ENDOMETRITIS

Background
Endometritis is inflammation of the endometrial lining of the uterus. In addition to the endometrium, inflammation may involve the myometrium and, occasionally, the parametrium. Endometritis can be divided into pregnancy-related endometritis and endometritis unrelated to pregnancy. When the condition is unrelated to pregnancy, it is referred to as pelvic inflammatory disease (PID). Endometritis is often associated with inflammation of the fallopian tubes (salpingitis), ovaries (oophoritis), and pelvic peritoneum (pelvic peritonitis). The Centers for Disease Control and Prevention (CDC) 2010 sexually transmitted diseases treatment guideline defines PID as any combination of endometritis, salpingitis, tuboovarian abscess, and pelvic peritonitis. The diagnosis of endometritis is usually based on clinical findings, such as fever and lower abdominal pain (see Clinical Presentation). Most cases of endometritis, including those following cesarean delivery, should be treated in an inpatient setting. For mild cases following vaginal delivery, oral antibiotics in an outpatient setting may be adequate (see Treatment and Management, as well as Medication).

Pathophysiology
Infection of the endometrium, or decidua, usually results from an ascending infection from the lower genital tract. From a pathologic perspective, endometritis can be classified as acute versus chronic. Acute endometritis is characterized by the presence of neutrophils within the endometrial glands. Chronic endometritis is characterized by the presence of plasma cells and lymphocytes within the endometrial stroma. In the nonobstetric population, pelvic inflammatory disease and invasive gynecologic procedures are the most common precursors to acute endometritis. In the obstetric population, postpartum infection is the most common predecessor. Chronic endometritis in the obstetric population is usually associated with retained products of conception after delivery or elective abortion. In the nonobstetric population, chronic endometritis has been seen with infections (eg, chlamydia, tuberculosis, bacterial vaginosis) and the presence of an intrauterine device.

Etiology
Endometritis is a polymicrobial disease involving, on average, 2-3 organisms. In most cases, it arises from an ascending infection from organisms found in the normal indigenous vaginal flora. Commonly isolated organisms include Ureaplasma urealyticum,Peptostreptococcus, Gardnerella vaginalis, Bacteroides bivius, and group B Streptococcus. Chlamydia has been associated with late-onset postpartum endometritis. Enterococcus is identified in up to 25% of women who have received cephalosporin prophylaxis.

Epidemiology
The incidence of postpartum endometritis in the United States varies depending on the route of delivery and the patient population. After a vaginal delivery, incidence is 1-3%. Following cesarean delivery, the incidence ranges from 13-90%, depending on the risk factors present and whether perioperative antibiotic prophylaxis had been given. In the nonobstetric population, concomitant endometritis may occur in up to 70-90% of documented cases of salpingitis.

Prognosis
Nearly 90% of women treated with an approved regimen note improvement in 48-72 hours. Delay in initiation of antibiotic therapy can result in systemic toxicity. Endometritis is associated with increased maternal mortality due to septic shock. However, mortality is rare in the United States because of aggressive antimicrobial management. In the PID Evaluation and Clinical Health (PEACH) study, endometritis was not found to be associated with subsequent pregnancy-related complications, chronic pelvic pain, or infertility.

History
Diagnosis usually is based on clinical findings, as follows: Fever Lower abdominal pain Foul-smelling lochia in the obstetric population Abnormal vaginal bleeding Abnormal vaginal discharge Dyspareunia (may be present in patients with pelvic inflammatory disease [PID]) Dysuria (may be present in patients with PID) Malaise In postpartum cases, patients present with fever, chills, lower abdominal pain, and foul-smelling lochia. Patients with PID present with lower abdominal pain, vaginal discharge, dyspareunia, dysuria, fever, and other systemic signs. However, PID caused by Chlamydia tends to be indolent, with no significant constitutional symptoms.

Physical Examination
Physical examination findings include the following: Fever, usually occurring within 36 hours of delivery, in the obstetric population Lower abdominal pain Uterine tenderness Adnexal tenderness if there is an associated salpingitis Foul-smelling lochia Tachycardia Uterine tenderness is the hallmark of the disease. An oral temperature of 38C or higher within the first 10 days postpartum or 38.7C within the first 24 hours postpartum is required to make the diagnosis of postpartum endometritis. For PID, the minimum diagnostic criteria are lower abdominal tenderness, cervical motion tenderness, or adnexal tenderness. In severe cases, the patient may appear septic.

Risk Factors
Women are particularly vulnerable to endometritis after birth or abortion. In both the postpartum and postabortal state, risk is increased because of the open cervical os, presence of large amounts of blood and debris, and uterine instrumentation. Major risk factors for obstetric endometritis include the following: Cesarean delivery (especially if before 28 weeks' gestation) Prolonged rupture of membranes Long labor with multiple vaginal examinations Severely meconium-stained amniotic fluid Manual placental removal Extremes of patient age Low socioeconomic status Minor risk factors include the following: Absence of the normal cervical mucus plug Administration of multiple courses of corticosteroids for prevention of premature delivery Prolonged internal fetal monitoring Prolonged surgery General anesthesia Postpartum anemia The following factors increase the risk for endometritis in general: Presence of an intrauterine device: the vaginal part of the device may serve as a track for the organisms to ascend into the uterus Presence of menstrual fluid in the uterus

Associated cervicitis secondary to gonorrhea or Chlamydia infection Associated bacterial vaginosis Frequent douching Unprotected sexual activity Multiple sexual partners Cervical ectopy

Potential Complications
Potential complications of endometritis include the following: Wound infection Peritonitis Adnexal infection Parametrial phlegmon Pelvic abscess Pelvic hematoma Septic pelvic thrombophlebitis Spread of infection from the endometrium to the fallopian tubes, ovaries, or the peritoneal cavity may result in salpingitis, oophoritis, localized peritonitis, or tubo-ovarian abscesses. Salpingitis subsequently leads to tubal dysmotility and adhesions that result in infertility, higher incidence of ectopic pregnancy, and chronic pelvic pain.

Diagnostic Considerations
Because of the physiologic changes associated with pregnancy, the presence of an elevated leukocyte count or neutrophil count does not indicate endometritis. Therefore, clinical findings are more reliable than laboratory findings in diagnosing postpartum endometritis. Other problems to be considered in patients with possible endometritis include the following: Pyelonephritis Viral syndrome Pelvic thrombophlebitis Chorioamnionitis

Differential Diagnoses
Appendicitis Pelvic Inflammatory Disease Urinary Tract Infection

Approach Considerations
Although the diagnosis of endometritis is principally made on clinical grounds, laboratory studies can be helpful for supporting the diagnosis and excluding or identifying other diagnostic possibilities. The 2010 CDC guidelines on sexually transmitted diseases treatment agree that cervicitis can be a sign of endometritis and that women who are experiencing a new episode of cervicitis should be tested for endometritis, as well as other PID, gonorrhea, and chlamydia.

Complete Blood Cell Count

The CBC count typically reveals leukocytosis with a left shift. However, in the postpartum period, this finding may reflect the physiological leukocytosis of pregnancy and it is therefore unreliable for diagnosis. Anemia is a risk factor for the development of endometritis.

Cultures
Blood culture is positive in 10-30% of cases, and a urine culture should be ordered. The role of endocervical cultures is controversial. They are not generally helpful in management, as positive results are usually the result of contamination from normal resident cervicovaginal flora. However, endocervical cultures (or DNA probe) are obtained for gonorrhea and chlamydia when appropriate.

Gram Stain
Gram stain or wet mount of the vaginal discharge may be useful in ruling out endometritis. If no pus cells are observed in the Gram stain, the negative predictive value for endometritis is 95%.

Imaging Studies
Perform imaging studies on patients who do not respond to adequate antimicrobial therapy in 48-72 hours. CT scanning of the abdomen and pelvis may be helpful for excluding broad ligament masses, septic pelvic thrombophlebitis, ovarian vein thrombosis, and phlegmon. Ultrasonography of the abdomen and pelvis may yield normal findings in patients with a clinical diagnosis of endometritis. Abnormal findings overlap with those of retained products of conception and intrauterine hematoma.

Endometrial Biopsy
Endometrial biopsy can be obtained to assess chronic endometritis in the nonobstetric population.

Histologic Findings
Pathologically, endometritis is defined as the presence of 5 or more neutrophils per high-power field (400) in the superficial endometrium and 1 or more plasma cells per high-power field (120) in the endometrial stroma.

Approach Considerations
After making the diagnosis of endometritis and excluding other sources of infection, the physician should promptly initiate broad-spectrum antibiotics. Improvement will be noted within 48-72 hours in nearly 90% of women treated with an approved regimen. Most cases of endometritis, including those following cesarean delivery, should be treated in an inpatient setting. For mild cases following vaginal delivery, oral antibiotics in an outpatient setting may be adequate. Pregnant women with symptoms of bacterial vaginosis (BV) should be treated because BV is associated with adverse pregnancy outcomes. Although treatment has not been demonstrated to prevent these outcomes, treatment does reduce signs and symptoms of vaginal infection. In adolescents who undergo termination of pregnancy, subsequent endometritis with associated salpingitis poses a significant risk of infertility. Therefore, earlier and more aggressive antibiotic therapy is warranted in this group.

Antibiotic Therapy
The combination of clindamycin and gentamicin administered intravenously every 8 hours has been considered the criterion standard treatment. Some studies have revealed adequate efficacy with once-daily dosing, as well.[6, 7, 8] The combination of a second- or third-generation cephalosporin with metronidazole is another popular choice. In teenagers, postabortion endometritis may be caused by organisms that causepelvic inflammatory disease (PID). The initial treatment regimen in these patients usually includes intravenous cefoxitin and doxycycline, in the same doses as for PID. A trend toward the use of broad-spectrum monotherapy has emerged; these agents are generally effective in 80-90% of patients. Cephalosporins, extended-spectrum penicillins, and fluoroquinolones are used as monotherapy. Improvement is noted within 48-72 hours in nearly 90% of women. Parenteral therapy is continued until the patient has been afebrile for longer than 24 hours. If the physical examination findings are benign, the patient may be discharged at that time. Further outpatient antibiotic therapy has proved to be unnecessary. If the patient does not improve in the expected 48- to 72-hour period, reevaluate for complications such as abscess. Prophylaxis
Prophylactic antibiotics reduce the incidence of postpartum febrile morbidity in patients undergoing cesarean delivery. Current research supports the use of preoperative administration of prophylactic antibiotics. Single-agent therapy with a first- or second-generation cephalosporin (eg, cefazolin) has been considered the best choice.

A joint publication by the American College of Obstetricians and Gynecologists (ACOG) and the American Academy of Pediatrics (AAP) supports the administration of antibiotics prior to skin incision rather than immediately after cord clamping. However, current research is also assessing the use of extended-spectrum regimens with a cephalosporin plus either azithromycin or metronidazole after cord clamping. Head-to-head comparisons between narrow-spectrum prophylaxis given before skin incision and extended-spectrum prophylaxis given after cord clamping still need to be done. A Cochrane database systematic review concluded that the use of vaginal chlorhexidine douching during labor does not prevent endometritis.[15] Preoperative use of povidone-iodine vaginal preparation prior to cesarean delivery appears to decrease the incidence of postcesarean endometritis but does not seem to decrease the overall risk of postoperative fever or wound infection.

Surgical Care
Surgical management is not usually necessary in acute endometritis in the obstetric population. Dilation and curettage may be advised for retained products of conception, however.

Medication Summary
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Antibiotics
Class Summary
A combination therapy with clindamycin and an aminoglycoside is considered the criterion standard by which most antibiotic clinical trials are judged. A combination regimen of ampicillin, gentamicin, and metronidazole provides coverage against most of the organisms that are encountered in serious pelvic infections. Doxycycline should be used if Chlamydia is the cause of the endometritis. Ampicillin sulbactam can be used as monotherapy. Single-agent therapies have been found to be effective in 80-90% of patients.

Clindamycin (Cleocin)
Clindamycin, which is used in combination with gentamicin, is a lincosamide that is useful as a treatment against serious skin and soft tissue infections caused by most staphylococci strains. It is also effective against aerobic and anaerobic streptococci, except enterococci. Clindamycin inhibits bacterial protein synthesis by inhibiting peptide chain initiation at the bacterial ribosome. It preferentially binds to the 50S ribosomal subunit, causing bacterial growth inhibition.

Gentamicin (Gentacidin, Garamycin)

An aminoglycoside antibiotic used for gram-negative bacterial coverage, gentamicin is used in combination with either clindamycin or in combination with metronidazole and ampicillin. Dosing regimens are numerous and are adjusted based on creatinine clearance and changes in the volume of distribution. Doses may be given IV or IM.

Ampicillin (Omnipen, Marcillin)

Ampicillin is used in combination with gentamicin and metronidazole. It interferes with bacterial cell-wall synthesis during active multiplication, causing bactericidal activity against susceptible organisms.

Metronidazole (Flagyl, Flagyl ER)

Used in combination with gentamicin and ampicillin, metronidazole is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Metronidazole appears to be absorbed into the cells and the intermediatemetabolized compounds that are formed bind DNA and inhibit protein synthesis, causing cell death.

Ampicillin and sulbactam (Unasyn)

The combination of ampicillin with the beta-lactamase inhibitor sulbactam sodium has been found to be effective as monotherapy in 80-90% of patients. This agent covers skin, enteric flora, and anaerobes. It is not ideal for nosocomial pathogens.

Doxycycline (Bio-Tab, Doryx, Vibramycin)

Doxycycline is used if Chlamydia is the cause of the endometritis. It inhibits protein synthesis and thus bacterial growth by binding with the 30S and possibly the 50S ribosomal subunits of susceptible bacteria.

Ertapenem (Invanz)
The bactericidal activity of ertapenem results from inhibition of cell wall synthesis and is mediated through ertapenem binding to penicillin binding proteins. This agent is stable against hydrolysis by a variety of beta-lactamases, including penicillinases, cephalosporinases, and extended-spectrum beta-lactamases. It is hydrolyzed by metallo-beta-lactamases.

Cefoxitin (Mefoxin)
Cefoxitin is a second-generation cephalosporin indicated for gram-positive cocci and gram-negative rod infections. Infections caused by cephalosporin- or penicillin-resistant gram-negative bacteria may respond to cefoxitin.

Piperacillin and tazobactam sodium (Zosyn)

The combination of ampicillin with the beta-lactamase inhibitor sulbactam sodium has been found to be effective as monotherapy in 80-90% of patients. This agent covers skin, enteric flora, and anaerobes. It is not ideal for nosocomial pathogens.

Cefotetan
Cefotetan is second generation and is used as a single-drug therapy to provide broad gram-negative coverage, broad anaerobic coverage, and some coverage against gram-positive bacteria. It inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, and it inhibits the final transpeptidation step of peptidoglycan synthesis, resulting in cell wall death.

Cefotaxime (Claforan)
Cefotaxime is a third generation cephalosporin with a broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. It arrests bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which, in turn, inhibits bacterial growth. It is used for septicemia and the treatment of gynecologic infections caused by susceptible organisms.

Ceftazidime (Fortaz, Tazicef)

Ceftazidime is a third generation cephalosporin with broad-spectrum, gram-negative activity, including pseudomonal organisms. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to one or more penicillin-binding proteins, which, in turn, inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell wall synthesis, thus inhibiting cell wall biosynthesis.

Cefazolin
Cefazolin is a first-generation cephalosporin, which by binding to 1 or more penicillin-binding proteins, arrests bacterial cell wall synthesis and inhibits bacterial replication. Prophylactic antibiotics reduce the incidence of postpartum febrile morbidity in patients undergoing cesarean delivery. Current research supports the use of preoperative administration of prophylactic antibiotics. Single-agent therapy with a first-generation such as cefazolin or a second-generation cephalosporin has been considered the best choice.

Levofloxacin (Levaquin)
Levofloxacin is a fluoroquinolone antibiotic. It is used for pseudomonal infections and infections due to multidrug resistant gram-negative organisms. A trend toward the use of broad-spectrum monotherapy has emerged, and these agents are generally effective in 80-90% of patients. Cephalosporins, extended-spectrum penicillins, and fluoroquinolones are used as monotherapy. If gonococcal infection is suspected, levaquin is contraindicated because many strains of the organism are now resistant to the quinolones.