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Review

New Concept and Management for Sepsis in Pregnancy and the Puerperium

Fan, Shang-Rong1,2,∗; Liu, Ping1; Yan, Shao-Mei1; Huang, Lei3; Liu, Xiao-Ping4

Editor(s): Shi, Dan-Dan

Author Information
doi: 10.1097/FM9.0000000000000058
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Abstract

Introduction

Maternal sepsis is a life-threatening condition with organ dysfunction resulting from infection during pregnancy, childbirth, post-abortion, or in the postpartum period.1 The World Health Organization estimated that the global prevalence of maternal sepsis is 4.4% among live births, with an incidence of 9–49 per 100 000 deliveries in high-income countries depending on the definition used and population studied.1 The incidence of pregnancy-associated severe sepsis in the USA has increased by 236% over the past decade, rising from 11 hospitalizations per 100 000 annual total estimated pregnancies in 2001–2002 to 26 in 2009–2010.2 Prospective studies in the UK have suggested that labor and the puerperium may have a 2- to 3-fold increased risk of sepsis compared to the antenatal period.3 Several studies from developed countries have shown that the rate of maternal sepsis has been increasing in the last decade, with high mortality rates.2–6

Maternal sepsis is the main cause of maternal death and a major contributor to severe maternal morbidity worldwide,5,7–24 accounting for 11% of maternal deaths worldwide and is the third most common direct cause of maternal death.20 Maternal sepsis is currently the third or fourth leading cause of maternal mortality in the USA, accounting for 13% of all maternal deaths with a cause-specific maternal mortality ratio of 2.2 deaths per 100 000 live births5,6 In low- and middle-income countries, rates of fatality after puerperal infection can be as high as 50%.1 Under new sepsis definitions,25 some representative reports gave ranges on the mortality of sepsis in the general population of 25%–30%. The mortality range for septic shock was 40%–70%.26

Failure to recognize sepsis early is a significant cause of preventable morbidity, resulting in delayed treatment and escalated care, which are critical if lives are to be saved.27 There are only a few evidence-based and pregnancy-specific guidelines for healthcare providers regarding how to best treat, prevent and recognize the early warning signs of peripartum sepsis.20,21 In this review, we aim to discuss the new definitions regarding sepsis and recommended diagnosis and management strategies of sepsis adapted to pregnant and postpartum women.

Pathophysiology

The pathophysiology core issue is a multifaceted host response to an infecting pathogen that may be significantly amplified by endogenous factors. The “sepsis 1” and “sepsis 2” focused solely on inflammatory excess. Sepsis is now recognized to involve early activation of both pro- and anti-inflammatory responses, along with major modifications in nonimmunologic pathways such as cardiovascular, neuronal, autonomic, hormonal, bioenergetic, metabolic, and coagulation, all of which have prognostic significance. Patients with sepsis can have clinical presentations in various systems, including respiratory, cardiovascular, hepatic and gastrointestinal, renal, hematological, endocrinological, and central nervous systems.25 Maternal sepsis may cause intra-amniotic infection, which results in (1) premature rupture of membranes or preterm labor or birth; (2) cerebral white matter damage or cerebral palsy or neurodevelopmental delay; (3) stillbirth; (4) early- or late-onset sepsis; (5) perinatal death.28–31Figure 1 shows the pathophysiology and manifestation of sepsis. Figure 2 shows the microscopic findings in the placenta of one 26 weeks pregnant woman with septic shock and stillbirth caused by Listeria monocytogenes infection.

Figure 1
Figure 1:
Causes and major related organ system changes in patients with sepsis. Maternal sepsis can result from chorioamnionitis, endomyometritis, pyelonephritis, or pneumonia, which cause multiple organ dysfunction or failure such as respiratory, cardiovascular, hepatic and gastrointestinal, renal, hematological, endocrinological, and central nervous system dysfunction or failure and adverse perinatal outcomes.
Figure 2
Figure 2:
Microscopic findings in the placenta of one 26 weeks of gestation pregnant woman with septic shock and stillbirth caused by Listeria monocytogenes infection. A The villi are distended and contain numerous acute inflammatory cells (acute villitis). B The villus was destroyed by the inflammation, and fibrinogen (placental villous fibrinoid necrosis). C Umbilical phlebitis shows amniotropic migration of fetal neutrophils into the muscle layer of the umbilical vein. D Umbilical arteritis is a stage 2 fetal inflammatory response. (HE staining, 100×). HE: hematoxylin and eosin.

Causes, risk factors, and microorganisms

Causes and risk factors

Changes in maternal immune responses occur during pregnancy to protect the unborn fetus from rejection. These changes may predispose pregnant patients to the development of infections. Sepsis may be due to obstetric or non-obstetric causes.32 The obstetric causes include uterine infection, such as chorioamnionitis and endomyometritis, septic abortion, and wound infection. Sepsis may follow invasive procedures such as amniocentesis, chorionic villus sampling, cervical cerclage, or percutaneous umbilical blood sampling. In a French study, the most common source of bacteremia was chorioamnionitis (47%).33 The non-obstetric causes of sepsis include pyelonephritis and pneumonia.32

Maternal sepsis may also be from obstetrical critical illness, such as obstetric severe hemorrhage,34 obstetric (amniotic fluid/pulmonary) embolism, acute fatty liver of pregnancy (AFLP),35 and congestive heart failure, cardiopulmonary arrest, major trauma, and 2019 coronavirus disease infection.36–38 In an Indonesian study, 12 of 18 patients with AFLP died due to maternal sepsis, and AFLP was the common direct cause of maternal death.39–41

Risk factors correlated with the development of sepsis during pregnancy are as follows. Obstetric-related risk factors: group A streptococcal infection in close contacts/family members; a history of group B streptococcal infection; the induction of labor; invasive procedures such as amniocentesis and cervical cerclage, prolonged rupture of membranes; instrumented or cesarean delivery; a lack of prenatal care; mastitis; preeclampsia; postpartum hemorrhage; retained products of conception; the use of antibiotics within 2 weeks of birth, including prophylaxis for cesarean sections; and wound hematoma. Patient-related risk factors: anemia; chronic hypertension; diabetes mellitus; decreased function of the spleen; group A streptococcal infection in patients with close contact with individuals with a history of pelvic infection; immunosuppression; obesity; poverty; and poor nutrition.42–48

Microorganisms

The most commonly reported pathogens in maternal sepsis include Escherichia coli, Streptococcus, Staphylococcus, and other gram-negative bacteria.49–51Streptococcus type A, although currently infrequent, may cause maternal sepsis following abortion or labor and cause shock, with a mortality of 30%–60%.52–55 Group A streptococcal infections are invasive, and toxin production allows the organism to spread across tissue planes and cause necrosis while evading containment and abscess formation by the maternal immune system.53–57 Maternal sepsis caused by Candida has been reported. Maternal Candida sepsis could cause chorioamnionitis, stillborn birth, abortion, preterm birth, and congenital Candida infection in newborns.58–61 The reported rare microorganisms in maternal sepsis include Clostridium innocuum, Clostridium novyi, Plasmodium vivax, and Chlamydia psittacosis.28,62–64Figure 3 shows the organisms isolated from maternal blood cultures in sepsis during pregnancy and the puerperium.3,33,49,51,65–72

Figure 3
Figure 3:
Organisms isolated from maternal blood cultures in sepsis during pregnancy and the puerperium. aIncluding: Clostridium perfringens 35 strains and Clostridium sp. 5 strains. bIncluding: Klebsiella pneumoniae 31 strains and Klebsiella oxytoca 2 strains. cIncluding: Acinetobacter baumannii 19 strains, Acinetobacter Lwoffii 5 strains and Acinetobacter junii 1 strain. dIncluding: Enterobacter cloacae 17 strains and Enterobacter Species 3 strains. eIncluding: Bacteroides fragilis 5 strains, Bacteroides capillosus 1 strain, Bacteroides melaminogenicus 1 strain and Bacteroides sp. 13 strains. fIncluding: Pseudomonas aeruginosa 5 strains, Pseudomonas fluorescens 2 strains, Pseudomonas alcaligenes 1 strains and Pseudomonas sp. 4 strains. gIncluding: Morganella morganii 6 strains, Haemophilus influenzae 5 strains, Citrobacter freundii 3 strains, Citrobacter sp. 1 strain, Meningococcus 3 strains, Moraxella sp.2 strains, Raoultella ornithinolytica 2 strains, Brucella sp.1 strain, Flavimonas oryzihabitans 1 strain, Fusobacterium necrophorum1 strain, Gardnerella vaginalis 1 strain, Salmonella Enteritidis 1 strain, Veillonella sp. 1 strain and Other gram-negative bacteria 19 strains. hIncluding: Streptococcus agalactiae 122 strains, Group A streptococcus 58 strains, β haemolytic streptococcus Lancefield group A 35 strains, Streptococcus pyogenes 23 strains, Streptococcus Miller 9 strains, Streptococcus unspecified 8 strains, haemolytic streptococcus Lancefield group B 5 strains, Group C streptococcus 3 strains, Group G streptococcus 2 strains, Streptococcus salivarius 2 strains, Streptococcus oralis 1 strain, Streptococcus Gallolyticus 1 strain, Streptococcus pyogenes (A) 1 strain, β haemolytic streptococcus Lancefield group C 1 strain, β haemolytic streptococcus Lancefield group D 1 strain and Streptococcus sp. 23 strains. iIncluding: Staphylococcus aureus 123 strains, Staphylococcus epidermidis 11 strains, coagulase negative staphylococci 4 strains, Staphylococcus Saprophyticus 2 strains, Staphylococcus lugdunensis 1 strain and Staphylococcal sp. 35 strains. jIncluding: Enterococcus faecalis 21 strains and Enterococcus spp. 17 strains. kIncluding: Tuberculosis 6 strains, Actinobacter 1 strain and other gram-positive bacteria sp.32 strains. lIncluding: human immunodeficiency virus 12 strains, H1N1 3 strains, Varicella 2 strains and Toxoplasma gondii 3 strains and Candida 1 strain.

Screening and diagnosis

To recognize maternal sepsis early, many early warning scores have been developed. Bauer et al. studied screening tools for sepsis in pregnant women.51 The sensitivity and specificity of sepsis screening tools with the highest to lowest sensitivity were systemic inflammatory response syndrome, maternal early warning, and quick sequential organ failure assessment (qSOFA) criteria, and the highest to lowest specificity were qSOFA, maternal early warning, and systemic inflammatory response syndrome. Foeller and Gibbs proposed an obstetrically modified qSOFA.46 Currently, there are no ideal screening tools for sepsis in pregnancy. Table 1 shows the common screening tools for sepsis in pregnancy.25,46,73–76 The diagnosis of sepsis is based on a sequential organ failure assessment (SOFA) score of ≥2 with a suspicion of infection. In individuals with no baseline disease, the initial SOFA score should be zero. The higher SOFA score, the probability of mortality is more increased. The present definition of sepsis emphasizes signs of organ dysfunction rather than signs of infection. The main diagnosis procedures include blood cultures and cultures from any suspected source of infection, additional laboratory tests, and imaging to confirm the suspected anatomic site of infection.25,32Table 2 shows the SOFA score criteria.77

Table 1
Table 1:
Definitions of SIRS, qSOFA, and omqSOFA criteria.
Table 2
Table 2:
Sequential (sepsis-related) organ failure assessment score.

The differential diagnoses include hypovolemic or hemorrhagic shock, pulmonary embolism, myocardial infarction, acute pancreatitis, diabetic ketoacidosis, primary adrenal insufficiency, and transfusion reaction.45

Management

The management includes initial respiratory and haemodynamic stabilization, the initiation of empiric antimicrobial treatment with broad-spectrum agent therapy within the first hour of diagnosis, source control within the first 12 hours if possible, and the prevention of complications and sequelae.

The elements of the 2018 bundle, intended to be initiated within the first hour, include blood cultures before antibiotics, lactate measurement, the administration of broad-spectrum antibiotics, the administration of a 30 mL/kg crystalloid fluid bolus in cases of hypotension or high serum lactate levels of at least 4 mmol/L, and the administration of vasopressors to maintain a mean arterial pressure of at least 65 mm Hg.78–80Figure 4 shows the main management of sepsis during pregnancy and the puerperium.32

Figure 4
Figure 4:
Management of sepsis during pregnancy and the puerperium. DVT: Deep venous thrombosis; FHR: Fetal heart rate; PCT: Procalcitonin.

Antibiotics

The early and appropriate use of antibiotics is crucial in the management of maternal sepsis.81 Mortality is increased by 7.6% with each hour delay in appropriate antibiotic administration in the general population.82 The spectrum might need to be broad, covering both gram-positive and gram-negative pathogens. Antibiotic coverage for maternal sepsis should be aimed at covering the most common bacteria: E. coli, Staphylococcus, Streptococcus, and other gram-negative bacteria. Viral and fungal cover should be considered, if suspected. Combination therapy is preferred over monotherapy.

Most often, a broad-spectrum carbapenem (eg, meropenem, imipenem/cilastatin, or doripenem) or extended-range penicillin/β-lactamase inhibitor combination (eg, piperacillin/tazobactam or ticarcillin/clavulanate) is used. Several third- or higher-generation cephalosporins can also be used, especially as part of a multidrug regimen.79 The surviving sepsis campaign strongly recommends antibiotic stewardship in the de-escalation of antibiotics tailored to specific microorganisms to prevent drug resistance. Optimal antibiotic duration remains contentious, and few prospective randomized controlled trials have been performed. The surviving sepsis campaign guidelines suggest 7–10 days.79 Procalcitonin levels can be used as a biomarker for the initiation, de-escalation, and discontinuation of antimicrobial therapy.79,83–85 Schuetz et al. found that the inability to decrease procalcitonin by more than 80% is a significant independent predictor of mortality.86 When suspected, invasive group A streptococcal infections should be treated emergently with aggressive fluid resuscitation, antibiotic administration (penicillin and clindamycin), and source control that may be extensive and may involve hysterectomy. Table 3 proposes broad-spectrum empiric antibiotic coverages in sepsis during pregnancy and the puerperium.32,44,75,79,87–92

Table 3
Table 3:
Proposed broad-spectrum empiric antibiotic coverage in sepsis during pregnancy and the puerperium.

Source control

Once a source of sepsis is identified, source control is a priority and may involve abscess drainage or the delivery of the fetus if the uterus is found to be the source of the infection. There is a direct increase in mortality with each 6-hour delay in achieving source control.32,75,79 If surgical intervention for source control, including cesarean section, is required, the decision about regional or general anesthesia should be made on a case-by-case basis. 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 gestational age to be 35 weeks (interquartile range 27–40 weeks) and the median diagnosis-to-delivery interval was 0 day (interquartile range 0–36 days).49 Hysterectomy were performed on 5.4% of severe sepsis cases.93

Extracorporeal membrane oxygenation (ECMO)

As a treatment for respiratory failure in patients in the intensive care unit, ECMO has been used increasingly during pregnancy and the puerperium.94–96 Based on published reports, overall maternal and fetal survival rate on ECMO were 80% and 70%, respectively.97 ECMO may be a choice for the treatment of refractory sepsis.

Fetal considerations

It is imperative to stabilize the mother first, and the fetal status will also improve. The decision of whether to deliver the fetus or to continue the pregnancy is influenced by a number of factors, including the patient's condition, the gestational age of the foetus, the fetal condition, the presence of chorioamnionitis and the stage of labor. In the setting of antenatal sepsis, there should be frequent assessment of fetal status after viability. Efforts should be aimed at treating maternal sepsis and prolonging pregnancies that are far from term if the source of infection is outside the uterus. If the source of sepsis is from the uterus, delivery of the fetus is required. If delivery is imminent, then betamethasone should be administered if gestational age is less than 34 weeks. A previable fetus (<23 to 24 weeks, depending on institutional practice) may not need fetal monitoring.32

Gaps and future directions

Seacrist et al.98 studied quality improvement opportunities identified through a review of cases of maternal death from sepsis and found several key deficiencies in the care of women who died from sepsis. Quality improvement opportunities were identified in the readiness, recognition, response, and reporting domains of the 4R framework. The single most common theme in their findings was women's lack of recognition of the signs and symptoms of sepsis or of the risk for sepsis during the initial birth hospitalization or postpartum period. Health-care facilities and providers need to reduce barriers for women who seek care, recognize early symptoms, and respond with appropriate treatment. Many cases of maternal sepsis give rise to litigation. The reasons for the litigations include failure to recognize sepsis; failure to instigate appropriate investigation; delayed treatment; incomplete treatment; failure to consider urgent delivery; failure to isolate the source of infection; failure to involve senior clinicians at an early stage; failure to utilize a multidisciplinary team, including anesthetists, intensivists, microbiologists, and infectious disease specialists, at an early stage; delay in recognizing failed treatment and instigating additional or alternative antimicrobials; and failure to transfer to the critical care setting.

It is important from both a clinical and research viewpoint to remain up to date and understand the change in terminology of sepsis. Further research into risk factors for maternal sepsis is required to reduce the incidence and to facilitate early identification and treatments. Interventions such as ECMO have gained increasing support and require more studies to assess their role in the management of maternal sepsis.

Conclusions and recommendations

Sepsis remains a major cause for the admission of pregnant women to the intensive care unit and is a leading cause of maternal morbidity and mortality. The causes of maternal sepsis include obstetric and non-obstetric causes. Maternal sepsis may also be from obstetrical critical illness. The most commonly reported pathogens in maternal sepsis include E. coli, Streptococcus, Staphylococcus, and other gram-negative bacteria. The management of sepsis during pregnancy should follow the same basic principles as that in the nonpregnant population, including early recognition, fluid therapy, timely broad-spectrum antibiotics, and source control.

Acknowledgment

Figure 1 was drawn by Shengmenart.

Funding

This research was supported by the Shenzhen Science and Technology Innovation Commission (JCYJ20180228162311024).

Conflicts of Interest

None.

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Keywords:

Sepsis; Pregnancy; Puerperium; Maternal; Fetal; Morbidity; Mortality; Maternal near-miss

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