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Septic Shock in Obstetrics and Gynecology

Septic shock is a life-threatening clinical syndrome caused by decreased tissue perfusion and oxygen delivery, as a result of severe infection and sepsis. The insertion of bacteria or viruses into the blood stream produces a condition called bacteremia or viremia. Sepsis is the systemic inflammatory response due to bacteremia. When sepsis worsen to the point where blood pressure cannot be maintained with intravenous fluid alone, then the condition is called septic shock and may be accompanied with multiple organ dysfunction (liver, kidney, heart, brain). The mortality rate remains high, range between 25 and 50%1. Septic shock is the first cause of deaths in intensive care units patients2.


Incidence of sepsis and septic shock
An accurate estimation of the incidence of sepsis and septic shock is hampered by the lack of reliable case definition. Inconsistent application of sepsis definition criteria contributes to confusion and variability in the literature 10 . The Centers for Disease Control estimated an incidence of 73.6 per 100,000 population in 1979, rising to 175.9 per 100,000 in 1989 11 . The rates have been probably increased because of more immuno-suppressed patients, new immunomodulating therapy, increased use of invasive devices (e.g., central venous catheters), and an increase in antibiotic resistance 5,6,12 . A review of discharge data on approximately 750 million hospitalizations in U.S.A. over a 22-year period (1979-2000) identified 10,319,418 cases of sepsis 5 . Sepsis was more common among men than among women (mean annual relative risk, 1.28; 95% CI: 1.24-1.32) and among non-white persons (mean annual relative risk 1.90; 95%CI: 1.81-2.00) 5 . However, these data is hampered due to the broad definition of sepsis and may be overestimate the accurate incidence of sepsis and septic shock since include all the ICD-9-CM * codes for definition of sepsis (038 [ into the myometrium in order to promote recrudescense of an inflammatory process 23,24 . A recent longitudinal study during uncomplicated pregnancies revealed a general trend toward enhanced counter-regulatory cytokine expression (IL- 10), and an overall decrease of pro-inflammatory (Th1; TNFa, IL-1β, and IL-6) cytokines expression 25 . Pregnancy itself does not impair the woman's immunological system and other risk factors have to be implemented to develop infections in pregnant women.

Risk factors and routes of infection in pregnancy
Sepsis during pregnancy usually is the result of invasion of the uterine cavity with bacterial pathogens. Although transplacental spread of infection can occur in women with bacteremia that doesn't correlate with pregnancy, the most common route is an ascending infection from bacteria colonize the vagina and/or the cervix 15 . Pelvic infections in pregnant women have their microbiologic origin in one of three sources: the endogenous vaginal microflora, the intestinal microflora, and sexual transmission 26 . The infection occurs via migration of the organisms from the vagina through the endocervix into the uterus. Some organisms may traverse the columnar epithelium, as is the case with infection caused by Neisseria gonorrhoeae and Chlamydia trachomatis 26 . Bacteria such as Streptococcus agalactiae may gain entrance to the uterus and fallopian tubes via the lymphatics 26 . A third route of migration is by ascending into the pregnant uterus and colonizing amniotic fluid. Then bacteria are able to reproduce and reach numbers in excess of 10 5 per milliliter of amniotic fluid 27 . Risk factors for the development of maternal sepsis include home birth in unhygienic conditions, low socioeconomic status, poor nutrition, primiparity, anaemia, prolonged rupture of membranes, prolonged labour, multiple vaginal examinations in labour (more than five), caesarean section, multiple pregnancy, artificial reproductive techniques, overweight and obstetrical manoeuvres 14,28 .

Reasons for infection and sepsis during pregnancy
Physiologic changes in the lower genital tract, such as a decreased in pH and increased glycogen in the vaginal epithelium, place the pregnant woman at risk for intra-amniotic infection. Pregnant women, with the enlargement of uterus, especially during the 3 rd trimester, may cause stricture or even obstruction of the ureter, predisposing for the development of pyelonephritis. In addition, normal pregnancy is characterized by numerous changes in the hemostatic system, creating the hypercoagulable state which increases the risk of venous thromboembolic event occurrence 29 . An elevated leukocyte count, associated with a slightly increased c-reacting protein, and increased heart rate of 15-20 bpm, may mask early signs and symptoms of infection favouring the dissemination of bacteria into the blood-stream. Conditions that predispose pregnant women to septic shock syndrome can be intra-amniotic infection, septic abortion, septic pelvis thrombophlebitis, postpartum endometritis, pyelonephritis, wound infection, necrotizing fasciitis, appendiceal abscess, cholecystitis and invasive procedures like amniocentesis, chorionic villus sampling, and cervical cerclage placement. Moreover, septic shock in pregnancy can be due to reasons that don't correlate with pregnancy. Non-obstetric septic shock can be caused by pneumonia and peritonitis with origin in colon, gastro-duodenum, post-duodenal small bowel, biliary tract and appendix. (Table 1

Chorioamnionitis and intra-amniotic infection
Intra-amniotic infections before 1970 was a major cause of maternal mortality because of patient delays in seeking treatment, unavailability of intensive care, and the absence of broad spectrum antibiotics 30 . Nowadays, the association of intraamniotic infections with septic shock, coagulopathy, and adult respiratory syndrome (ARDS) is rare, accounting for less than 1% in cases of intraamniotic infections 30,31 . It is important to note that intraamniotic infections in pregnancy usually are polymicrobial in nature. The most common route is an ascending infection from one or more of the endogenous flora of the cervix or vagina. The (Table 2). It is important to note when group B β-Streptococcus or Escherichia coli are the causative pathogens, the incidence of bacteremia is higher (18% and 15%, respectively) 30 . As a consequence of intraamniotic infection is the spontaneous rupture of membranes by weakening the membranes, either by a direct effect of microorganisms on the membranes or indirectly by activation of the host defense mechanisms. However, there is not an absolute and exclusive correlation between intra-amniotic infection and spontaneous rupture of membranes. Rupture of membranes predispose but not secure the development of intraamniotic infection. This is especially true, after the administration of broad spectrum antibiotics. An estimated 5-10% of women with intraamniotic infections have bacteremia 30 . Almost half of the patients with bacteremia will demonstrate signs and symptoms of sepsis 32 . Approximately 40% of patients with sepsis have the condition progress to septic shock 33 . Progression from intraamniotic infections to bacteremia, sepsis, and septic shock can occur in a few days or several hours. Typical clinical manifestations of septic shock appeared additionally to the signs of intraamniotic infections and include altered mental status, peripheral vasodilation, tachypnea, tachycardia, temperature instability, hypotension, increased cardiac output, and decreased peripheral resistance 31,34 . If the condition is not promptly identified and aggressively treated, progressive symptoms of peripheral vasoconstriction, oliguria, cyanosis, ARDS, disseminated intravascular coagulation, decreased cardiac output, and decreased peripheral resistance may occur 34 .

Aerobic bacteria
Group Chorioamnionitis is an acute inflammation of the membranes and chorion of the placenta. Typically is the result of ascending polymicrobial bacterial infection in the setting of membrane rupture. It can also occurs with intact membranes after infection with Ureaplasma species and Mycoplasma hominis, found in the lower genital tract 35 . Only rarely is hematogenous spread implicated in chorioamnionitis, as occurs with Listeria monocytogenes 36 .Overall, 1-4% of all births in the U.S.A. are complicated by chorioamnionitis 36 ; however, the frequency varies markedly by diagnostic criteria, specific risk factors, and gestational age 37,38 . The key clinical findings include fever, uterine fundal tenderness, maternal tachycardia (>100/min), fetal tachycardia (>160/min), and purulent or foul amniotic fluid 36,39 . The most common organisms isolated in up to 47% and 30% respectively, in cases of culture confirmed chorioamnionitis are Ureaplasma urealyticum and Mycoplasma hominis 40,41 . Chrorioamnionitis leads to a 2 to 3-fold increased risk for caesarean delivery and to 2 to 4fold increase in endomyometritis, would infection, pelvic abscess, bacteremia, and postpartum hemorrhage [42][43][44] . Women with chorioamnionitis in 10% have positive blood cultures (bacteremia) 36 . Fortunately, septic shock, disseminated intravascular coagulation, adult respiratory distress syndrome, and maternal death are only rarely encountered 44,45 . In contrast, fetal exposure to infection may lead to fetal death, neonatal sepsis, and septic shock. In one study, neonatal pneumonia, sepsis, and perinatal death occurred respectively, in 4%, 8%, and 2% of term deliveries associated with chorioamnionitis 46 . The frequency of neonatal sepsis is reduced by 80% with intrapartum antibiotic treatment 47 . Prompt initiation of antibiotic therapy is essential to prevent both maternal and fetal complications in the setting of clinical chorioamnionitis 44 . Time-to-delivery after institution of antibiotic therapy has been shown to not affect morbidities; therefore caesarean section to expedite delivery is not indicated for chorioamnionitis unless there are other obstetric indications 44,48 .

Does the mode of delivery affect the incidence of sepsis and septic shock?
Nowadays, rates of caesarean section (CS) are progressively increasing in many parts of the world. There has been an increasing tendency for pregnant women without justifiable medical indications for CS to ask for this procedure. Despite the World Health Organization's estimate that CS rates should not be >15%, in the developed world, CS rates are already above 30% 49,50 . Following CS, maternal mortality and morbidity may result from a number of infections including endometritis, urinary tract infection and surgical site infection, which if deep rather than superficial, increase hospital stay and cost per case 51-53 .
The most common infection-related complication following CS is endometritis 53 . A major risk factor for post-CS infection is emergency CS (compared with elective).
The rate of infection following CS is 1.1-25% compared with 0.2-5.5% following vaginal birth [54][55][56] . In antepartum patients the most common infection is asymptomatic bacteriuria with an incidence estimated at 4-7%. However, with the use of prophylactic antibiotic treatment is extremely rare these infections to become sepsis and septic shock, regardless of the mode of delivery. Recent evidence suggests that pre-incision broad spectrum antibiotics are more effective in preventing post-CS infections than post-clamping of the cord narrowrange antibiotics, without prejudice to neonatal infectious morbidity 57 . Prophylactic antibiotics can reduce the incidence of endometritis following CS by two thirds to three quarters 53 . Data from Europe for the years 2003-2004 showed a range of maternal mortality ratio from 2/100,000 live births in Sweden, to 29.6/100,000 in Estonia 58 . Direct maternal mortality associated with CS was about 0.06‰ 59 . However, very few women are dying from primary infection and sepsis. Haemorrhage is the main cause of death following by thromboembolism and preeclampsia. Even though the majority of women are dying during puerperium (60%), the infection mostly started during pregnancy or delivery and only in rare cases after delivery and subsequently was not correlated with the mode of delivery. Collectively, we can suggest that CS affects the incidence of infection and hospitalization of women but is not correlated with severe sepsis and septic shock.

Amniocentesis, chorionic villous sampling (CVS): Routine procedures but invasive?
Although amniocentesis and CVS are routine procedures in prenatal diagnosis and are nowadays performed in most clinics under continuous ultrasonographic vision and aseptic conditions, they are invasive procedures carrying potential risks of serious complications for both the mother and the fetus. Intrauterine infection is a rare event after invasive prenatal diagnostic procedures 60 . According to data from large studies, the incidence of chorioamnionitis is 5 per 1,000 cases after CVS; 3.7 per 1,000 cases after amniocentesis; and 8.8 per 1000 cases after cordocentesis, compared with 3 per 1,000 cases in non-exposed women 61,62 . Infection is usually mild to moderate. There are, however, sporadic reports in the literature describing cases of post-procedure sepsis with devastating results60. Deterioration to septic shock may develop in 0.03% to 0.19% of intra-amniotic infection cases 63 . Contamination of the uterine cavity after amniocentesis or CVS may occur through ascending infection, direct inoculation of intestinal germs, and rarely, after use of deficiently sterilized equipment and direct spread of the infection from the vagina to the blood stream, by-passing the uterus 64 . Direct inoculation of vaginal or cervical pathogens into the uterine cavity may underlie the development of sepsis after trans-cervical CVS [65][66][67] . The reported rate of transient post-procedure bacteremia is 4.1% for transcervical CVS and nearly zero for transabdominal procedure 64,68 . Inoculation of intestinal germs has been implicated in cases of sepsis after transabdominal procedures. In such cases, peritoneal signs are expected to predominate 69 . Incubation time is usually short, and the onset of symptoms is usually manifested within 24 hours after the procedure. The onset can be insidious, but the clinical and laboratory indicators deteriorate quickly, and the progress can be fulminant 60 . Clostridium perfrigens, together with Escherihia coli, are the most common pathogens encountered in cases of sepsis after prenatal diagnosis and they are associated with severe and serious complications. Other pathogens isolated from endometrial remnants or blood cultures after amniocentesis or CVS include Klebsiella pneumoniae, Enterobacter, Staphylococcus aureus, Serratia rubidaea, Citrobacter, Clostridium welchii, group B β-hemolytic streptococcus, and Candida albicans ( Table 3). Administration of prophylactic antibiosis is not recommended since most retrospective studies failed to prove a direct association between needle insertion and maternal or fetal complications [70][71][72] . Prospective, double-blind studies in this topic are lacking. In cases of sepsis, evacuation of the uterine cavity and suction curettage can be performed. In severe cases prompt hysterectomy with the dead fetus in situ may be advisable if there is evidence of sepsis with hemolysis, multiple organ failure and rapid progress of infection. However, the decision to perform hysterectomy is difficult, especially in a case of a young nulliparous woman or a woman with an affected child and should be performed only in cases where woman's life is at risk. Although very rare, potentially fatal sepsis can occur after invasive prenatal diagnostic procedures. Sepsis can begin with very subtle clinical signs and symptoms, but quickly develop complications, which can become irreversible if intervention is delayed.

Septic abortion
Septic abortion, an abortion related with infection and complicated by fever, endometritis, and parametritis, remains one of the most serious threats to the health of women throughout the world 85 . More than 95% of the septic abortion and septic shock cases are synonymous with illegal, criminal or non-medical abortions 86 63 Amniocentesis Hysterectomy NA Recovery C. welchii Fray et al. 73 Amniocentesis Hysterectomy NA Recovery Clostridium+S. rubidaea+Citrobacte r Muggah et al. 74 CVS Hysterectomy DIC-ARDS Recovery E. coli Hovav et al. 75 Amniocentesis D&C ARDS-ARF Recovery C. perfrigens+E.coli Ayadi et al. 76 Amniocentesis  Table 3. Case report of sepsis after invasive prenatal diagnosis The risk of sepsis from abortion rises from the first trimester of pregnancy to the second 89 . In the first trimester, abortion is readily performed by vacuum curettage, usually in an outpatient setting. Incomplete abortions produced by incompetent physicians represent another risk factor. Insertion of rigid foreign objects into the uterus or cervix increases the risk of perforation and infection 93 . Intrauterine instillation of soap solution containing cresol and phenol has been abandoned, due to the risk of uterine necrosis, renal failure, toxicity to the central nervous system, cardiac depression, and respiratory arrest 94  Chlamydia trachomatis are all possible pathogens 86,97 . Because of the variety of bacterial agents that can be associated with septic abortion, no-one antibiotic agent is ideal. The regimens recommended for outpatient management of pelvic inflammatory disease (PID) are appropriate for early post-abortion infection limited to the uterine cavity 95 . The diagnosis of septic abortion must be considered when any woman of reproductive age presents with vaginal bleeding, lower abdominal pain, and fever. If the woman has had symptoms for several days, a generalized, serious illness may be present. Bacteremia, which is more common with septic abortion than with other pelvic infection, may result in septic shock and the adult respiratory distress syndrome 98 . Management of severe sepsis requires eradication of the infection and supportive care for the cardiovascular system and other involved organ systems. Any tissue remaining from the pregnancy must be evacuated without delay as soon as antibiotic therapy and fluid resuscitation have been started. In critically ill women with severe sepsis, a hysterectomy will probably be needed. Other indications of laparotomy are uterine perforation with a suspected bowel injury, a pelvic abscess, and clostridial myometritis 98 . Cervical dilation with laminaria placement has been also associated rarely, with septic abortion and septic shock 99 . Laminarias are sea plant with hydroscopic properties that enable their expansion up to five times in diameter over 12-24 hours, thereby gradually dilating the cervix. The potential of laminarias to harbor pathogens led some investigators to speculate that colonization of laminaria tents may lead to post-abortion infection. However, with modern sterilization techniques, the associated infection rates are similar to those achieved with standard methods for cervical dilation 99 . Nowadays, medical termination of pregnancy using mifepristone and/or misoprostol doesn't require admission to the hospital or anesthesia and is alternative to surgical termination 100 . The incidence of uterine infection after medical termination of pregnancy is very low. However, severe and fatal infections have been reported in certain cases; most of them were associated with Clostridium infections and development of toxic shock syndrome [101][102][103] . Klebsiella pneumoniae has also been reported as the cause of septic shock after medical termination of pregnancy with misoprostol-only regimen 100 . Although a direct association of these drugs and septic shock has established, it was postulated that mifepristone blocks both progesterone and glucocorticoid receptors and affects the innate immune system 104 . However, most of these severe and occasionally fatal complications are the result from inappropriate usage of drugs without any medical monitoring and consultation.

Non-obstetric causes of septic shock
Septic shock in the pregnant woman usually results from an infection in the urinary or genital tract. Pyelonephritis is the most frequent cause of bacterial shock associated with pregnancy 105 . Enlargement of the uterus during the 2 nd and 3 rd trimester of pregnancy may cause stricture and/or obstruction of the ureters, a condition that predisposes to urinary infections and pyelonephritis. Escherichia coli is responsible for most of the cases. Klebsiella pneumoniae, Proteus species, and Enterobacter-Citrobacter are less common pathogens. All pregnant women should be screened for the presence of bacteriuria at their first prenatal visit. Failure to treat bacteriuria during pregnancy may result in as many as 25% of women experiencing acute pyelonephritis106. Acute pyelonephritis has an incidence of approximately 0.1-1% in pregnancy; most occurs at second trimester107. It is associated with multiple complications, including fetal growth restriction, preterm labour, cerebral palsy and septicemia, although the underlying mechanisms are poorly understood 108 . One mechanism could be the alteration in the profile of angiogenic and anti-angiogenic factors (increased expression of vascular endothelial growth factor [VEGF], decreased expression of PIGF and sVEGFR-2) observed in cases with acute pyelonephritis that resembles the one observed in sepsis 109 . In most reports of acute pyelonephritis the incidence of bacteremia is not stated. However, 20% of women with severe pyelonephritis will develop complications that include septic shock syndrome or its presumed variants 110 . These latter include renal dysfunction, hemolysis and thrombocytopenia, and pulmonary capillary injury. In another series of 55,621 pregnant women with acute pyelonephritis, the incidence of septic shock in pregnancy was 3.77% 111 . The first fatal case of gestational interstitial tubulonephritis and chronic pyelitis caused by Escherichia coli has been recently described 112

Septic shock in gynecologic patients
In Gynecology, incidence of sepsis have been increased during the last 15 years, presumably due to an aging population, an increase in the number of invasive procedures performed, and possibly due to a resistance to the current antibiotic treatment appeared in the infecting pathogens. Sepsis-related situations in Gynecology can be found, in women using intra uterine devices (IUD), after untreated pelvic inflammatory disease (PID), after toxic shock syndrome provoked mainly by the use of tampons during menstrual period, and in patients with gynecological cancer. The above causes will be discussed explicitly, thereafter.

Toxic shock syndrome
Toxic shock syndrome (TSS), is a rare, life-threatening, multiorgan illness that is caused by toxins that circulate in the bloodstream. Development of TSS involves three distinct stages: local proliferation of toxin-producing bacteria at the site of infection, production of toxin, and exposure of this toxin to the immune system with resultant immune response 113,114 . Toxic shock syndrome was initially identified as a pediatric infection in 1978 115 . Subsequent reports identified an association with tampon use by menstruating women. [116][117][118] . Menstrual TSS is more likely in women using highly absorbent tampons, using tampons for more days of their cycle, and keeping a single tampon in place for a longer period of time. Over the past two decades, the number of cases of menstrual TSS (1 case per 100,000) has steadily declined; this is thought to be due to the withdrawal of highly absorbent tampons from the market 116 .
In the most typical form of toxic shock syndrome, the bacteria, most commonly, group A Streptococcus, Staphylococcus aureus and Clostridium sordellii produce an enterotoxin that transfers into the bloodstream, provoking the overstimulation of the immune system. This, in turn, causes the severe symptoms of TSS, such as: fever, rash, myalgias, diarrhea, vomiting, headache, sore throat, vaginal discharge, rigors, desquamation (typically of the palms and soles), hypotension, and multi-organ failure (involving at least 3 or more organ systems 116,119,120 . The mortality rate of toxic shock syndrome is approximately 5-15%, and recurrences have been reported in as many as 30-40% of cases 121,122 .
The role of tampons in the pathogenesis of TSS is incompletely understood. Although tampons are not a source for toxigenic S.aureus and do not appear to increase the S. aureus cell density vaginally, studies have shown that tampons used during menstruation often colonized with this pathogen 123,124 . Vaginal conditions during menses and tampon use, contribute to the proliferation of toxin-producing S.aureus. An elevated vaginal temperature and neutral pH, both of which occur during menses are enhanced by tampon use, allowing bacterial proliferation 125 . Endometrial blood can serve as a medium for bacterial growth; persistence of this blood in the cervical and vaginal canal with tampon use has been also shown to increase the proliferation of S.aureus 126 . In addition, synthetic fibers are thought to alter the availability of certain substrates to lactobacilli, a normal vaginal colonist that limits the proliferation of S.aureus. The same conditions also aid in the production of TSS Toxin-1.
Menses and tampon use increase the partial pressure of both oxygen and carbon dioxide, which also stimulate toxin production 127 . In addition, tampons obstruct the flow of endometrial blood and may even cause the reflux of blood and bacteria into the uterus. Toxic shock syndrome is the typical example of a systemic inflammatory response syndrome, with virtually all of the effects derived from immune mediators rather than as a direct result of infection. The diagnosis of TSS should be considered in a patient who presents with septic shock but without any obvious source of infection. The case fatality rates for menstrual-related STSS have declined from 5.5% in 1980 to 1.8% in 1996 121,122 .
Organ supportive therapy remains the standard of care with antibiotics used to prevent recurrence, although newer immune-based therapies are being developed that may help in the treatment of TSS and other inflammatory syndromes in the future.

Pelvic inflammatory disease (PID)
Pelvic inflammatory disease (PID) refers to acute infection of the upper genital tract structures in women, involving any or all of the cervix, uterus, fallopian tubes, ovaries and surrounding structures. By definition, PID is a community-acquired infection, initiated by a sexually transmitted agent, distinguishing it from pelvic infections due to medical procedures, pregnancy and other primary abdominal processes. Pelvic inflammatory disease in the United States annually accounts for about 2,5 million outpatient visits, 200,000 hospitalizations and 100,000 surgical procedures 128 133 . Then an ascending infection occurs causing: cervicitis, endometritis, salpingitis or hydro-, pyosalpinx. In tubes and ovaries, salpingo-oophoritis (acute, subacute and chronic) or a tuboovarian abscess may also occur. In the peritoneal cavity spreading of the infection causes pelvic and/or generalized peritonitis or a pelvic abscess. Infection may be also spread through the uterine wall into broad ligaments to cause pelvic cellulitis (parametritis), a broad ligament abscess or septic thrombophlebitis of the ovarian or uterine veins, leading to septicemia with few local signs 134 . Bacteremia is an unusual condition and is not correlated with PID. Blood cultures for women hospitalized with acute PID showed negative results in 97% of the cases 135 . The results of blood culture are not affect the clinical management of PID and routine specimens may not be needed from patients hospitalized for acute PID 135 . However, if diagnosis and treatment are not performed in a timely manner, PID may cause sepsis, septic shock and even death. Even if they survive, as many as 15% to 20% of these women experience longt e r m s e q u e l a e o f P I D , s u c h a s e c t o p i c p r e g n a n c y , t u b o -o v a r i a n a b s c e s s , i n f e r t i l i t y , dyspareunia and chronic pelvic pain. The best treatments for PID are interventions that lead to prevention and early detection 136 .

Intrauterine devices (IUD)
Intrauterine contraceptive devices (IUDs) are highly effective, long-term methods of contraception. It is also one of the most cost-effective method available, providing long-term protection 137 . Most modern IUDs are medicated; they contain either copper or a progestin to enhance the contraceptive action of the device. The total number of current IUD users is estimated at over 150 million women worldwide 138 . Infection risk is a relative contraindication to fitting any woman with an IUD, it is only present for a few weeks after insertion and probably arises from an undiagnosed cervical infection at the time of insertion. Although evidence of a direct association between IUD use and PID is scarce, concerns about PID related to IUDs use has limited their use throughout the world. On the other hand, bacteriologic cultures of removed IUDs have shown that the bacterial flora of the removed IUDs consisted of common aerobic and anaerobic microorganisms that do not account for PID 139 . In a study with 200 subjects, the most common bacteria identified from removed IUDs were Staphylococcus coagulase negative, Esherichia coli, and Enterococcus faecalis 139 . The authors concluded that culture of the removed IUDs and therapeutic management of women with positive cultures are not recommended when women are asymptomatic for PID 139 . A systematic review reported the risks of PID with insertion of an IUD in the presence of existing infection. With IUD insertion in the presence of Chlamydia infection or gonorrhoea, subsequent PID rates were 0-5%, compared to insertion in the absence of infection (0-2%) 140 . Although trial results do not indicate the need to screen for and treat sexually transmitted diseases before inserting and IUD 141 , it is rationale to suggest that the insertion of an IUD is indicated only in women with negative vaginal cultures (  Table 4. Conditions in which intrauterine contraception is and is NOT contraindicated (WHO, 2004) In cases of vaginal infection, it is possible that the insertion of an IUD carries bacteria into the uterus and traumatizing the endometrium causes several infections. Cases of vaginitis 143 , transfer of actinomyces into the uterine cavity 144 , PID 145 , and even toxic shock syndrome 146 , and sepsis 147 , have occasionally been reported. Three cases of streptococcal toxic shock syndrome following insertion of an IUD have been reported, recently 146,148,149 . This pathogen is not normally found in the vaginal flora or after an intrauterine device is inserted 150 . However, an association between the use of IUD and the risk for infection and sepsis does not exist. Conditions which represent an unacceptable health risk if an IUD is inserted are: current PID, current purulent cervicitis, chlamydial or gonorrheal infection, as well as, pelvic tuberculosis, puerperal sepsis, and septic abortion (Table 4) 151 .

Gynecologic cancer
Sepsis and septic shock are not directly associated with gynecologic cancer. The female cancer patient is a vulnerable patient. Usually after having undergone a difficult operation, followed up by several chemotherapy cycles, has reduced defenses against infection due to: a) reduced antibody formation; b) deficient cell immunity; c) reduced or abnormal granulocytes; d) damaged mucocutaneous barriers, such as, ulceration of the oropharynx due to methotrexate toxicity; e) obstruction of biliary and urinary tracts. Thus, myelosuppression may also give rise to an acute septic problem associated with neutropenia, granulocytopenia. In these patients, any infection may have an acute form leading to rapid septicemia and severe shock developing rapidly. The frequency of patients with gynecologic cancer and septic shock is not seen very often. In a recent study, the mortality rate was 33% (of 6 reported cases, 2 died) 152 . Sepsis can occur independently of the optimal management of cancer. Among 74 women with gynecologic cancer, there was one death due to the development of septic shock in a patient with optimal cytoreductive operation 153 . Toxic shock syndrome has been developed in a patient with a metastatic cervical cancer 154 . In advanced operations (pelvic exenterosis) where a colostomy has been performed, there is also a possibility of sepsis due to spillage of stool upon maturing the colostomy 155 . When operations for gynecologic cancer involve the intestine there is increased possibility for sepsis. In a series of 113 patients three died due to sepsis post-operatively 156 . Early diagnosis, careful monitoring, prompt removal of septic foci, and appropriate antibiotic and supportive treatment are the most important factors influencing prognosis in these patients.

Conclusion
Sepsis and septic shock are not specifically correlated with obstetrics or gynecologic conditions. Risk factors that may predispose an Ob/Gyn patient to infectious agents are essentially the same risk factors that place any patient in harm's way. In Obstetrics, a prior history of peripatum infection, prolonged rupture of membranes, or genitourinary instrumentation associated with cardiovascular instability and fever should raise the possibility of septic shock. Patients with obstetrics or gynecologic problems are not different in the management of septic shock with other patients that sepsis results from other organs. Management of a patient with septic shock requires simultaneous administration of agents to reverse the pathophysiologic processes set in motion. It is important to treat patients with sepsis early and vigorously. Volume expansion and correction of hypovolemia are critical. Understanding the pathways, mediators, feedback loops and interactions involved in the pathogenesis of sepsis and organ failure has advanced profoundly, giving us the opportunity to treat sepsis-related multiple organ failure, and therefore, improve both survival rates and quality of life of women patients.