A 22-year-old female recent migrant presented at 31 weeks gestation (gravida 2 para 0) to the obstetric unit. She was complaining of diminished fetal movements. She had been well up to that morning but was complaining of increasing abdominal discomfort, and was becoming distressed. Examination showed she was not in labour but her abdomen was tender. Cardiotocograph showed a fetal heart rate of 130 bpm and poor variability. Two hours post admission, she was re-examined by obstetricians. Abdominal ultrasound failed to identify a fetal heartbeat. A diagnosis was made of intrauterine death, and initially a placental abruption was suspected. Ultrasound showed no thrombus and an intact placenta and so this was excluded. She was diagnosed as having a late miscarriage and the pain was assumed to be due to ongoing miscarriage. She was transferred to labour ward and a morphine PCA commenced for analgesia.
She received a dose of IV antibiotics on arrival to labour ward. At this point it was noted her oxygen saturations were falling and she was becoming increasingly drowsy, and this was felt to be due to sensitivity to the PCA. She was reviewed by obstetric anaesthetists who performed an arterial blood gas, which showed a marked metabolic acidosis with serum lactate of 6.3, and a diagnosis of severe sepsis was made. There was concern that the retained fetal material was the focus, and she was taken to theatre for emergency caesarian section. She was then transferred to ITU. By this stage she had developed established disseminated intravascular coagulation and pulmonary oedema. She developed rapidly worsening multiorgan failure and shock refractory to large doses of noradrenaline and died that evening, 8 hours post admission. Cause of death was found to be group A streptococcal sepsis.
What is the significance of sepsis in obstetric patients?
Sepsis was until recently the leading cause of direct maternal death in the UK (1), commonly due to group A streptococcal sepsis. Severe sepsis carries a mortality rate of 20-40%, increasing to 60% in presence of septic shock. Despite a decline in the overall UK maternal mortality rate, there has been an increase in deaths related to genital tract sepsis, particularly from community acquired Group A streptococcal disease. The mortality rate related to sepsis increased from 0.85 deaths per 100,000 maternities in 2003-2005 to 1.13 deaths in 2006-2008.
Risk factors for maternal sepsis include obesity, diabetes, anaemia, history of pelvic infection or Group B Streptococcal infection and black or minority ethnic origin, particularly recent migrants.
Invasive Group A β–Haemolytic Streptococcus (Streptococcus pyogenes or GAS) sepsis is relatively rare but can be catastrophic (2), as in this case. It is a gram-positive bacterium, which is responsible for a broad spectrum of diseases that range from simple and uncomplicated pharyngitis and skin infections (impetigo, erysipelas, and cellulitis) to scarlet fever and life-threatening invasive illnesses including pneumonia, bacteremia, necrotizing fasciitis, streptococcal toxic shock syndrome (TSS) and peripartum sepsis. It produces a number of virulence factors that play a major role in the pathogenesis of scarlet fever, TSS, invasion of soft tissues and skin and necrotizing fasciitis. These are the extracellular pyrogenic exotoxins A, B, and C as well as exotoxin F and streptococcal superantigen (SSA). All these toxins are able to trigger massive non-specific activation of T cells and production of inflammatory interleukins and cytokines, fuelling the systemic inflammatory response.
GAS also secrete a variety of proteins that play a major role in tissue invasion, including hydrolases that degrade proteins and nucleic acids, allowing it to cross tissue planes and produce fascial invasion.
Treatment for GAS sepsis is largely supportive, based on current doctrine of early, goal directed therapy established by Rivers (3), and optimizing oxygen delivery based on the work of Shoemaker (4, 5) and others collated by the Surviving Sepsis campaign. (6) The mainstay of antibiotic therapy remains beta-lactams such as benzyl-penicillin or macrolides such as clindamycin or a combination of the two in cases of invasive disease. Resistance is unusual. Other treatments suggested for severe GAS sepsis include continuous veno-venous haemofiltration to reduce antigenic and cytokine load.
There have been a number of studies exploring the use of intravenous immunoglobulins (IVIG) in the treatment of streptococcal sepsis and toxic shock. Immunity and the presence of antibodies to superantigens and exotoxins are thought to convey a degree of protection in some patients, and lower levels have been measured in those with more severe manifestations of GAS infection. Adjuvant Immunoglobulins have therefore been postulated as a potential treatment. IVIG is pooled immunoglobulin from a large number of donors, comprising mainly of IgG. A randomized controlled trial (7) investigated the use of high-dose intravenous immunoglobulin G (IVIG) as adjunctive therapy in streptococcal toxic shock syndrome in a multicenter, randomized, double-blind, placebo-controlled trial. The trial was prematurely terminated because of slow patient recruitment, and results were obtained from 21 enrolled patients (10 IVIG and 11 placebo recipients). The primary end point was mortality at 28 days, and a 3.6-fold higher mortality rate was found in the placebo group. However due to the small numbers this did not reach the level of statistical significance. There are a number of case reports where IVIG has been used to treat GAS sepsis (8) but conclusive evidence is yet to be delivered. Despite this, the Royal College of Obstetricians and Gynaecologists of the UK recommend considering its use in any case of maternal sepsis refractory to other treatments.(9)
Group A strep sepsis can be invasive, rapidly progressive and devastating. This is particularly the case during the puerperal period. Survival hinges on early recognition and prompt aggressive treatment. There may be a promising role for IVIG but this had yet to be fully elucidated.
1. Cantwell R, Clutton-Brock T, Cooper G et al. Saving Mothers’ Lives: Reviewing maternal deaths to make motherhood safer: 2006-2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG. 2011;118 Suppl 1:1-203.
2. Yamada T, Yamada T, Yamamura MK et al. Invasive group A streptococcal infection in pregnancy. J Infect. 2010;60:417-424.
3. Rivers E, Nguyen B, Havstad S et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.
4. Shoemaker WC, Appel PL, Kram HB. Role of oxygen debt in the development of organ failure sepsis, and death in high-risk surgical patients. Chest. 1992;102:208-215.
5. Shoemaker WC, Appel PL, Kram HB, Bishop MH, Abraham E. Temporal hemodynamic and oxygen transport patterns in medical patients. Septic shock. Chest. 1993;104:1529-1536.
6. Dellinger RP, Levy MM, Rhodes A et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41:580-637.
7. Darenberg J, Ihendyane N, Sjolin J et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2003;37:333-340.
8. Raithatha AH, Bryden DC. Use of intravenous immunoglobulin therapy in the treatment of septic shock, in particular severe invasive group A streptococcal disease. Indian J Crit Care Med. 2012;16:37-40.
9. Maternal Sepsis (Bacterial) Green top guide 64a. RCOG 2012.