Genital tract sepsis can occur throughout pregnancy as well as during the postpartum period and after miscarriage and termination of pregnancy. Death rates from genital tract sepsis have risen considerably over the last decade, from 0.85 deaths per 100 000 maternities in 2003–5 to 1.13 deaths in 2006–8 (Figure 1). It has become the leading cause of direct maternal mortality in the UK for the first time. In the most recent report of the Confidential Enquiries into Maternal Deaths in the United Kingdom there were 26 direct and 3 late direct deaths due to genital tract infection and almost 70% of them occurred due to substandard care (Figure 2). There is wide variation in the incidence in the published literature because of differing definitions.
Genital sepsis can cause severe maternal morbidity and mortality and result in increased healthcare expenses linked to prolonged hospital stay and readmission.[3, 4] Fetal complications include intrauterine death, while abnormal cardiotocographs can necessitate delivery, neonatal resuscitation and admission to a special care unit.
This article highlights parameters for screening and assessment and identifies measures to facilitate early diagnosis and treatment of genital tract sepsis. A significant percentage of maternal deaths can be prevented by changes in patient, practitioner and system factors.
Puerperal pyrexia is defined as a temperature rise to >38°C maintained over 24 hours or recurring during the period from the end of the first to the end of the tenth day after childbirth, miscarriage and termination of pregnancy (International Classification of Diseases [ICD]-10). Common causes include endometritis, wound infection, urinary tract infection, deep vein thrombosis, mastitis, pyelonephritis and pneumonia.
Puerperal pyrexia is no longer favoured as a diagnostic category. Contemporary terminology specifies:
The specific target of infection
This refers to infection of the fetal membranes (chorion and amnion) usually secondary to their spontaneous rupture. Bacteria in the genital tract ascend through the intact or ruptured membranes, causing infection.
Endometritis, endomyometritis and parametritis
This refers to infection of the endometrium and decidua, myometrium or parametrium, respectively. Postpartum endometritis occurs much more frequently subsequent to caesarean birth, with a reported rate of 5–30%, compared with 0.2–0.9% for vaginal birth.
Bacteraemia, viraemia or fungaemia
This occurs when viable bacteria, viruses or fungi are present in the bloodstream.
Systemic inflammatory response syndrome
This is defined as a response to a wide variety of severe clinical insults, manifested by two or more of the following:[8, 9]
temperature >38°C or <36°C
heart rate >90 beats/minute
respiratory rate >20 breaths/minute or partial pressure of carbon dioxide (PaC02) <32 mmHg
white blood cell count >12 000 mm3, <4000 mm3 or >10% immature forms.
This is a clinical syndrome defined as a systemic response to bacteraemia with identifiable pathogenic organisms. Severe sepsis is said to be present if there is organ dysfunction, hypoperfusion or hypotension.
Septic shock is defined as sepsis with refractory arterial hypotension, despite adequate fluid resuscitation, or blood lactate concentration >4 mmol/l.
This is a rare, aggressive, rapidly spreading necrosis of soft tissue infection associated with a high incidence of maternal mortality (ranging from 13–48%).
Risk factors for genital tract sepsis
Maternal morbidity and mortality could be reduced further by identifying contributing factors. Some risk factors stem from relatively predetermined maternal health and socioeconomic circumstances, whereas others are amendable factors.[6, 10, 11]
Identifiable factors that can trigger infection are shown in Box 1.
Table Box 1. Risk factors for genital tract sepsis
Factors relating to labour and delivery
• Genital infections, e.g. bacterial vaginosis, chlamydia, gonorrhoea, trichomoniasis
• Labour-related, e.g. preterm labour, prolonged rupture of membranes, prolonged labour, post-dates pregnancy, intrapartum fever, thick meconium staining, haemorrhage
• System disorders, e.g. diabetes, anaemia
• Procedure-related, e.g. use of internal fetal electrode, intrauterine pressure catheter or Foley catheter, multiple vaginal examinations, operative vaginal delivery, length of surgical procedure
• Complications of procedures, e.g. uterine perforation, retained products of conception, manual removal of placenta, residual dead space following wound closure• Invasive procedures, e.g. amniocentesis, cervical cerclage, delayed or omitted prophylactic antibiotics• Practitioner experience
• Teenage mothers, primigravidae
• Group B streptococcus infection, pelvic inflammatory disease
Genital tract sepsis is a polymicrobial infection in which aerobic and anaerobic bacteria are presumed to ascend from the lower genital tract into the fallopian tubes and pelvic peritoneum, as well as into the incised edges of the uterine myometrium following caesarean section.
The most common pathogens identified in genital tract tract sepsis are: β-haemolytic Streptococcus pyogenes; Lancefield group A streptococcus; Escherichia coli; Enterococcus faecalis; Pseudomonas; Staphylococcus aureus; Proteus; Streptococcus pneumoniae; Morganella morganii; Citrobacter koseri; Acinetobacter and Listeria. Mixed infection with two or more organisms can also occur. Methicillin-resistant Staphylococcus aureus (MRSA) infection can develop in some women during a prolonged stay in a critical care unit.
The pathophysiology of sepsis
Once septicaemia develops, the clinical condition of the woman can deteriorate very rapidly over the course of a few hours, particularly when endotoxin-producing organisms are responsible. Septicaemia triggers the production of pro-inflammatory mediators, tumour necrosis factor, interleukin-6 and interleukin-1, which causes neutrophil–endothelial cell adhesion, consumption of clotting factors and the formation of microthrombi.
In the initial stage of sepsis, the arteries and arterioles dilate (decreased resistance) and there is increased cardiac output (‘warm shock’), followed by decreased cardiac output and low blood pressure; subsequently, the typical features of shock appear (see Box 2). Poor capillary flow and obstruction by microthrombi decrease the delivery of oxygen and impair the removal of carbon dioxide and waste products, which leads to multisystem organ failure.
Sepsis can resemble the normal physiological changes of pregnancy (peripheral vasodilatation, tachycardia and increased cardiac output). However, these changes are severe in sepsis and continue along the septic shock spectrum.[12, 13]
Enhanced pulmonary microvascular pressure and permeability and the release of inflammatory mediators may promote effusion,[14, 15] leading to respiratory failure and acute respiratory distress syndrome; the mortality rate is 30–60%.[16, 17]
Acute renal failure occurs in approximately 19% of cases with moderate sepsis, 23% with severe sepsis and 51% with septic shock (when blood cultures are positive). Vasoconstriction is caused by increased renal sympathetic and angiotensin activity and cytokine-mediated renal cell injury.
Thrombocytopenia and consumption coagulopathy are often associated, favouring the formation of intravascular fibrin and contributing to the pathogenesis of disseminated intravascular coagulation.
Gastrointestinal and hepatic
Uncontrolled production of inflammatory cytokines by the Kupffer cells, ischaemia and endotoxins leads to cholestasis, hyperbilirubinemia and jaundice.
The goal is to exclude or identify generalised, system-specific sepsis (in the kidneys, lung, breasts, etc.) or genital tract sepsis.[21, 22] Many signs and symptoms of sepsis are similar to normal findings in pregnancy and postpartum, therefore, it is important to review the woman's notes before commencing history taking, paying attention to discharge notes. A vigilant, detailed history is crucial to identify risk factors (see Box 1). The presenting symptoms often give clues as to the source of infection.
The associated features of sepsis are shown in Box 3. It should be noted that pyrexia is not always a presenting symptom.
Table Box 3. Signs and symptoms of genital tract sepsis
aPTT = activated partial thromboplastin time; FiO2 = fractional inspired oxygen; INR = international normalised ratio; PaO2 = partial pressure of oxygen in arterial blood
▪ Fever (core temperature >38.3°C)
▪ Hypothermia (core temperature <36°C)
▪ General malaise, shaking chills
▪ Heart rate >90 beats/minutes or >2 standard deviations above the normal value for age
▪ Altered mental status (confusion, lethargy)
▪ Significant oedema or positive fluid balance (>20 ml/kg over 24 hours)
▪ Hyperglycaemia (plasma glucose >120 mg/dl or 7.7 mmol/l) in the absence of diabetes
▪ Normal white blood cell count with >10% immature forms
▪ Plasma C-reactive protein >2 standard deviations above the normal value
▪ Plasma procalcitonin >2 standard deviations above the normal value
▪ Arterial hypotension (systolic blood pressure <90 mmHg, mean arterial blood pressure <70 mmHg, or a decrease in systolic blood pressure >40 mmHg in adults or <2 standard deviations below the normal for age)
▪ Mixed venous oxygen saturation >70%
▪ Cardiac index >3.5 l/minute/m2
Organ dysfunction variables
▪ Arterial hypoxaemia (PaO2/FiO2 ratio <300)
▪ Acute oliguria (urine output <0.5 ml/kg/hour or 45 mmol/l for at least 2 hours)
▪ Creatinine increase >0.5 mg/dl
▪ Coagulation abnormalities (INR> 1.5 or aPTT >60 seconds)
▪ Ileus (absent bowel sounds)
▪ Thrombocytopenia (platelet count <100 000/μ1)
▪ Hyperbilirubinaemia (plasma total bilirubin >4 mg/dl or 70 mmol/l
Tissue perfusion variables
▪ Hyperlactataemia (>1 mmol/l)
▪ Decreased capillary refill or mottling
The breasts should be examined for redness, tenderness, localised masses and cracked nipples. The fundal height should be measured and the abdomen examined for tenderness and any masses or swellings. A subinvoluted, tender uterus with lower abdominal pain and purulent and foul-smelling lochia are characteristic of genital tract sepsis. Abdominal and perineal wounds should be inspected for signs of infection, haematoma or dehiscence. The heart sounds and lung fields should be checked for signs of infection. The legs should be inspected for signs of deep venous thrombosis such as tenderness along the course of the deep veins or unilateral oedema of the lower leg.
Full blood count
The white cell count may not be elevated; however, a trend of repeated counts will map the progress of the infection. The C-reactive protein may be elevated early in the course of the illness. A low platelet count may be the first indication of complications such as septicaemia or disseminated intravascular coagulation.
Blood culture and other investigations
Blood should be taken for culture (preferably two cultures) before the first dose of antibiotics is given. If necessary, samples for culture from other sites should be taken, including vaginal swabs and samples of body fluids such as urine and cerebrospinal fluid. A number of bacterial infections can be identified by rapid detection testing of urine. These should be repeated at intervals if the woman remains unwell (even if the results are negative) and are best obtained during the peak of temperature and chills.[4, 23, 24]
The levels of blood urea, creatinine and electrolytes and the erythrocyte sedimentation rate may be altered. Blood gases, serum lactate levels and a coagulation screen should be performed if the woman is clinically unwell. Liver function test results may be elevated during the course. Infections such as hepatitis, HIV, tuberculosis and cytomegalovirus should be excluded if suspected.
The D-dimer test is non-specific during pregnancy; however, it can be useful in the puerperium.
Ultrasound evaluation may be performed to determine the presence of retained products of conception, to ensure that the uterus is empty following manual or surgical evacuation and to assess any pelvic collection.
A colour flow Doppler scan can enable precise diagnosis and localisation of pelvic vein thrombosis.
A chest X-ray, electrocardiogram, Doppler examination of the leg, ventilation/perfusion scan and computed tomography (CT) pulmonary angiogram may help to exclude venous thromboembolism. Computed tomography of the abdomen may detect pelvic or abdominal abscesses. Additionally, blood films, testing for anti-nuclear antibodies and rheumatoid factor, and echocardiography may be useful in selected women.
The management of genital tract sepsis
Treatment of sepsis is based on the timing and clinical severity of the illness and consists of supportive inpatient care, antipyretics, antibiotics (parenteral or oral), fluid replacement and possible uterine exploration if retained products are suspected.
Consultant involvement with a multidisciplinary team (microbiologists, anaesthetists and intensive care specialists) should be provided as early as possible. Critically ill women should be looked after in an intensive care or high dependency unit.
Routine observation of vital signs is essential for the early detection of severe illness. In hospital practice the Modified Obstetric Early Warning Scoring system (systolic blood pressure, respiratory and heart rates, temperature and level of consciousness) is recommended to help reduce deaths through early recognition of serious illness.
If genital tract infection (chorioamnionitis) occurs in the antenatal period, delivery may need to be expedited.
Endometritis is frequently a diagnosis of exclusion after thorough evaluation fails to identify physical or laboratory evidence of infection on another site.[4, 23]
First-line broad-spectrum antibiotics which cover for β-lactamase-producing anaerobes are recommended.[23, 24] Although combination therapy (clindamycin and an aminoglycoside) is the gold standard treatment of endometritis, empirical treatment with a cephalosporin and metronidazole is frequently used as first-line therapy. (See Box 4.)
Table Box 4. Guiding principles for antibiotic therapy in genital tract sepsis[1, 9]
• Prompt and early treatment with a combination of high-dose, broad-spectrum intravenous antibiotics, such as co-amoxiclav, cefuroxime and metronidazole, can be life saving.
• Microbiology results should be obtained as soon as possible.
• You should not wait for microbiology results
• The expert advice of a consultant microbiologist should be sought at an early stage.
• Serum levels of antibiotics should be within the therapeutic range.
• The duration of therapy should typically be 7–10 days.
• If the woman is allergic to penicillin and cephalosporins, clarithromycin 500 mg twice daily or clindamycin 600 mg–1.2 g by intravenous infusion, three to four times daily, should be considered.
• Antibiotic prophylaxis for termination of pregnancy (metronidazole 1 g rectally at the time of termination, plus, commencing on the day of the termination, either doxycycline 100 mg orally twice daily for 7 days or azithromycin 1 g orally) is offered routinely in accordance with RCOG guidelines.
• In cases of preterm, prelabour rupture of membranes, prophylactic erythromycin is recommended.
• If group A streptococcal infection is suspected, clindamycin (600 mg–1.2 g by intravenous infusion, three or four times daily) is more effective.
• In severe sepsis or septic shock: piperacillin with tazobactam 4.5 g every 8 hours or a carbapenem such as meropenem (500 mg–1 g every 8 hours by intravenous injection over 5 minutes or by intravenous infusion).
• If there is no response within 24–48 hours or the woman's condition is deteriorating, the antibiotics should be changed and gentamicin or alternative antibiotics added, as guided by microbiological advice.
Once adequate therapy is initiated, rapid improvement is anticipated. Failure of fever to resolve within 48–72 hours requires multidisciplinary input; an atypical organism or extragenital cause of sepsis should be suspected.[24, 26, 27] Surgical treatment in the form of evacuation of the uterus or even laparotomy may be necessary to drain any abscesses that form after caesarean or vaginal delivery.
Figure 3 shows an algorithm for the management of suspected genital tract sepsis.
If the woman is well enough systemically, oral combinations of amoxicillin and metronidazole are advocated. If chlamydia is suspected, doxycycline should be prescribed.
Management of septic shock
In cases of septic shock, critical care management involves the administration of intravenous antibiotics within 1 hour and resuscitation with fluids. According to the 2005 Surviving Sepsis Campaign guideline, each hour of delay in starting appropriate antibiotics decreases the chance of survival by 7.9%.
During the first 6 hours of resuscitation the aim should be to achieve:
central venous pressure 8–12 mmHg
mean arterial pressure >65 mmHg
urine output >/0.5 ml/kg per hour
central venous (superior vena cava) or mixed venous oxygen saturation >70% or >65%, respectively.
The role of vasopressors
In severe cases, where the mean arterial pressure cannot be achieved by fluid infusion, vasopressor agents such as noradrenaline or dopamine should be used. Dobutamine is preferred if the cardiac filling pressure is elevated and there is reduced cardiac output.
The role of steroids
There is some evidence to support the use of low-dose steroids (hydrocortisone <300 mg/day) if a woman does not respond to fluid and vasopressors.
Recombinant human activated protein C
This is reserved for women who are at high risk of death (APACHE II score >25).
Transfusion may be required to keep the haemoglobin level between 7–9 mg/dl and the platelet count >5 x 109/l at all times (>50 x 109/l if surgery is required).
Infection of the perineum
A small proportion of women experience significant delays in healing due to infection (midline episiotomy, third or fourth-degree lacerations, episiotomy extension and vaginal haematoma). The perineum should be evaluated for pain, oedema, redness, ecchymosis, purulent discharge, abscess formation and gaping of the tissues. Rectovaginal examination, under adequate analgesia, should be performed to exclude occult rectal injury (with the potential for rectovaginal fistula), inadvertent rectal stitches or the presence of haematoma. Infection should be treated before dealing with rectal injury.
In the case of perineal abscess, prompt evaluation, initiation of antibiotic therapy and surgical debridement (removal of all suture material, along with removal of all necrotic tissue) under appropriate analgesia may be required.
Superficial breakdown in the absence of local or systemic signs or symptoms should be treated with expectant management (frequent use of a bidet and perineal hygiene), as antibiotic therapy may not be necessary. Early closure of perineal wounds may be attempted to maintain perineal integrity.[28, 30]
Scrupulous attention to hand washing and firm adherence to aseptic technique remain the fundamentals of sepsis prevention. Critical evaluation of individual risk for infection, coupled with conscientious postpartum assessment, allows improved detection and prompt treatment.[6, 11, 21]
After medical management of miscarriage in early pregnancy, infection is often delayed (this occurs in 0.1–4.7% of cases)[31, 32] and the prophylactic use of antibiotics for evacuation of retained products of conception or for medical management of miscarriage is not standard care in most units.
Prophylactic antibiotic administration during caesarean birth has been shown to decrease the incidence and severity of postpartum endometritis, fever and wound infection by as much as 75%.[33, 34]
A recent randomised, double-blind, placebo-controlled trial by Sullivan et al. demonstrated that administration of cehalosporins 15–50 minutes before skin incision resulted in decreased infectious morbidity (relative risk [RR] 0.4, 95% CI 0.18–0.87) and endometritis (RR 0.2, 95% CI 0.15–0.94). The control group received cephalosporins at the time of cord clamping, suggesting that delaying antibiotic administration resulted in bacterial contamination of the uterus and subcutaneous tissues.
Another Cochrane review concludes that a single dose of either ampicillin or a first-generation cephalosporin administered at caesarean birth has similar efficacy in reducing the incidence of post-caesarean endometritis and wound infections, with an odds ratio of 1.27 (95% CI 0.84–1.93).
Use of a combined broad-spectrum antibiotic regimen should be considered for women at significant risk for post-caesarean infection.
Preventative measures for vaginal delivery do not differ substantially from those for surgical delivery, termination of pregnancy and miscarriage, apart from antibiotic prophylaxis for group B streptococcus carriers and limiting the number of vaginal examinations in labour.
In the latest report on the Confidential Enquiries into Maternal Deaths1 it is clearly highlighted that genital tract sepsis is still a problem due to missed diagnosis and failure to treat aggressively enough in the early stages. Sepsis should be considered in all recently delivered women who feel unwell and who have pyrexia. Prompt recognition and treatment of sepsis is required to prevent the onset of systemic infection or localised tissue necrosis. Nevertheless, the clinical picture of life-threatening sepsis often develops very rapidly and in some cases a poor outcome cannot be prevented.
Any problems noted during a hospital stay should be reported directly to community carers (general practitioners, midwives and health visitors) so that they can provide appropriate follow-up visits and recognise the development of significant symptoms. Early discharge means that some women develop complications after they return home.
Consistent documentation and reporting of sepsis are needed to improve epidemiological evaluation of the true magnitude of this problem.
The development of a reproducible and accepted standard of care is needed, which includes individualised risk assessment, clinical evaluation, objective diagnostic criteria and evidence-based treatment to minimise the morbidity and mortality related to genital sepsis.
There is a clear need to raise both maternal and professional awareness about genital tract sepsis so that it can be prevented and, where possible, recognised quickly and managed effectively and immediately.
Screening for infection (high vaginal and cervical swabs) should be undertaken in high-risk cases.
Prophylactic antibiotics should be given to women undergoing surgical or medical termination of pregnancy, evacuation of retained products of conception or caesarean section, or who have third and fourth-degree perineal tears.
Disseminated intravascular coagulation and uterine atony are causes of massive postpartum haemorrhage in the presence of genital tract sepsis.
Delivery should be expedited to avoid rapid deterioration.
Any problem during an inpatient stay should be communicated to general practitioners and community carers for appropriate follow-up visits.
Sepsis is often insidious in onset, with a fulminating course, therefore, the severity of illness should not be underestimated.
Vigilant and early referral to hospital can be life saving.
Sepsis should be considered in all delivered women who have a high temperature or who feel unwell.
All maternity units should have guidelines for the investigation and management of genital tract sepsis.
If sepsis is suspected, regular observations should be recorded using the Modified Obstetric Early Warning Scoring system.
High-dose intravenous broad-spectrum antibiotics should be started without waiting for microbiology results.
Maternal tachycardia, constant severe abdominal pain and tenderness are important early features of genital tract sepsis.
All health professionals must be aware of the signs and symptoms of genital tract sepsis and the possibility of rapid deterioration, which is potentially lethal.