196/574 patients) and a
median RR reduction of 44%. The analysis revealed that the
cumulative z-curve surpassed the boundary of superiority of
IEB over CEI for reducing the risk of developing breakthrough
pain. Additionally, the optimal information size of 679 patients
was exceeded, suggesting an adequate sample size to make a
reliable statistical inference for this outcome (Fig. 4).
Discussion
Our systematic review and meta-analysis provide moderate-to
high-quality evidence demonstrating the analgesic superiority
of IEB over CEI for labouring patients. Moderate-quality evi-
dence appears to suggest that IEB reduces the risk of devel-
oping breakthrough pain, whilst also providing a clinically
meaningful improvement in AUC pain over the first 4 h after
epidural placement. Meta-regression analysis also suggests
that this reduction in risk of breakthrough pain does not
appear to be statistically related to (i) local anaesthetic con-
sumption, (ii) use of additional neuraxial anaesthesia, (iii) use
of an additional PCEA component, (iv) time frame of inter-
mittent bolus, and (v) infusion rate of intermittent bolus.
Furthermore, when analysed individually, improved pain
control with CEI is limited to the 1 h time interval, whilst IEB
appears to provide superior pain control that extends to 3 and
4 h. Patients receiving IEB also appear to be more satisfied with
their pain relief, have shorter durations of labour, and have a
lower risk of motor block. The remainder of analgesic and
maternal delivery outcomes appear to be no different between
the groups. Finally, both techniques perform similarly for
safety outcomes.
Novelty
Our meta-analysis is the first to provide moderate-to high-
, low risk of
quality evidence supporting the analgesic superiority of IEB
over CEI for labouring patients. Three prior reviews on the
 572 - Hussain et al.

Fig 2. Forest plot of relative risk of developing breakthrough pain with intermittent epidural bolus (IEB) vs continuous epidural infusion
(CEI). The pooled estimates of the weighted risk ratio are shown with 95% confidence intervals (CIs). The pooled estimates are represented
as diamonds and the lines represent the 95% CIs. MeH, ManteleHaenszel.

topic by Xu and colleagues,17 Sng and colleagues,18 and George
and colleagues9 were not definitive, albeit suggesting some
benefit with IEB. Furthermore, the largest of these reviews was
limited to 12 randomised trials.18 With 27 randomised trials,
inclusive of 3133 patients, our review provides the most
comprehensive and precise overview to date on this highly
debated topic. Importantly, because of a larger number of
included trials, we were able to statistically pool a variety of
outcomes and are the first to uniquely demonstrate improved
AUC pain scores with IEB over the first 4 h of epidural place-
ment. The magnitude of improvement in pain scores appears
to be realised clinically as our review demonstrated improved
maternal satisfaction with IEB use. Our results are also
different from recent meta-analyses through the inclusion of
meta-regression and trial sequential analysis. These suggest
that IEB provides a reliable decrease in the incidence of

Fig 3. Star plot of the area under the curve of the pooled weighted mean pain scores at rest as measured by the VAS (0e100 mm) over 30
min to 4 h (five time points) for each of intermittent epidural bolus (IEB) and continuous epidural infusion (CEI).
Table 3 Secondary endpoint results. CEI, continuous epidural infusion; GRADE, Grading of Recommendations Assessment, Development and Evaluation; IEB, intermittent epidural bolus;
N/A, not applicable; SD, standard deviation. Legend: 4444, high-quality evidence; 4442, moderate-quality evidence; 4422, low-quality evidence; 4222, very low-quality
evidence.

Outcome Studies IEB, mean CEI, mean Mean difference or P-value for P-value for I2 test for Quality of
included (SD) or n/N (SD) or n/N risk ratio (95% statistical heterogeneity heterogeneity (%) evidence
confidence interval) significance (GRADE)

Rest pain at 30 min (mm) 9 10.07 (12.17) 10.34 (11.27) e0.48 (e1.16 to 0.19) 0.16 0.24 23 4444
Rest pain at 1 h (mm) 11 12.01 (13.69) 12.38 (14.36) 0.47 (0.07e0.87) 0.02 0.79 0 4444
Rest pain at 2 h (mm) 13 10.65 (15.45) 14.68 (17.57) e2.40 (e5.16 to 0.35) 0.09 <0.00001 98 4442
Rest pain at 3 h (mm) 10 10.20 (15.63) 16.87 (15.56) e5.82 (e11.62 to e0.03) 0.05 <0.00001 99 4442
Rest pain at 4 h (mm) 13 9.05 (12.72) 20.01 (20.54) e8.96 (e16.37 to e1.54) 0.02 <0.00001 100 4442
Local anaesthetic 19 6.94 (3.81) 8.89 (6.19) e1.14 (e1.60 to e0.68) <0.00001 <0.00001 89 4442
consumption (ml h1)
Duration of analgesia (min) 9 366.63 (154.73) 357.04 (193.15) 27.21 (e19.28 to 73.71) 0.25 <0.0001 91 4442
Degree of motor block 15 45/715 95/720 0.52 (0.31e0.87) 0.01 0.09 38 4444
Maternal satisfaction (cm) 15 90.24 (10.13) 82.99 (12.09) 5.16 (0.15e10.18) 0.04 <0.00001 98 4442
Duration of labour (min) 21 412.64 (200.96) 419.39 (198.11) e15.45 (e21.70 to e9.21) <0.00001 0.37 7 4444
Mode of delivery
Instrumental delivery 21 96/1033 121/1042 0.87 (0.65e1.16) 0.34 0.20 21 4444
Caesarean section 20 137/972 154/982 0.90 (0.73e1.11) 0.31 0.99 0 4444
Epidural side-effects
Hypotension 15 21/526 17/524 1.15 (0.61e2.16) 0.67 0.74 0 4444
Nausea/vomiting 10 19/356 21/376 0.93 (0.49e1.76) 0.82 0.55 0

IEB vs CEI for labour analgesia

4444
Pruritus 8 96/294 96/294 1.00 (0.65e1.53) 0.99 0.92 0 4444
Shivering 4 67/137 66/137 1.02 (0.70e1.48) 0.92 0.09 54 4442
Pyrexia 4 10/209 21/207 0.57 (0.28e1.17) 0.13 0.41 0 4444

-
573
 574 - Hussain et al.

Fig 4. Trial sequential analysis for the risk of developing breakthrough pain. Analysis is based on a relative risk (RR) reduction of 58% and a
control event rate of 61%. The red line represents the cumulative Z-score. The inward sloping green lines represent the trial sequential
monitoring boundaries. The outward sloping green lines represent the futility region. The horizontal blue lines represent the threshold for
significance. CEI, continuous epidural infusion; IEB, intermittent epidural bolus.

breakthrough pain that does not appear to be associated with
several peripartum factors, including intermittent bolus
regimen and infusion rate. That said, there are still several
ongoing randomised trials that are exploring the optimal IEB
technique in detail.84,85 Nonetheless, the findings of our re-
view continue to add new, definitive, and more precise evi-
dence for healthcare practitioners desiring to incorporate IEB
into practice for analgesia in labouring patients.
IEB approach
The challenges of IEB research relate to the multifactorial and
unique nature of the labour experience. As a result, individual
trials that aim to compare this new technology against the
conventionally accepted continuous infusion have yielded
conflicting results.10e16 Labour pain is multifaceted, having
visceral components, which occur during the first stage and
are mediated by the T10 to L1 spinal segments, and somatic
components, which occur during the second stage and are
mediated by the S2 to S4 spinal segments.86 A central outcome
lending support for the adoption of IEB has focused on evi-
dence suggesting improved duration and quality of pain relief,
and decreased adjunct analgesic requirements for the treat-
ment of breakthrough pain in labouring women6,19,25; how-
ever, other studies have contradicted these findings.10e12,16,73
In line with this, our review provides additional moderate-to
high-quality evidence, suggesting that IEB provides a clini-
cally meaningful improvement in pain across the first 4 h of
epidural placement and reduces the risk of developing
breakthrough pain. This makes clinical sense as intermittent
bolus regimens are known to have a wider spread in the
epidural space in comparison with continuous infusions,
suggesting a clear benefit over the duration of labour as more
spinal segments are covered.87 Further, in lieu of current
research aimed at discovering the optimal IEB settings,64,88,89
such as timing of the ‘next’ bolus after epidural placement,
the volume delivered with each intermittent bolus, the infu-
sion rate, and the time between these deliveries, our meta-
regression suggests a uniform benefit of IEB independent of
changes in these variables. Yet, our analysis of individual pain
scores revealed that CEI augments analgesia earlier than IEB
(i.e. at 1 h post-epidural placement). This finding is also clini-
cally relevant given that early pain control may be superior
with CEI, likely owing to the early continuous administration
of local anaesthetic in the epidural space rather than the delay
seen with intermittent bolus. It is plausible that the delay in
pain control seen with IEB may be remedied with CSE,25 DPE,35
or additional neuraxial anaesthesia before epidural analgesia.
Other novel techniques, such as the addition of a low-dose
continuous infusion to IEB,90,91 may also have a role in reme-
dying this possible shortcoming of IEB in the early period.
Maternal labour outcomes
Important to the adoption of IEB for labour analgesia are
improved patient satisfaction and improved or equivalent

labour outcomes. Indeed, our review suggests that labouring
women have improved satisfaction with IEB with similar
instrumental and Caesarean delivery rates compared with CEI.
This improved satisfaction may be a result of several factors,
including improved pain control, reduced risk of motor block,
and a shorter duration of labour, findings that are different from
prior reviews.9,17,18 It is important to note, however, that
maternal satisfaction during labour does not always correlate to
analgesic improvement, as evidenced by the satisfaction seen
with nitrous oxide labour analgesia, and other factors may be
playing a role.92 This may also be seen in our review given that
the lower end of our 95% CI for maternal satisfaction was e0.15
cm in favour of IEB, which is approaching the threshold for non-
significance. As such, it is entirely possible that there are many
other factors that affect maternal satisfaction other than qual-
ity of analgesia. For instance, compared with a continuous
infusion of local anaesthetic, boluses delivered intermittently
do not reach the threshold for motor block because of passive
diffusion of local anaesthetic out of the nerve in between bolus
doses.93,94 This advantage of IEB is critical given that it may
provide labouring patients adequate strength to progress
quicker through the second stage of labour.95 Empirically, fac-
tors, such as these, make sense as key predictors for improved
maternal satisfaction; however, there are likely other non-
analgesic contributors as well, such as the setting of the birth
room, non-medical pain relief, personal involvement in the la-
bour process, and a sense of being and control.96,97
Safety
Ultimately, safety concerns for any intervention affect the rate
of its adoption. These concerns may be implicit, based on
one’s grasp of principles or on analogy to past or similar in-
terventions. These safety concerns may also be explicitly
founded on initial outcomes. Encouragingly, our review
explicitly found no differences in any of the clinically signifi-
cant side-effects of epidurals, such as hypotension, nausea/
vomiting, pruritus, pyrexia, and shivering. Hypotension at the
time of epidural bolus is a natural concern with IEB, and
indeed, any epidural bolus or additional dose when given at
large volumes and short intervals could contribute to a rapid
decrease in blood pressure and possibly motor block.76 As
mentioned earlier, the analgesic outcomes appear to be inde-
pendent of IEB dosing regimen, but whether this indepen-
dence also holds true for safety outcomes remains to be seen
as there is currently ongoing research investigating various IEB
dosing strategies.84,85
Limitations
Our review also has limitations. First, several key outcomes
had a high level of heterogeneity, which limits validity and
requires careful interpretation. Second, we were unable to
resolve heterogeneity in our primary outcome through meta-
regression or sensitivity analysis. This could have been
because of variations in IEB technique, different patient pop-
ulations, and lack of standardised protocols for the care of
labouring patients across different countries. Third, we were
unable to provide pooled estimates for prolonged pain scores
beyond the 4 h time point, which limits extrapolating the po-
tential benefits of IEB for the entire duration of labour. Fourth,
our analysis for maternal satisfaction was at a high risk for
publication bias, and the results call for careful interpretation.
Finally, there is a risk of multiple testing bias in our secondary
IEB vs CEI for labour analgesia - 575
outcomes as a 95% CI was calculated. In relation to this,
methodological bias continues to be a concern as the majority
of trials were characterised by an unclear risk of bias.
Conclusions
In conclusion, there appears to be moderate-to high-quality
evidence that IEB provides superior analgesia to CEI for labour.
The analgesic benefits of IEB appear to be related to improved
pain severity during the first 4 h of epidural placement and a
reduced risk of developing breakthrough pain. This mode also
appears to reduce the risk of developing motor block and de-
creases the overall duration of labour. Nonetheless, CEI does
appear to provide minor analgesic advantages that are limited
to early labour, at the 1 h time interval; however, both modes
appear to be no different for mode of delivery and rate of
epidural side-effects. These findings suggest that IEB may be
considered an effective and safe alternative to CEI for anal-
gesia in labouring patients.
Authors’ contributions
Study design: NH, FWA
Study methodology: NH, FWA
Study conduct: NH, CL, NK, FWA
Archiving of study files: FWA
Data analysis: NH, CL, BH, TW, ME, JR, FWA
Writing of paper: all authors
Approval of paper: NH, CL, BH, NK, TW, ME, JR, RHS, FWA
Acknowledgements
The authors would like to thank Stephen Halpern and Cynthia
Wong for their insightful suggestions on this review. FWA
receives research time support from the Department of
Anesthesiology and Pain Medicine and the Ottawa Hospital
Research Institute, University of Ottawa.
Declarations of interest
The authors declare that they have no conflicts of interest.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.bja.2020.05.060.
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Handling editor: Jonathan Hardman