Cohen, Adam L. MD, MPH1,2; Bhatnagar, Julu PhD3; Reagan, Sarah MPH3; Zane, Suzanne B. DVM; D'Angeli, Marisa A. MD5; Fischer, Marc MD, MPH3,4; Killgore, George DrPH2; Kwan-Gett, Tao Sheng MD, MPH5; Blossom, David B. MD1,2; Shieh, Wun-Ju MD, PhD3; Guarner, Jeannette MD3,7; Jernigan, John MD2; Duchin, Jeffrey S. MD5,6; Zaki, Sherif R. MD, PhD3; McDonald, L Clifford MD2
Severe and fatal infections from Clostridium species in women after pregnancy or abortion are rare. In December 2005, the Centers for Disease Control and Prevention (CDC) reported four cases of fatal toxic shock–like illness in previously healthy women after medically induced abortions with a common off-label regimen of 200 mg of oral mifepristone followed by 800 mcg of intravaginal misoprostol.1 As had been described in a similar case report from Canada,2 the causative agent in these four cases was Clostridium sordellii, which is an uncommon cause of infection in humans and can cause toxic shock most often after pregnancy, injection drug use, trauma, or surgery.3 Like C sordellii, Clostridium perfringens (formerly known as Clostridium welchii) is an uncommon cause of fulminant septic disease in pregnant women after abortion. Most reported cases of obstetric C perfringens infection occurred before 1980 and were a result of illegal surgical or home abortions,4–7 but there have been rare case reports of C perfringens deaths after legal induced abortions,8–10 spontaneous abortion,11 vaginal delivery,12 cesarean delivery,13 and amniocentesis.14 To better understand the pathophysiology and epidemiology of serious Clostridium species infections after pregnancy or abortion, CDC has continued to investigate reports of toxic shock or death suggestive of Clostridium species infection after medical or spontaneous abortion.
MATERIALS AND METHODS
We used passive and active surveillance to identify previously unreported cases of toxic shock associated with pregnancy or abortion. In July 2005, the U.S. Food and Drug Administration (FDA) released a public health advisory,15 and CDC released a dispatch asking clinicians to report additional known or suspected postpartum or postabortion toxic shock cases.16 Queries for pregnancy-related toxic shock cases were sent to members of the Infectious Diseases Society for Obstetrics and Gynecology, the Emerging Infections Network of the Infectious Diseases Society of America, the National Association of Medical Examiners, CDC's Unexplained Deaths Project sites in four states, and groups of abortion providers in the United States that perform surveillance for potentially infectious complications after abortion. The U.S. Food and Drug Administration and CDC also contacted the World Health Organization; the International Planned Parenthood Federation; and public health organizations in China, Finland, France, Sweden, and the United Kingdom to identify cases of severe infection or death associated with induced abortion with mifepristone or misoprostol.
We reviewed medical and autopsy records for each potential case patient. Centers for Disease Control and Prevention determined that this investigation was undertaken as part of a public health response; as such, approval of institutional review boards and consent of the patient or next of kin were not required.
Available clinical Clostridium species isolates were sent to CDC where species identification was confirmed using standard microbiologic methods. Characterization of C sordellii isolates consisted of a polymerase chain reaction (PCR) assay for C sordellii cytotoxin L (tcsL). Characterization of C perfringens isolates included typing using PCR for genes encoding alpha, beta, epsilon, and iota toxins. All PCR primers were designed at CDC; genetic sequences and GenBank Accession Numbers of the primers are available on request from the authors. We performed immunohistochemical assays for Clostridium species, Staphylococcus aureus, group A Streptococcus, and Neisseria species on formalin-fixed, paraffin-embedded surgical and autopsy tissue sections as previously described.17,18 We extracted DNA from formalin-fixed tissues using the QIAamp DNA Mini Kit (QIAGEN, Valencia, CA). Deoxyribonucleic acid was evaluated with C sordellii-specific PCR assays targeting the C sordellii tcsL and phospholipase C (csp) genes1 and C perfringens–specific PCR assays targeting the C perfringens alpha toxin (cpa) gene19 using the High Fidelity PCR kit (Roche Diagnostics, Indianapolis, IN). Amplified PCR products were separated on 1.8% agarose gel, extracted from the gel using QIAquick gel extraction kit (QIAGEN), and directly sequenced on a CEQ 2000 XL sequencer (Beckman Coulter, Fullerton, CA). We searched for homologies to known DNA sequences using the Basic Local Alignment Search Tool (BLAST) available at http://www.ncbi.nlm.nih.gov/BLAST/.
We report four cases of toxic shock associated with Clostridium species after medical or spontaneous abortion. All occurred from July 2003 to July 2007 in four different states. No cases from outside the United States were identified. All four patients had rapidly progressing shock including abdominal pain, hypotension, and tachycardia. All four had necrotizing endomyometritis on pathology examination. Immunohistochemical assays for S aureus, group A Streptococcus, and Neisseria species were negative for all cases.
In addition to these four cases, we identified a 29-year-old woman who had rapidly progressing, nonfatal toxic shock–like symptoms after a medical abortion with mifepristone at 8.5 weeks of gestation; evaluation of tissues at CDC found no evidence of Clostridium species or other bacterial infection, so this case was not included in this series.
Patient 1 was a 28-year-old gravida 1, para 0 woman who took carbamazepine for a seizure disorder and levothyroxine for hypothyroidism. The pregnancy was complicated by a fetus with multiple morphologic anomalies secondary to amniotic bands. The patient presented for medical abortion at 19 weeks of gestation. Laminaria were inserted in the cervix at an outpatient clinic, and the patient was admitted to the hospital the following morning for 400 mcg intravaginal misoprostol every 6 hours. Spontaneous rupture of membranes occurred less than 2 hours after the second dose of misoprostol. Nearly 5 hours after the second dose of misoprostol, the patient complained of feeling warm and experienced shaking chills.
Five hours after the third dose of misoprostol, the patient developed hypotension (lowest recorded blood pressure, 74/30 mm Hg) and difficulty breathing. She was given intravenous fluids, phenylephrine, and ephedrine. She developed a fever (38.4°C) and reported abdominal pain. On examination, she was tachycardic (112 beats per minute [bpm]) and demonstrated a small amount of vaginal bleeding and pitting edema in the upper and lower extremities. Within an hour, her respiratory difficulty increased, and she developed pulmonary edema. The patient was given intravenous furosemide and a fourth dose of misoprostol. Laboratory studies showed significant hemolysis with a hematocrit less than 10%, which had dropped from 31% on admission. The patient did not have an elevated white blood cell count. The patient was started on metronidazole and ciprofloxacin. No blood cultures were obtained. Over the next few hours, the patient experienced worsening respiratory distress that required mechanical ventilation and then went into cardiopulmonary arrest. Cardiopulmonary resuscitation was initiated, but the patient died soon thereafter, less than 2 days after initiation of abortion.
Autopsy findings included necrotizing endomyometritis, diffuse subcutaneous edema, and serosanguineous pleural effusions and ascites. Fibrin thrombi were present in the vessels of the lungs. The placenta was diffusely necrotic. No gas was noted in the pelvis. Gram stain of both the uterus and placenta showed large gram-positive rods consistent in morphology with Clostridium species. No postmortem cultures were performed. Formalin-fixed, paraffin-embedded uterine and placental tissues were positive for Clostridium species by immunohistochemical assay. Both C sordellii–specific PCR assays targeting the tcsL and csp genes were negative in the uterus and placenta DNA samples; however, C perfringens–specific PCR assay was positive in both of these samples. Deoxyribonucleic acid sequence analysis of positive cpa amplification products showed 99% identity with the alpha toxin gene sequence of C perfringens.
Patient 2 was a 24-year-old, gravida 2, para 1 previously healthy woman who underwent a medically induced abortion at 8.5 weeks of gestation by means of 200 mg oral mifepristone followed the next day by 800 mcg of intravaginal misoprostol. The following day, the patient developed vaginal bleeding, abdominal cramping, vomiting, diarrhea, and chills. She contacted her family planning clinic and was advised to take ibuprofen or hydrocodone as prescribed for pain and to call back if symptoms persisted.
Five days after taking oral mifepristone, the patient presented to an emergency department with abdominal pain. On physical examination, the patient was hypotensive (lowest recorded blood pressure, 82/66 mm Hg) and tachycardic (116 bpm) but afebrile (36.34°C). On abdominal examination, the patient had lower abdominal tenderness and firmness. She was admitted to intensive care and empirically started on cefotaxime and clindamycin. Laboratory studies showed an elevated white blood cell count (42,800 cells per microliter) and hematocrit (maximum recorded hematocrit 66.8%). Abdominal ultrasonography showed evidence of endometritis, salpingitis, and moderate ascites.
Seven days after taking oral mifepristone, the patient was transferred to another hospital for further evaluation where she was started on vancomycin and piperacillin/tazobactam. No pleural effusions were noted. Nine hours after admission, she developed dyspnea and severe abdominal distention. The patient underwent suction dilatation and curettage and exploratory laparotomy. The uterus was found to be enlarged and necrotic. Five liters of peritoneal fluid were drained. During a second laparotomy to reassess the bowel 8 hours later, frank necrosis of the ascending and descending colon and retroperitoneum were found. Microthrombi were evident throughout the mesentery. She expired in intensive care 7 days after initiation of medical abortion. A cervicovaginal swab collected premortem grew C perfringens and Peptostreptococcus species. A postmortem uterine swab obtained at autopsy grew C perfringens.
On autopsy, the uterus showed inflammation and necrosis of the endometrium and myometrium; the intestine had focal areas of mucosal necrosis and hemorrhage, with inflammatory infiltrates in the lamina propria. Gas was noted in the pelvis. Gram-positive bacilli were observed. Immunohistochemical assay of formalin-fixed, paraffin-embedded uterine tissue was positive for Clostridium species; intestinal tissue was negative. Both C sordellii PCR assays were negative in extracts from the uterus, whereas C perfringens PCR assay was positive and was confirmed by sequence analysis of cpa amplification products showing 97% identity with the alpha toxin gene of C perfringens. Two isolates (one from cervix–vagina and another from uterus) were confirmed as C perfringens at CDC. Both isolates were positive by PCR assay for alpha toxin but negative for beta, epsilon, and iota toxin, indicating these isolates were C perfringens Type A.
Patient 3 was a 25-year-old gravida 3, para 1 woman with a history of hypothyroidism and previous spontaneous abortion who became aware of vaginal discharge at approximately 17 weeks of gestation. One day later, she developed lower abdominal pain and fever and sought medical care at an emergency department. On presentation, the patient was febrile (38.4°C) and had suprapubic and mild right lower quadrant tenderness with guarding. Her cervix was effaced and dilated to 1 cm. A moderate amount of yellowish-green, blood-tinged vaginal discharge was noted, which was negative for Trichomonas, yeast, and clue cells on wet mount. Ultrasonography demonstrated an intrauterine pregnancy consistent with 18 weeks of gestation, with cardiac activity. White blood cell count was 22,100 cells per microliter. The patient was admitted and given ceftriaxone.
Five hours after presenting to the emergency department, the patient had a spontaneous abortion with no excessive bleeding. Her blood pressure began fluctuating (lowest recorded blood pressure 78/40 mm Hg), and she became tachycardic (140 bpm) and febrile (39.0°C). She received intravenous fluids. First, azithromycin was added; she was then started on dopamine, penicillin, gentamicin, and clindamycin empirically for septic shock. The patient improved clinically and was discharged home from the hospital on hospital day 7 in improved condition.
A blood culture drawn before the patient was administered antimicrobial agents grew C sordellii. Cervical cultures grew normal vaginal flora, and anaerobic subculture grew C sordellii and Veillonella species. Urine, placenta, and fetal cultures were negative; however, no anaerobic cultures were performed. No abdominal gas and no pleural or peritoneal effusions were noted. Histopathologic review of the placenta showed severe acute chorioamnionitis and large gram-positive rods. Immunohistochemical assay of formalin-fixed placental tissue indicated presence of Clostridium species. Deoxyribonucleic acid extracted from placenta was positive by C sordellii csp gene PCR assay and positive csp amplification products showed 98% identity with the corresponding sequence of C sordellii. The same sample was negative by C sordellii tcsL gene PCR assay and C perfringens cpa PCR assays. The blood culture isolate was confirmed at CDC as C sordellii; results of PCR assays performed on this isolate for tcsL were negative.
Patient 4 was an 18-year-old gravida 1, para 0 previously healthy woman who underwent a medically induced abortion at 6.5 weeks of gestation by means of 200 mg of oral mifepristone followed 2 days later by 800 mcg of buccal misoprostol. She had moderate vaginal bleeding and mild abdominal cramping for 2 to 3 days, followed by a period of feeling well. Approximately 5 days after the medical abortion, she developed chills, abdominal pain, nausea, vomiting, and dizziness. Six days after taking mifepristone, due to worsening symptoms, she sought care at her outpatient clinic. On physical examination she was found to be afebrile, and she had diffuse lower abdominal pain and pelvic tenderness but no cervical motion tenderness. A wet mount showed clue cells and was amine positive. She was given intravenous hydration, prescribed oral metronidazole and doxycycline for bacterial vaginosis, and discharged to home.
The following day, the clinic referred the patient to a local emergency department for continued worsening symptoms. In the emergency department, the patient was hypotensive (lowest recorded blood pressure, 56/21 mm Hg) and tachycardic (149 bpm), but afebrile (37°C). The patient had diffuse abdominal tenderness to palpation, especially in the lower quadrants, and distension. Laboratory studies showed an elevated white blood cell count (79,700 cells per microliter) and hematocrit (60.1%). Abdominal ultrasonography showed a large amount of intrapelvic free fluid and a right adnexal cystic mass. The patient was started on ceftriaxone, piperacillin/tazobactam, and metronidazole. An exploratory laparotomy revealed 2.5 L of cloudy peritoneal fluid, no evidence of ectopic pregnancy, mildly edematous fallopian tubes without purulence, and peritoneal inflammation. The right cystic mass seen on ultrasound examination was a corpus luteum cyst. She was admitted to the intensive care unit, treated with intravenous fluid resuscitation, including albumin, and continued on antibiotics for presumed sepsis due to C sordellii. During her hospital course, antibiotic coverage also included levofloxacin and vancomycin, the final regimen being clindamycin, piperacillin/tazobactam, and metronidazole. Approximately 16 hours after presentation to the emergency department, the patient had a cardiopulmonary arrest and died.
A rectal culture taken during surgery grew coagulase-positive S aureus, Arcanobacterium pyogenes and Prevotella bivia. Cervical culture obtained during the intraoperative dilation and curettage grew normal genital flora with no anaerobes. Aerobic and anaerobic blood (obtained before antibiotics), peritoneal fluid, and urine cultures were negative. Surgical pathology evaluation of samples revealed necrotizing endometritis. Autopsy findings were consistent with necrotizing endometritis. Tissue Gram stain demonstrated abundant gram-positive bacilli, and immunohistochemical assay of formalin fixed uterine tissue was positive for Clostridium species. PCR assay for C sordellii on uterine tissue was positive for both the tcsL and csp genes. Polymerase chain reaction for C perfringens was negative.
We report four cases of toxic shock associated with Clostridium species endometrial infection after medical and spontaneous abortion. Clostridium species are anaerobic, gram-positive, spore-forming rods that are found commonly in the soil and the intestinal tracts of many animals, including humans. The incidence of vaginal carriage of C sordellii is not known, and from 2% to 4% of vaginal cultures reveal C perfringens.20,21 Because C perfringens, and possibly C sordellii, are found in the vaginal tract of pregnant women, it is likely the bacteria ascend from colonized vaginal tracts to cause disease after abortion with or without cervical instrumentation.
We identified nine case reports in the literature of fatal C sordellii toxic shock in women after delivery of liveborn infants.3,22–26 Additionally, two deaths due to C sordellii (one with C perfringens coinfection) after second-trimester spontaneous abortions were reported to CDC's Pregnancy Mortality Surveillance System between 1986 and 2001.27 In addition to Patient 4, five previous cases of rapidly fatal infection after medical abortion with mifepristone and misoprostol that were caused by C sordellii have been reported1,2; we report the first case of C perfringens infection following the same medical regimen.
Much of the use of mifepristone in the United States is with intravaginal misoprostol, but the approved regimen is 600 mg of mifepristone orally and 400 mcg of misoprostol orally. The safety and effectiveness of the off-label use of intravaginal misoprostol has not been established by the FDA.15 However, in the most recent clinical management guidelines of the American College of Obstetricians and Gynecologists,28 the intravaginal route of administration is given as an option for misoprostol in medical abortion due to fewer side effects, improved complete abortion rates, and lower cost. Some have postulated that the intravaginal insertion of misoprostol may lead to ascending infection; however, there is no evidence in the literature that the route of misoprostol administration affects infection,29 and one of the patients we report had taken misoprostol by the buccal route. Some have postulated that the antiprogesterone and antiglucocorticoid actions of mifepristone may favor the growth of C sordellii or enhance the body's susceptibility to shock in some individuals.30
McGregor and Equils (McGregor JA, Equils O. Response to letter to the editor [letter]. Contraception 2006;74:175–6) suggested a syndromic definition of C sordellii–associated toxic shock in previously healthy women with recent mifepristone and misoprostol pregnancy termination: nonspecific complaints that rapidly progress to shock, identification of C sordellii and exclusion of staphylococcal toxic shock, and laboratory findings including dramatically increased hematocrit and white cell count. C sordellii toxic shock is also characterized by the absence of fever, presence of refractory tachycardia, local edema at the infected site, and subsequent pleural and peritoneal effusions.1 Among all obstetric and nonobstetric C sordellii infections reported in the literature, the case fatality ratio is 70%. Among the 16 identified cases of obstetric C sordellii infections reported in the literature,3,31 all were fatal except that of Patient 3 reported in this series.
Clinical findings of C perfringens infection may differ from those of C sordellii. Clostridium perfringens infections may be as mild as endometritis but can progress to gas gangrene and fulminant septicemia. Clostridium perfringens can cause myonecrosis like C sordellii, but serious C perfringens infection may also be complicated by hemolytic anemia with associated renal failure, jaundice, and hemoglobinuria. Fulminant septicemia of C perfringens after abortion carries a mortality as high as 70%.32
Clinicians should be aware of the clinical presentation of Clostridium species infections during pregnancy and after abortion. The four cases we report are more heterogeneous in presentation than previous reports of C sordellii toxic shock after medical abortion with mifepristone and misoprostol. Vomiting, diarrhea, and abdominal pain may rapidly progress to shock and herald C sordellii infection after abortion; however, these symptoms may also be associated with the use of mifepristone and misoprostol. The findings of abdominal pain after abortion may signify C perfringens sepsis even without a history of surgical instrumentation. Clinicians should gather an anaerobic culture of the cervix to aid in diagnosis if they suspect Clostridium species infection. In addition, it is important to do histopathologic, immunohistochemical, and molecular studies of surgical or autopsy tissue to confirm diagnosis of necrotizing endometritis and the presence of Clostridium species. Clostridium species must have an anaerobic environment to survive and multiply, which can happen during the process of abortion or when necrotic tissue remains after abortion. Older reports suggested that total hysterectomy32 or surgical debridement5 is necessary to remove necrotic tissue and prevent death in cases of C perfringens infection.
Clostridium sordellii and C perfringens both secrete toxins that can cause septic shock and death. Clostridium sordellii secretes two large clostridial toxins that are regarded as its major virulence factors: a lethal toxin and a hemorrhagic toxin. We report in this series the only known case of C sordellii infection after pregnancy where the patient survived (patient 3). Intriguingly, CDC laboratory testing indicated that patient 3 was infected with a strain of C sordellii that did not produce lethal toxin. In addition, patient 3 did not have a high white cell count, a factor which has been associated with mortality in C sordellii infection.3
This investigation is subject to a few limitations. First, the clinical information is from retrospective chart review, so some data, such as the method of estimating gestational age, were not available. Second, we are not able to discern if there have been genetic changes in C sordellii or C perfringens leading to increased virulence. Such genetic changes have been reported in a related Clostridium species, Clostridium difficile, leading to increased rates and severity of C difficile disease.33 Lastly, two of the four patients reported in this series had underlying hypothyroidism. We do not know of a theoretical reason why hypothyroid patients would be at increased risk for Clostridium species toxic shock, and previous case reports in the literature have not reported hypothyroidism.
These cases provide further evidence that serious C perfringens as well as C sordellii infections can occur rarely after induced or spontaneous abortion with medical regimens other than mifepristone and misoprostol. Previous data have shown that serious Clostridium species infection can also arise from childbirth and surgical abortion. Future investigations should focus on understanding acquisition and carriage of C sordellii among pregnant women and identifying risk factors for invasive disease and toxic shock due to Clostridium species after medical or spontaneous abortion.
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Figure. No caption available.
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