International Journal of Obstetric Anesthesia (2018) 36, 96–107

0959-289X/$ - see front matter Ó 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.ijoa.2018.04.010

REVIEW ARTICLE
www.obstetanesthesia.com

Sepsis in pregnancy and the puerperium

C.E.G. Burlinson,a D. Sirounis,b,c K.R. Walley,b,d A. Chaua,c
a
Department of Anesthesia, British Columbia Women’s Hospital, Vancouver, BC, Canada
b
Division of Critical Care Medicine, Department of Medicine, St. Paul’s Hospital, Vancouver, BC, Canada
c
Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada
d
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada

ABSTRACT
Sepsis remains a leading cause of maternal morbidity and mortality. Recognition and treatment of maternal sepsis are often
delayed due to the physiological adaptations of pregnancy and vague or absent signs and symptoms during its initial presentation.
Over the past decade, our understanding of sepsis has evolved and maternal early warning systems have been developed in an
effort to help providers promptly identify and stratify parturients who are at risk. In addition, new consensus definitions and care
bundles have recently been published by the World Health Organization and the Surviving Sepsis Campaign to facilitate earlier
recognition and timely management of sepsis. In this narrative review, we summarize the available evidence about sepsis and pro-
vide an overview of the research efforts focused on maternal sepsis to date. Controversies and challenges surrounding the anes-
thetic management of parturients with sepsis or at risk of developing sepsis during pregnancy or the puerperium will be
highlighted.
Ó 2018 Elsevier Ltd. All rights reserved.

Keywords: Pregnancy; Sepsis; Puerperium; Obstetric anesthesia; Maternal sepsis

Introduction lished and used to define sepsis in the general population

Sepsis during pregnancy and the puerperium remains a
leading cause of maternal morbidity and mortality world-
wide.1 The frequent publications from the World Health
Organization (WHO), the Surviving Sepsis Campaign
(SSC) and the Mothers and Babies: Reducing Risk
through Audits and Confidential Enquiries collaboration
(MBRRACE-UK) are highlighting the importance and
persistence of this problem. The failure to recognize sepsis
and institute prompt treatment underlies most cases of
maternal sepsis with poor outcomes.2 The physiological
adaptations in pregnancy, combined with the high rates
of trauma and surgical intervention that occur during
the peripartum periods, put pregnant women at risk of
developing infections that may go unrecognized until
there is substantial clinical deterioriation.3 The initial
alteration of hemodynamics may be falsely attributed to
labor pain or blood loss subsequent to delivery.4,5 More-
over, normal laboratory values in obstetric patients differ
from non-obstetric patients, and much of what is estab-
Accepted April 2018
Correspondence to: Anthony Chau, Department of Anesthesia, British
Columbia Women’s Hospital, 4500 Oak Street, Vancouver, BC V6H
3N1, Canada.
E-mail address: anton.chau@ubc.ca
has not been fully validated in pregnancy. Efforts to
implement early warning systems, revise the definition
of sepsis, and develop maternal sepsis care bundles, stem
from the knowledge that early recognition, diagnosis and
management of maternal sepsis lead to better maternal
and fetal outcomes. In this narrative review, we summa-
rize the recent changes in sepsis definitions, provide an
overview of maternal sepsis and review the current evi-
dence on early warning systems. Furthermore, we discuss
strategies, controversies and challenges surrounding the
anesthetic management of parturients with sepsis, or at
risk of developing sepsis, during pregnancy and the
puerperium.
Scope of the problem
Globally, sepsis is the direct cause of over 260 000 mater-
nal deaths a year; approximately 5% of maternal deaths
in developed countries and 11% of maternal deaths in
developing nations.1 Approximately 1 in 1000 women
giving birth will develop severe infection with a systemic
inflammatory response; half of these will progress to
sepsis with organ dysfunction and 3–4% to septic
shock.6 While the absolute risk of death from maternal
sepsis is low in developed countries such as the United
C.E.G. Burlinson et al. 97

States (US) (0.1 per 100 000)7 and United Kingdom
(UK) (0.6 per 100 000, based on the most recent report
by MBRRACE-UK covering 2013–2015; and having
fallen from 2.0 per 100 000 in 2009–2012),8 the risk of
morbidity from maternal sepsis remains high. For every
parturient who dies from sepsis, 50 women are estimated
to suffer severe maternal morbidity (SMM) from sepsis,
which includes any unexpected outcomes of labor and
delivery that result in significant short- or long-term
consequences to a women’s health, as defined by the
Centers for Disease Control and Prevention.9 Severe
maternal morbidity may lead to fetal morbidity, includ-
ing fetal infection, preterm delivery and fetal demise.10
Long-term complications such as chronic pelvic pain,
pelvic adhesions and secondary infertility can also
result.11
Definitions
Evolution of sepsis definitions
The original definitions of sepsis and its related
disorders are now over 20 years-old and have undergone

Table 1 Previous and revised definitions of sepsis

PREVIOUS DEFINITIONS
Sepsis-1: 1991 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Definitions119
 Systemic inflammatory response syndrome (SIRS): a systemic inflammatory response manifested by two or more of the following conditions:
(1) temperature >38 °C or <36 °C; (2) heart rate >90/min; (3) respiratory rate >20/min or PaCO2 <32 mmHg; and (4) white blood cell count
>12 000 or <4000/mm3, or >10% immature neutrophils
 Sepsis: SIRS associated with infection
 Severe sepsis: Sepsis complicated by organ dysfunction, hypoperfusion, or hypotension
 Septic shock: Severe sepsis with persistent hypotension despite adequate volume resuscitation or need for inotropic or vasopressor agents

REVISED DEFINITION
Sepsis-3: 2016 Third International Consensus Definitions for Sepsis and Septic Shock13
 Sepsis: a life-threatening organ dysfunction caused by a dysregulated host response to infection. Severity of organ dysfunction is assessed
using the Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score.20 Organ dysfunction can be identified as an acute change in
total SOFA score 2 points, consequent to the infection. Baseline SOFA score should be assumed to be zero unless patient is known to have
pre-existing organ dysfunction
 Septic shock: Sepsis with persistent hypotension requiring vasopressors to maintain mean arterial pressure (MAP) 65 mmHg and a serum
lactate level >2 mmol/L (18 mg/dL)

WORLD HEALTH ORGANIZATION MATERNAL SEPSIS CONSENSUS DEFINITION15

 Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from infection during pregnancy, childbirth, post-abor-
tion, or the postpartum period

Fig. 1 Evolution of sepsis definitions. SIRS: systemic inflammatory response syndrome. SOFA: Sequential (Sepsis-related)
Organ Failure Assessment. qSOFA: quick SOFA.
98 Sepsis in pregnancy and the puerperium

several revisions by multinational societies (Table 1,
Fig. 1). In 2001, the original definitions were retained,
despite an admission that they lack specificity, and
hopes were raised for future biomarkers to aid future
diagnosis.12 Recently, definitions and clinical criteria
were updated in the 2016 Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3).13 The
new definitions acknowledge that sepsis is not simply an
infection with two or more systemic inflammatory
response syndrome (SIRS) criteria, and that there are
three essential components to sepsis: infection, host
response to infection and organ dysfunction.14 Since
the inclusion of organ dysfunction in the definition of
sepsis in Sepsis-3, the concept of ‘severe sepsis’ no longer
exists. Thus, the Sepsis-3 ‘sepsis’ definition is equivalent
to ‘severe sepsis’ used in previous publications, irrespec-
tive of SIRS status. Epidemiological figures and study
outcomes quoted are from publications prior to the
adoption of this new terminology, although in this
review we use Sepsis-3 terminology for consistency.
The new WHO maternal sepsis consensus definition is
developed from Sepsis-3 and is based on a systematic
review of literature and expert consultations.15
Assessment of organ dysfunction
Organ dysfunction or failure may manifest in different
ways. In 4158 cases of maternal sepsis in the US, respi-
ratory dysfunction was seen to be most common at 34%,
followed by coagulopathy (19%), kidney injury (16%),
cardiovascular dysfunction (12%), hepatic dysfunction
(10%) and altered consciousness (8%).7 Sepsis in obstet-
ric patients can become rapidly fatal, with a large study
from the Netherlands demonstrating that time from first
symptom of infection to ‘full blown sepsis’ was less than
24 hours in 39% of patients, and time from infection to
death was less than 24 hours in 50% of patients.16 In the
UK, a national study of maternal sepsis showed that in
75% of women with a Group A Streptococcal infection,
there was less than nine hours between the first signs of
systemic infection to the diagnosis of sepsis with organ
dysfunction; and in 50% of women, this was less than
two hours.17
The presence of organ dysfunction can effectively be
identified by a predictive scoring system called the
Sequential (or Sepsis-related) Organ Failure Assessment
(SOFA) score (Table 2).
Organ failure-based scores appear to be superior to
obstetric-specific scoring systems and APACHE II
scores.18,19 The SOFA score was originally developed
to sequentially assess the severity of organ dysfunction
from sepsis.20 When measured serially, it can facilitate
the identification of septic patients in the Intensive Care
Unit (ICU) who are at a higher risk of death, with sta-
tistically greater predictive validity than SIRS criteria.21
For patients outside the ICU, a bedside assessment
tool called the quickSOFA (qSOFA) score predicts in-
hospital mortality with statistically greater predictive
validity than SOFA and SIRS.22,23 The qSOFA scoring
system is quicker and simpler to use, without the need to
wait for laboratory results. This is an advantage given
the increasing emphasis on the early recognition of sep-
sis (Table 3). The qSOFA score ranges from 0 to 3
points; the presence of 2 of 3 qSOFA points in adult
patients with suspected infection indicates a greater risk
of death or prolonged ICU stay.22
The SOFA and qSOFA criteria may be used without
modification in the obstetric population. Among obstet-
ric patients admitted to the ICU, the mean total SOFA

Table 2 Sequential (Sepsis-related) Organ Failure Assessment (SOFA) scorea

SOFA 1 2 3 4
Respiration: PaO2/FiO2, <400 (53.3) <300 (40) <200 (26.7) with <100 (13.3) with
mmHg (kPa) respiratory support respiratory support
Coagulation: <150 <100 <50 <20
Platelets  103/mL
Liver: bilirubin, 1.2–1.9 (20–32) 2.0–5.9 (33–101) 6.0–11.9 (102–204) >12.0 (204)
mg/dL (mmol/L)
Cardiovascular: MAP <70 mmHg dopamine dopamine >5 mg/kg/min, dopamine
Hypotension 5 mg/kg/min, or epinephrine >15 mg/kg/min,
or dobutamine 0.1 mg/kg/min or epinephrine
(any dose) or norepinephrine >0.1 mg/kg/min,
0.1 mg/kg/min or norepinephrine
>0.1 mg/kg/min
Central nervous system: 13–14 10–12 6–9 <6
Glasgow Coma Scale Score
Renal: serum creatinine, 1.2–1.9 (110–170) 2.0–3.4 (171–299) 3.5–4.9 (300–440), >5.0 (440) or urine
mg/dL (mmol/L) or urine output output <200 mL/day
or urine output <500 mL/day
PaO2: partial pressure of oxygen; FiO2: fraction of inspired oxygen; MAP: mean arterial pressure.
a
Adapted from Vincent et al.20
C.E.G. Burlinson et al.
Table 3 Quick sepsis-related organ failure assessment
score (qSOFA)a
Assessment qSOFA score
Tachypnea: (22 breaths/min) 1
Hypotension: (SBP 100 mmHg) 1
Altered mentation: (GCS <15) 1 white blood cell count is a normal finding during preg-
SBP: systolic blood pressure; GCS: Glasgow Coma Scale.
a
Adapted from Singer et al.22
score has been shown to perform well as a predictor of
mortality, with a sensitivity of 87%, specificity of 90%
and an area-under-the-curve of 0.95 when using a cut-
off value of 9 for the total SOFA score at admission.24
An abnormal qSOFA score should prompt investigation
of organ dysfunction and initiation or escalation of ther-
apy as necessary. However, in a patient at high risk of
developing sepsis, clinical suspicion alone should
prompt escalation of care, as therapy for sepsis should
not be withheld even if qSOFA criteria are not met.
Some of the SOFA and qSOFA criteria, such as a respi-
ratory rate greater than 22, may overlap with normal
physiologic parameters in the context of different stages
of pregnancy, labor and delivery. Therefore, it is impor-
tant to remember that these scoring systems may assist,
but do not replace, clinical judgement.
Risk factors for maternal sepsis
Several risk factors for maternal sepsis have been identi-
fied,2,6,25 leading to the widespread implementation of
guidelines for the prevention of sepsis in this vulnerable
patient population. It is now routine to screen and treat
asymptomatic bacteriuria (present in 2–7% of pregnant
women)26 and sexually transmitted diseases27 in early
pregnancy and to administer antibiotic prophylaxis for
cesarean delivery.28 Importantly, women who are trea-
ted with antibiotics in the perinatal period have been
found to remain at risk of sepsis and septic shock, sug-
gesting that a proportion of infections progress follow-
ing antibiotic treatment.17 Sepsis is more common in
parturients who are more than 35 years-old; and those
that have co-morbid conditions such as diabetes mellitus
and obesity, as well as those who have had invasive or
surgical procedures. With the increase in maternal age,
success of assisted reproductive technologies and
increased rates of cesarean delivery, a large proportion
of parturients will have at least one risk factor for mater-
nal sepsis.
Diagnosis and recognition of maternal sepsis
Challenges in early recognition of maternal sepsis
The physiological changes of pregnancy overlap with
hemodynamic changes associated with the initial presen-
tation of sepsis. For example, tachycardia represents a
normal physiological adaptation to pregnancy and
99
may also result from pain and increased maternal effort
required during second stage labor. The expanded
plasma volume in pregnancy and progesterone-induced
vasodilatation allow women to compensate for longer
before rapid deterioration.29 Furthermore, elevation in
nancy, making this parameter less distinctive in the fore-
warning of an activated host immune response.
Moreover, signs of systemic inflammation may be pre-
sent in various stages of labor and delivery, as a result
of prostaglandin treatment for induction of labor or
treatment of postpartum hemorrhage. A high index of
suspicion, with a detailed history and examination, are
therefore paramount for the early recognition of mater-
nal sepsis. The 2014 report by MBRRACE-UK states
‘think sepsis’ when presented with any unwell pregnant,
or recently pregnant, patient.30
Maternal signs and symptoms will vary depending on
the source of sepsis, but particularly ominous signs are
tachypnea, neutropenia, hypothermia and altered men-
tal status.2 Presentation may be associated with early
pregnancy loss, intrauterine death, fetal tachycardia or
fetal bradycardia. While fever is often the first vital sign
change that raises the index of suspicion of maternal
sepsis for clinicians, temperature alone is not a reliable
indicator of sepsis. In the Michigan series of maternal
deaths, 73% of women who died of sepsis were afebrile
at presentation and 25% did not develop a fever at all
during their hospitalization.31
Maternal early warning scoring systems
In the last decade, multiple early warning scoring sys-
tems have been developed to facilitate timely identifica-
tion of septic patients at risk for poor outcomes.
Unfortunately, many of these systems, such as the Mod-
ified Early Warning System (MEWS), have not proven
to be as useful as hoped in the maternal population,
because they do not take into account the physiological
changes of pregnancy, which overlap with clinical crite-
ria for diagnosing sepsis in the general population.32
Attempts have been made to adapt existing scores for
the obstetric population – for example, the ‘Sepsis
in Obstetrics Score’ has a higher positive predictive
value for admission to the ICU (16.7%) than its
non-obstetric comparators – the Rapid Emergency
Medicine Score (11.1%) and the MEWS (4.6%).33 In
the US, the National Council for Patient Safety pro-
posed the use of the maternal early warning criteria
(MERC)34 and in the UK, the 2007 Confidential
Enquiry into Maternal and Deaths report recommended
routine use of the Modified Early Obstetric Warning
System (MEOWS).2 While uptake of maternal early
warning systems following the recommendation has
been high over the past 10 years,35 clear evidence of out-
come benefit is lacking36 and validation studies have
shown high sensitivity but low specificity.37–39 Neither
100
the MERC nor the MEOWS have been formally evalu-
ated to determine if their use might lead to a reduction
in maternal morbidity.
A recent large, prospective, multicenter impact study
by Shields et al.40 investigated whether maternal mor-
bidity could be reduced with the implementation of
the ‘Maternal Early Warning Trigger (MEWT)’ tool.
Unlike the MERC and MEOWS, the MEWT tool was
designed to identify four of the major causes of maternal
morbidity resulting in ICU admission (i.e. sepsis, car-
diopulmonary dysfunction, preeclampsia-hypertension
and hemorrhage), and includes prompts to help expedite
patient assessment, investigation, management and a
differential diagnosis (for example it reminds providers
to consider the overlap in signs and symptoms between
sepsis and cardiopulmonary dysfunction). Using the
CDC-defined SMM and composite maternal morbidity
(at least one of CDC-defined SMM, namely hemorrhage
>500 mL for vaginal delivery or 1000 mL for cesarean
delivery without transfusion; need for dilation and
curettage; or ICU admission) as outcome measures,
the authors found that using the MEWT tool led to a
significant reduction in CDC-defined SMM ( 18.4%,
P=0.01) and in composite maternal morbidity
( 13.6%, P=0.01) when compared to pre-
implementation of the MEWT tool. Despite these
promising results, the positive predictive value for pre-
dicting sepsis was only 7% and the authors acknowl-
edged that the MEWT tool may not be generalizable
to centers with a low rate of sepsis. This finding is con-
sistent with others that have noted the poor ability of
screening tools to predict maternal sepsis.32,36
Maternal early warning scores need further refine-
ment to improve their ability to predict those with signs
of early sepsis and at risk of deterioration. The develop-
ment of obstetric scoring systems is, in part, hindered by
the lack of consensus regarding which vital signs should
be used and what values reflect normality in the obstet-
ric population.41 It has even been suggested that these
values should change depending on the stage of
Table 4 Updated initial sepsis bundles from the Surviving Sepsis Campaigna
To be completed within 3 hours of time of presentation:
1. Measure lactate level
2. Obtain blood cultures prior to administration of antibiotics
3. Administer broad spectrum antibiotics
4. Administer 30 mL/kg crystalloid over the first three hours for hypotension
or lactate 4 mmol/L
To be completed within 6 hours of time of presentation:
5. Apply vasopressors (for hypotension that does not respond to initial fluid
resuscitation) to maintain a mean arterial pressure 65 mmHg
6. In the event of persistent hypotension after initial administration (MAP
<65 mmHg) or if initial lactate was 4 mmol/L, reassess volume status
and tissue perfusion and document findings
7. Re-measure lactate if initial lactate elevated
a 120
Adapted from survivingsepsis.org MAP: mean arterial pressure.
Sepsis in pregnancy and the puerperium
pregnancy in which they are being measured.42 The
Pregnancy Physiology Pattern Prediction Study (4P
Study) aims to develop a database of physiology during
pregnancy and the postpartum period (NCT01509378).
It will provide data to define pregnancy-specific
thresholds at which an alert should be triggered and
from which more robust evidence-based scores can be
developed.43
Management of maternal sepsis
Sepsis care bundles
Shortly after the 2001 consensus conference, the SSC
was launched by the Society for Critical Care Medicine
(SCCM), the European Society for Intensive Care Med-
icine (ESICM), and the International Sepsis Forum
(ISF), with a goal of reducing sepsis mortality by 25%
in five years. They published management guidelines,
together with condensed versions of these guidelines or
‘care bundles’. Care bundles are groups of interventions
designed to guide the timing and implementation of
individual elements of care to improve outcome. The
first care bundles for sepsis were published in 2003,44
drawing many recommendations from those described
by Rivers et al. in the landmark randomized controlled
trial (RCT) of Early-Goal Directed Therapy (EGDT) in
2001.45 They have since been updated in 2008,46 2012,47
and most recently in 201648 (Table 4), to take into
account the publication of three large RCTs on EGDT,
all of which demonstrated no mortality benefit after ini-
tial volume resuscitation was complete and early antibi-
otic treatment had been initiated.49–51 Survival in all
three of these trials was much better than the original
Rivers study,45 suggesting that the management of septic
shock has improved with early implementation of
protocol-driven care, even if not strictly adherent to
the original EGDT protocol. The Royal College of
Obstetricians and Gynaecologists (RCOG) recommends
that sepsis should be managed in accordance with the
care bundles,52 because there is evidence to suggest that
Strength of recommendation, grade of evidence
Weak, low quality
Best practice statement
Strong, moderate quality
Strong, low quality
Strong, moderate quality
Best practice statement
Weak, low quality
C.E.G. Burlinson et al.
survival in sepsis is improved by following this guid-
ance.53 The elements of the bundles are based on the
currently available evidence and are designed to be com-
pleted in a specific time period. For each element, the
strength of recommendation and grade of evidence are
provided, or it is described as a ‘best practice statement’.
No modifications are suggested for the care of obstetric
patients. The UK Sepsis Trust has recently developed a
specific ‘sepsis toolkit’ for use in pregnancy and up to six
weeks postpartum.54 This decision support tool is based
on the 2016 National Institute for Health and Care
Excellence (NICE) recommendations on maternal sep-
sis, published after the preceding MBRRACE-UK
report.55
It must be remembered that almost all the evidence
used to develop management guidelines for sepsis are
based on RCTs in which pregnancy was an exclusion
criterion. To date, there are no large-scale studies of
sepsis management in the obstetric population, due
to ethical challenges in conducting randomized
research in septic parturients. The management of sep-
sis in the obstetric population is therefore largely
extrapolated from that of the general population (see
Appendix A).
Antimicrobial therapy
Observational studies have repeatedly demonstrated
that delay in initiation of antimicrobial therapy is asso-
ciated with poor outcome in sepsis. In an international,
multicenter study of over 17 990 patients with sepsis or
septic shock, there was a linear increase in mortality
per hour of delay in administration of antibiotics upon
recognition of sepsis.56 Similar results were demon-
strated in two recent retrospective studies involving
35 000 septic patients from 21 emergency departments57
and over 40 000 septic patients reported to the New
York State Department of Health.58 These data suggest
that antibiotics should be commenced as soon as possi-
ble after collection of blood cultures and within the first
hour of diagnosis.
The genitourinary tract is colonized with a large
variety of organisms. Not all of these cause infection
and sepsis but pregnant women who develop sepsis
are likely to be infected by more than one organism.59
Therefore, the initial choice of antibiotic should be
broad and based on local guidelines and patterns of
resistance, especially if the source is unknown.
Because Group A Streptococcus (GAS) and Escheri-
chia coli are the most common contributors to sepsis
in pregnancy and responsible for a significant propor-
tion of deaths, empiric coverage should include these
organisms. Compared to vaginal delivery, cesarean
delivery confers a five to 20-fold increase in risk of
infection and morbidity:28,60 this risk can be substan-
tially reduced by the use of prophylactic antibiotics
preoperatively.61 Although GAS is sensitive to
101
b-lactam antibiotics in vitro, sensitivity does not
always predict efficacy. Protein synthesis inhibitors
(e.g. clindamycin) have been demonstrated to be more
effective than b-lactams in animal models of GAS
infection62 and therefore, the Infectious Diseases Soci-
ety of America (IDSA) recommends that patients with
invasive GAS infection promptly receive penicillin (2–
4 million units every 4–6 hours intravenously) plus
clindamycin (600–900 mg every 8 hours intravenously)
for 10–14 days.63
Early involvement of an infectious disease specialist
can help with optimization of antimicrobial therapy,
especially when there is failure to respond to first-line
treatment.64 Once the culture and sensitivity informa-
tion is available, the spectrum of coverage should be
narrowed. Individualized antibiotic dosing may help
improve mortality in the sickest septic patients.65 In
accordance with the new SSC guidelines, dosing strate-
gies should be based on pharmacokinetic and pharma-
codynamic principles where possible. This
recommendation is based on the observation that ini-
tial doses of antibiotics are often insufficient due to
an increase in volume of distribution and augmented
renal clearance,66 two physiological changes invoked
by pregnancy. Moreover, maternal obesity is increasing
worldwide67 and is an independent risk factor for
maternal sepsis.68 Standard dosing of antibiotics in
the obese parturient may be inadequate due to altered
pharmacokinetics and tissue penetration. Swank et al.69
found that using 3 g instead of 2 g of prophylactic cefa-
zolin at the time of cesarean delivery, significantly
more women with body mass index >30 kg/m2 were
able to achieve the recommended minimum inhibitory
concentration for cefazolin. Other proposals to reduce
infections in the obese population include topical and
subcutaneous antibiotic regimens,70,71 prophylactic
subcutaneous drains72 and complex wound dress-
ings.73–75
Fluid therapy
Fluid management is challenging in a septic parturient.
A persistent positive fluid balance has been shown to
be an independent risk factor for mortality in sepis.76
Despite its low incidence, fluid overload and pulmonary
edema have contributed to maternal morbidity and
mortality.2 Concomitant use of oxytocin, pre-existing
cardiac disease or preeclampsia may further complicate
fluid management. The improvement in survival from
preeclampsia is largely attributable to more cautious
restrictive fluid regimens.77 The SSC guidelines recom-
mend crystalloid at an initial 30 mL/kg bolus; however,
this may be too aggressive in the obstetric population.
The choice of crystalloid has long been debated but
there is evidence that balanced crystalloid solutions are
associated with a lower mortality in sepsis as compared
to normal saline.78
102
Measuring adequacy of resuscitation
The goal in sepsis resuscitation is to restore normal tis-
sue perfusion. Central venous oxygen saturation (ScvO2)
and central venous pressure (CVP) have been used as
markers for adequate tissue perfusion and volume
replacement.45 However, these measurements require
the insertion of a central venous catheter and current
evidence does not support its widespread adoption.
The optimal CVP is unknown in pregnancy and is a
poor marker of intravascular volume.79,80 Furthermore,
ScvO2 has not been consistently shown to be a good
prognostic indicator or predictor of fluid responsive-
ness;81 however, very high ScvO2 levels are associated
with increased mortality in sepsis and may reflect
impairment of the microcirculation and mitochondrial
dysfunction.82,83 Using serum lactate clearance to guide
resuscitation in septic shock was shown to result in sim-
ilar mortality as using ScvO2.84 However, neither lactate
clearance nor central venous-to-arterial carbon dioxide
pressure difference (DP(v-a)CO2) have been shown to
consistently indicate an end-point to treatment or to
guide further treatment to improve outcome.85 Recent
consensus recommendations in cardiac output monitor-
ing suggest that echocardiography should be the pre-
ferred method for diagnosis and sequential monitoring
of response to resuscitation in shock, and that invasive
cardiac output monitoring is only required in those that
do not respond to initial treatment.86 Overall, there is a
trend away from more invasive to less invasive methods
of cardiac output monitoring. The new SSC guidelines
accordingly state volume status and tissue perfusion
may be assessed with either focused clinical examination
or two of the following: CVP, ScvO2, bedside cardiac
ultrasound, or dynamic assessment of fluid responsive-
ness via passive leg raise (PLR) or fluid challenge.87
For many obstetric units, the equipment and knowl-
edge to perform bedside echocardiography may not
always be obtainable. It has been suggested that PLR
is a quick, non-invasive and reversible way to assess
for fluid responsiveness,88 with some evidence to suggest
the hemodynamic response is similar between non-
pregnant controls and pregnant women at 22–24 weeks’
gestation.89 A standard PLR challenge does require
direct measurements of cardiac output and stroke vol-
ume using a non-invasive cardiac monitor, or other reli-
able surrogates such as changes in carotid or femoral
Doppler response before and after the maneuver.90 To
perform this on a pregnant patient, after obtaining base-
line measurements in a 45° semi-recumbent position
with left lateral displacement of 30° to minimize aorto-
caval compression, the head of the bed is flattened and
the legs are elevated to 45° for 30 seconds while main-
taining uterine displacement. One small study in sponta-
neously breathing healthy volunteers found that PLR
was 72% sensitive (95% CI 55% to 85%) and 100% speci-
fic (95% CI 40% to 100%) for predicting the presence of
Sepsis in pregnancy and the puerperium
fluid responsiveness.91 In ventilated patients, an increase
in the cardiac output or a surrogate measure, such as
mean arterial pressure (MAP) of 10%, after PLR indi-
cates fluid-responsiveness.92 While this remains to be
validated in the maternal sepsis population, PLR may
represent a useful alternative in units without access to
echocardiography.
Vasopressors and inotropes
Sepsis-mediated hypotension is the result of venous and
arterial vasoplegia, relative hypovolemia and myocar-
dial depression. If vasopressors are required to maintain
MAP after fluid resuscitation, SCC recommends nore-
pinephrine as the first-line agent,93 although a target
MAP may need to be individualized, as a MAP of
65 mmHg may well be too high in a previously healthy,
young patient. The MAP should therefore be interpreted
with reference to organ perfusion, urine output, lactate
clearance and fetal heart rate tracing if applicable, which
will give information about placental perfusion.47,94
Again, the SSC guidelines are based on evidence from
non-pregnant patients and there are little data on the
effect on placental blood flow of vasopressors, although
in a dual-perfused single-cotyledon human placental
model, norepinephrine did not affect perfusion on the
‘fetal side’.95
Regional anesthesia
Neuraxial techniques are generally deemed to be rela-
tively contraindicated in the septic patient. First, the
presence and degree of systemic vasodilation and cardio-
vascular compromise in sepsis makes further sympa-
thetic blockade resulting from neuraxial techniques
dangerous. Second, there may be concomitant thrombo-
cytopenia or coagulopathy, increasing the risk of bleed-
ing complications. Third, there may be an increased risk
of meningitis and epidural or spinal abscess.
A recently updated joint report from the American
Society of Anesthesiologists (ASA) and the American
Society of Regional Anesthesia (ASRA) recommends
individualized plans in patients with suspected sepsis
where neuraxial techniques are considered.96 Specifi-
cally, the guidelines recommend that providers should
consider pre-procedure history, physical examination,
and review laboratory results, when considering
alternatives in patients that are ‘high risk’– although
the term ‘high risk’ is not defined. In addition, the use
of prophylactic antibiotics for suspected bacteremic
patients is advocated and selection of the neuraxial tech-
nique should be made on a case-by-case basis.96 These
recommendations are based on case reports, case series
and surveys of practice and are not specific to the obstet-
ric population.
The obstetric anesthesiologist is frequently faced with
a dilemma when a febrile parturient with suspected
chorioamnionitis is requesting epidural labor analgesia.
C.E.G. Burlinson et al.
There is concern that a neuraxial technique may result in
seeding of the epidural or subarachnoid space in a bac-
teremic patient. It is difficult to base a decision on
whether to perform neuraxial anesthesia on laboratory
results, due to the normal increase in white cell count
in labor, and the poor correlation between white cell
count and presence of bacteremia in pregnancy.97 Few
guidelines exist to guide the use of neuraxial techniques
in the septic or bacteremic parturient.
Fortunately, infections related to labor epidural anal-
gesia are extremely rare in obstetric patients. This is
likely due to relatively short catheter durations (recent
evidence in the non-obstetric population indicates that
infection risk with epidural catheterization increases
over time, especially after four days),98 the use of pro-
phylactic antibiotics in chorioamnionitis and operative
delivery, and the fact that this population is generally
healthy. The Third National Audit Project (NAP 3) of
The Royal College of Anaesthetists found an incidence
of 1 in 47 000 cases of epidural abscess in the whole pop-
ulation of the project, with only one case in an obstetric
patient.99 Another retrospective review found only one
case in 505 000 women who received epidural anesthesia
for vaginal or cesarean delivery over a four-year
period.100 Although epidural abscesses are rare in the
obstetric population and often attributed to a break in
sterile technique, the presence of underlying medical
conditions such as diabetes may increase the baseline
risk. To complicate matters, epidural abscesses have also
occurred in low-risk postpartum women who did not
receive neuraxial analgesia.101
The risk of central infection from neuraxial tech-
niques is deemed to be very small in patients treated
with antibiotics.99,102 The current recommendation sug-
gests that patients with evidence of systemic infection
may safely receive single-shot spinal anesthesia, pro-
vided antibiotics have been commenced and a response
to treatment has been demonstrated.102 However, the
placement of an indwelling epidural catheter is more
controversial, although similar criteria are often used
in a clinical setting.
At present, there is no consensus on neuraxial tech-
niques in obstetric patients with intrapartum fever, bac-
teremia or sepsis. In a UK national survey sent to all
members of the Obstetric Anaesthetists Association
(OAA) via their approved survey system, there was sig-
nificant variation in provider responses in relation to
insertion of labor epidural catheters in the presence of
intrapartum fever. In this survey of 571 anesthesiolo-
gists, which was limited by only a 31% response rate,
31% stated they would site an epidural after antibiotics,
30% would site an epidural without antibiotics, 22%
would decide on a case-by-case basis, and 17% would
refuse to site an epidural and offer alternative analge-
sia.103 The findings of this survey highlight a need for
clearer guidance on this matter; however, the lack of
103
robust, high-quality evidence currently defies a definitive
statement on the risk of central nervous system infection
in patients with chorioamnionitis or bacteremia under-
going regional anesthesia.
General anesthesia
General anesthesia is often required in a septic parturi-
ent due to the inability to safely provide regional anes-
thesia or the need to control ventilation and
hemodynamics. The same precautions should be taken
for all pregnant and postpartum patients undergoing
general anesthesia, taking into account their increased
risk of aspiration, aortocaval compression from the
gravid uterus in the supine position, laryngeal edema
exacerbated by fluid resuscitation leading to increased
risk of difficult intubation, and the degree of cardiovas-
cular compromise due to sepsis.104 In the severely com-
promised patient, ketamine may be considered instead
of propofol as the induction agent for general anesthe-
sia.105 Once general anesthesia is achieved, invasive
monitoring should be placed to assist detection of early
hemodynamic changes and to guide vasopressor and
inotropic support. Early consultation of an intensivist
and transfer of the patient to ICU should be considered.
Effective communication with critical care physicians is
vital. Often serious incident and root-cause analysis will
be required to learn from what is a relatively rare event
in the majority of hospitals.106,107
Delivery considerations
The decision of whether as to deliver the fetus or con-
tinue the pregnancy is influenced by a number of factors
including the patient’s condition, the gestational age of
the fetus, the fetal condition, the presence of chorioam-
nionitis and the stage of labor. Attempting early delivery
in patients with severe cardiovascular compromise due
to sepsis may increase maternal and fetal mortality,108
unless chorioamnionitis is suspected as the source of
sepsis or a septic abortion has occurred.59,109 If the risks
of continuing the pregnancy outweigh those of early
delivery, administration of antenatal steroids and mag-
nesium should be considered to improve the outcome
of a premature fetus.110 Decisions relating to delivery
of the baby are ultimately the responsibility of the obste-
trician, although the anesthesiologist may advise on tim-
ing in relation to resuscitation of the mother.
Collaboration and discussion with the neonatal, inten-
sive care and microbiology teams; and the patient, are
also vital. If surgical intervention for source control,
including cesarean section, is required, the decision
about whether to proceed under regional or general
anesthesia should be made on a case-by-case basis, hav-
ing considered the risks and benefits of each approach.
To date, no large, RCTs has addressed the question of
whether neuraxial or general anesthesia would result in
better or worse outcomes in maternal sepsis.
104
One of the goals of sepsis management in the perina-
tal period is to maintain oxygenation and perfusion of
vital organs and the placenta, whilst identifying the
source of infection and treating it. In the antenatal per-
iod, maternal resuscitation is the key to ensuring fetal
wellbeing.111,112 Antepartum sepsis arising from the
uterus will require delivery for source control, despite
the fact that neonatal survival is correlated with gesta-
tional age. Attempts to delay delivery in this setting
are often too dangerous for the mother. Sepsis arising
antenatally from a non-uterine source is a more difficult
scenario. When sepsis is diagnosed in the antepartum
period, one prospective case-control study of a national
database in the UK from 2011 to 2012 found the median
(IQR) gestational age to be 35 weeks (27–40 weeks) and
the diagnosis-to-delivery interval to be zero days (1–7
days).9
Future developments
The overlapping physiological changes of pregnancy
and clinical features of sepsis in this high-risk patient
population would make a reliable biomarker particu-
larly useful. There is currently no ideal biomarker that
can indicate prognosis, predict progression of the dis-
ease and guide treatment in sepsis. Early identification
of those at risk of developing life-threatening septic
shock would enable early triage and treatment.
Biomarkers could also aid the differentiation of sepsis
from non-infective systemic inflammation in the inten-
sive care community, and in the parturient, and may
help distinguish likely benign ‘epidural fever’ from infec-
tious fever. This could reduce the unnecessary use of
antibiotics in both mothers and neonates, in an age of
increasing antimicrobial resistance.
Procalcitonin (PCT), a pro-inflammatory biomarker,
has been studied to help differentiate bacterial sepsis
from non-infective SIRS and guide antimicrobial stew-
ardship decisions.113 However, a PCT-guided antimicro-
bial escalation strategy did not improve survival, and in
fact prolonged ICU admission.114 A recent large,
prospective US study showed that PCT levels that do
not decrease by more than 80% independently predict
mortality in sepsis;115 however, it remains unclear what
measures should be used in patients with non-decreasing
PCT levels to improve outcomes.
Other potential areas of interest in developing novel
biomarkers are endothelial proteins, such as angiopoi-
etins; cell surface receptors, such as leucocyte surface
receptors; cytokine/chemokine signaling molecules;
immunomodulatory biomarkers; and potential genomic
regulators.116 The ExPRES-Sepsis Study that is cur-
rently in progress aims to explore the predictive value
of leucocyte surface markers in sepsis.117 Ultimately,
with a better understanding of the pathophysiology
and cellular processes driving sepsis, we can better define
Sepsis in pregnancy and the puerperium
sepsis as a set of distinct biochemical disorders that
can be targeted when creating diagnostic tests and
therapies.
Many challenges remain in the diagnosis and man-
agement of maternal sepsis. Further research is needed
to establish robust diagnostic criteria for sepsis and sep-
tic shock in the obstetric population and then develop
specific protocols accordingly. The new maternal defini-
tion and identification criteria will be tested and vali-
dated in a large global one-week cross-sectional study–
The Global Maternal Sepsis Study.118 Information on
prevention and management will be collected to inform
the development of strategies for reducing maternal
infections and sepsis in all-income countries. The Global
Maternal and Neonatal Sepsis Initiative will further the
development of identification criteria, prevention strate-
gies and management bundles, with the aim of accelerat-
ing the reduction of preventable sepsis deaths during
pregnancy and the puerperium by 2030.118
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Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at https://doi.org/10.
1016/j.ijoa.2018.04.010.