Endometritis

Etiology

Endometritis primarily results from the ascension of microorganisms from the lower genital tract (ie, the cervix and vaginal vault) into the endometrial cavity. The specific pathogens more frequently found to infect the endometrium vary depending on the type of endometritis and are sometimes difficult to identify.[3][4]

Acute Endometritis

In acute endometritis, >85% of infectious etiologies are caused by sexually transmitted infections (STIs). Unlike chronic and postpartum endometritis, which have multiple organisms linked to causation, the primary microbial etiology of acute endometritis is Chlamydia trachomatis, followed by Neisseria gonorrhoeae and BV-associated bacteria.[3][6] 

Risk factors for acute endometritis include age <25 years, a history of STIs, engaging in high-risk sexual behavior such as having multiple partners, and undergoing gynecologic procedures like placing intrauterine devices or endometrial biopsies. These factors contribute to the increased susceptibility to this condition among certain individuals.[9][5][6]

Chronic Endometritis

The etiology of chronic endometritis is often unknown. Some studies have shown possible endometrial inflammation associated with noninfectious etiologies (eg, intrauterine contraceptive devices, endometrial polyps, submucosal leiomyomas).[10] However, when a causative organism is identified, it is frequently a polymicrobial infection comprised of microorganisms commonly found in the vaginal vault. Additionally, genital tuberculosis can result in chronic granulomatous endometritis, most often seen in developing countries.[5] Unlike acute endometritis, Chlamydia trachomatis and Neisseria gonorrhoeae are not the most common etiologies.[5] The primary causative organisms found include:

• Streptococcus species
• Enterococcus faecalis
• Escherichia coli
• Klebsiella pneumoniae
• Staphylococcus species
• Mycoplasma
• Ureaplasma
• Gardnerella vaginalis
• Pseudomonas aeruginosa
• Saccharomyces cerevisiae and candida species[11] 

Chronic endometritis is associated with several risk factors, including the use of contraceptive intrauterine devices, a history of multiple pregnancies (multiparity), previous abortions, and experiencing abnormal uterine bleeding. These factors are important considerations in understanding the potential causes and contributors to chronic endometritis.[5]

Postpartum Endometritis

During pregnancy, the amniotic membrane protects the uterine cavity from infection, and endometritis is uncommon. As the cervix dilates and the fetal membranes rupture, the opportunity for colonization of the uterine cavity by organisms from the vaginal vault increases. This risk is increased further with instrumentation and insertion of foreign bodies into the uterine cavity. Bacteria are also more likely to colonize uterine tissue that has been devitalized or otherwise damaged.[4][12] Similar to intraamniotic infections, postpartum endometrial infection is polymicrobial, involving both aerobic and anaerobic bacteria, including:

• Gram-positive cocci: Groups A and B Streptococci, Staphylococcus, Enterococcus
• Gram-negative bacilli: Escherichia coli, Klebsiella pneumoniae, Proteus
• Anaerobic organisms: Bacteroides, Peptostreptococcus, Peptococcus, Prevotella, and Clostridium
• Others: Mycoplasma, Neisseria gonorrhoeae[3][13][14]

Chlamydia trachomatis is an uncommon cause of postpartum endometritis, though it is often associated with late-onset presentations.[15] Although rare, severe infections with Streptococcus pyogenes, Staphylococcus aureus, Clostridium sordellii, or Clostridium perfringens are associated with increased morbidity and mortality.[16]

Postpartum endometritis is associated with a variety of risk factors, including cesarean delivery, intrapartum intraamniotic infection (known as chorioamnionitis), prolonged rupture of membranes or prolonged labor, the insertion of foreign bodies into the uterus (such as multiple cervical examinations and invasive uterine and fetal monitoring devices), manual extraction of the placenta, operative vaginal delivery, and certain maternal factors like HIV infection, diabetes mellitus, and obesity. Recognizing these risk factors is crucial in identifying and addressing postpartum endometritis, as they can contribute to the development of this condition and guide preventive measures and treatment strategies.[4][17]

Epidemiology

Acute Endometritis

The incidence of acute endometritis alone is challenging as it often occurs in the setting of PID, which has an incidence of approximately 8% in the United States (US) and 32% in developing countries.[18] Cases of PID in the US are frequently associated with Chlamydia trachomatis and Neisseria gonorrhoeae infections, accounting for 50% of such cases.[19]

Chronic Endometritis

Given the generally mild presentation, the true prevalence of chronic endometritis is difficult to estimate. In people with recurrent pregnancy loss, some studies have found the incidence estimated to be nearly 30%. However, the incidence varies, even in the same study, depending on which menstrual phase endometrial biopsies were performed.[7][10]

Postpartum Endometritis

Postpartum endometritis is the leading cause of postpartum maternal fever.[20] Its incidence ranges from 1% to 3% in patients without risk factors after a normal spontaneous vaginal delivery, increasing to about 5% to 6% with risk factors.[4] Cesarean delivery is a significant risk factor associated with a 5- to 20-fold increase in the risk of postpartum endometritis compared to spontaneous vaginal deliveries. If cesarean deliveries occur after the amniotic membrane rupture, the risk is even higher.[21][22][13][14] Appropriate antibiotic prophylaxis can reduce the risk of postpartum endometritis, with 20% of patients developing the condition without antibiotic prophylaxis.[13] Left untreated, postpartum endometritis can have a fatality rate estimated as high as 17%.[14]

Pathophysiology

Acute endometritis is due to ascending infection from the cervix and vaginal vault, caused most often by Chlamydia trachomatis. Endocervical infections disrupt the barrier functions of the endocervical canal, allowing the infection to ascend.[5]

Conversely, chronic endometritis is characterized by endometrial infection by microorganisms not necessarily associated with concurrent cervical or vaginal colonization. The microbial infection leads to an immune response and chronic inflammation, with significant infiltrates of endometrial stromal plasmacytes and the development of micropolyps.[5][23] Elevations in interleukin-1b and tumor necrosis factor-alpha are also present, increasing estrogen synthesis in endometrial glandular cells. This increased estrogen synthesis may be associated with micropolyps, often seen on hysteroscopic evaluation in patients diagnosed with chronic endometritis.[5] 

With postpartum endometritis, rupture of the amniotic membrane allows bacterial flora from the cervix and vagina to enter the endometrial lining.[4] This bacteria is more likely to colonize uterine tissue that has been devitalized, bleeding, or otherwise damaged (such as during a cesarean delivery). This bacteria can also invade the myometrium, causing inflammation and infection.[4]

Histopathology

Acute and chronic endometritis can be distinguished through histological characteristics. Acute endometritis is marked by microabscesses and the invasion of neutrophils into the superficial endometrial epithelium, glandular lumens, and the endometrial cavity.[5] 

In contrast, chronic endometritis is identified by the infiltration of ESPCs, the presence of small polyps (micropolyps) measuring less than 1 mm, edematous changes during the proliferative phase, and out-of-phase morphology reflecting a mismatch in maturation between the stroma and epithelium.[5][23][7] Additionally, B cells tend to accumulate in the endometrial stroma and glands of patients with chronic endometritis, although the exact significance of this observation remains uncertain.[5][23][7]

History and Physical

Clinical History

Acute and postpartum endometritis are clinically diagnosed based on characteristic symptoms and exam findings; chronic endometritis is often asymptomatic and typically requires histologic confirmation. Clinical histories and symptoms can overlap between the different types of endometritis and with differential diagnoses; however, some clinical features are associated more with one type of endometritis than others. Therefore, a thorough history is essential to an accurate diagnosis. Clinicians obtaining a history should also attempt to identify common risk factors for PID (eg, multiple sex partners, history of STIs) and evidence of differential diagnoses through a comprehensive obstetrical and sexual history.[6]

Acute endometritis

Symptoms characteristic of acute endometritis are abrupt onset of pelvic pain, dyspareunia, and vaginal discharge, most commonly seen in sexually active individuals, although patients may be asymptomatic also.[6][9] Depending on the severity of the disease, systemic symptoms, such as fever and malaise, may also be present, though they are frequently absent in milder cases. Additional symptoms include abnormal uterine bleeding (eg, postcoital, intermenstrual, or heavy menstrual bleeding), dyspareunia, and dysuria.[9][24] Symptoms secondary to perihepatitis (ie, Fitz-Hugh-Curtis syndrome), tubo-ovarian abscess, or salpingitis can occur in patients with PID, including right upper quadrant pain and lower abdominal pain.[6]

Chronic endometritis

Patients with chronic endometritis often have histories of recurrent pregnancy loss, repeated implantation failure, and infertility.[5][23] Chronic endometritis is often asymptomatic. If symptoms are present, they are typically nonspecific, with the most common complaints being abnormal uterine bleeding, pelvic discomfort, and leukorrhea.[5]

Postpartum endometritis

A key clinical feature of postpartum endometritis is fever following a recent delivery or miscarriage. Early-onset disease occurs within 48 hours postpartum, and late-onset disease refers to presentations up to 6 weeks postpartum.[4] Symptoms that support this diagnosis include uterine tenderness, significant lower abdominal pain, purulent, foul-smelling lochia, and subinvolution of the uterus.[22] Generalized symptoms such as malaise, headache, and chills may also be present.[22] 

Clinical Examination

A focused abdominal and pelvic examination should be performed to assist in clinical diagnosis. A speculum examination to assess for evidence of infection is essential; vaginal discharge is a common finding of acute and chronic endometritis and should be sampled for diagnostic testing, while acute endometritis primarily presents with cervical motion tenderness and friability.[9][24] During the bimanual examination, uterine and adnexal tenderness to palpation is characteristic of acute endometritis; however, mild uterine discomfort on an exam may also be found with chronic endometritis.[3]

Clinical findings of postpartum endometritis include pronounced suprapubic and uterine tenderness, enlarged postpartum uterine size, and additional vital sign abnormalities such as fever and tachycardia.[1][9] Maintaining a high index of suspicion for maternal sepsis is also important. In addition to fever and tachycardia, signs can include hypotension, hypothermia, altered mental status, and unexplained end-organ dysfunction.[25] Endometritis caused by Group A streptococcus or Clostridium species is often particularly severe and can quickly develop into toxic shock syndrome and necrotizing fasciitis.

Evaluation

Acute and postpartum endometritis are clinically diagnosed primarily based on history, physical exam, and risk factors. Imaging may be performed because of diagnostic uncertainty, persistent symptoms despite treatment, or differential diagnoses that cannot be excluded. The diagnosis of chronic endometritis typically relies on histologic examination or findings on hysteroscopy.[1][8]

Acute Endometritis

Clinical features are very similar between acute endometritis and PID due to endometritis being a component of PID. Because of the severe complications that may occur with undiagnosed PID, the Centers for Disease Control and Prevention (CDC) recommends presumptively diagnosing and treating patients with the minimum criteria of adnexal tenderness, uterine tenderness, or cervical motion tenderness with PID. Consequently, patients with isolated acute endometritis may be diagnosed with PID due to difficulty differentiating these conditions by symptoms alone.[6][9][3] 

Diagnostic laboratory studies should include testing for STIs and BV. The presence of Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma genitalium is best assessed with nucleic acid amplification tests on endocervical specimens; Trichomas vaginalis and BV can be diagnosed on microscopic evaluation of vaginal discharge using a wet prep. In areas where microscopy is unavailable, commercially available molecular tests may be used.[9][3] Additionally, it is recommended that patients suspected of having PID should be screened for HIV and syphilis due to similarities in risk factors and the frequency of concurrent infections.[9] An endometrial biopsy is generally not indicated.[9][6] Other laboratory studies that may be used to support a diagnosis of acute endometritis or PID are erythrocyte sedimentation rate and C-reactive protein, which are often elevated but are nonspecific findings. Leukocytosis is common, but white blood cell count may be normal in milder cases.[9][6] 

Imaging with transvaginal ultrasonography should be considered when patients fail to respond to appropriate antibiotic therapy or to rule out other diagnoses in patients with moderate to severe symptoms. Pelvic CT or MRI may help rule out other causes of the patient's symptoms in complex cases.[9][6]

Chronic Endometritis

Chronic endometritis is frequently asymptomatic and has nonspecific diagnostic serum and culture results. Therefore, diagnosis typically requires histologic or hysteroscopic confirmation. An endometrial biopsy sample can be obtained and assessed for the presence of multiple endometrial stromal plasmacytes (ESPCs), either by traditional tissue staining techniques or using immunohistochemistry marker CD138. However, experts have no consensus on how many ESPCs are considered diagnostic.[5][23][7]

Therefore, the International Working Group for Standardization of Chronic Endometritis Diagnosis developed criteria for the definitive diagnosis of chronic endometritis. According to their criteria, a histological diagnosis could be made if 1 to 5 endometrial stromal plasmacytes (ESPCs)/high-power field or discrete clusters of <20 ESPCs by CD138 staining.[8] Moreover, the following hysteroscopic findings obtained during the follicular phase of the menstrual cycle were defined as being diagnostic for chronic endometritis:

• Endometrial micro polyposis (ie, 1-2 mm protrusions from the endometrial surface)
• Stromal edema causing a thick, pale appearance of the endometrium in the follicular phase instead of the secretory phase, as is usually seen
• Focal-reddened areas of the endometrium with sharp and irregular borders
• Large regions of hyperemic endometrium flushed with white central points
• Focal hyperemia[8][7]

Postpartum Endometritis

Postpartum endometritis is also primarily a clinical diagnosis in any postpartum patient with unexplained fever. Early-onset postpartum endometritis is defined as the onset of symptoms within 48 hours of delivery; late-onset postpartum endometritis has symptom onset within 6 weeks of delivery.[4] Laboratory studies help exclude differential diagnoses or monitor for progressive infection (eg, sepsis). Serum laboratory studies can support a diagnosis but do not confirm endometritis. Endocervical cultures, when negative, do not exclude an endometrial infection, and positive cultures may result from contamination from the vaginal vault during collection.[4][26]

Leukocytosis is a normal finding immediately postpartum, especially in those who underwent cesarean delivery. However, leukocytosis of 15,000 to 30,000 cells/μL is often present in cases of peripartum chorioamnionitis and postpartum endometritis, and a complete blood count with differential should be ordered during evaluation.[27] An increasing left shift (ie, bandemia >10%) is also suggestive of infection. A urinalysis and culture should also be obtained to rule out urinary tract infections (UTIs), which can have similar symptomatology.[25] Cervical and endometrial cultures are generally not indicated, as they rarely change management. They may be helpful, however, if group A streptococcus or an STI is suspected.[22] Blood cultures, serum lactate, comprehensive metabolic panel, coagulation panel, and surgical site cultures should be obtained if patients have findings suspicious for sepsis (eg, fever >102 °F [38.9 °C], tachycardia, tachypnea, or hypotension).[25]

In most cases, pelvic ultrasound is recommended as the first-line modality if imaging is performed. However, imaging is rarely helpful unless an alternative diagnosis (eg, retained products of conception or septic pelvic thrombophlebitis) is suspected. Imaging findings in postpartum endometritis are generally nonspecific, and there is a significant overlap with normal postpartum findings (eg, minimal amounts of gas in the endometrial cavity, enlarged uterus); therefore, any findings should be correlated to clinical history. A pelvic CT may also be considered in some suspected conditions (eg, pelvic abscess or septic pelvic thrombophlebitis).[1] 

Treatment / Management

Acute Endometritis

The CDC recommends several different antibiotic regimens.[28][29] The following oral regimens are recommended for mild to moderate cases that can be managed as an outpatient.

• Option 1:
  • Ceftriaxone 500 mg intramuscularly one time
  • + doxycycline 100 mg orally twice daily for 14 days 
  • + metronidazole 500 mg orally twice daily for 14 days[28][29]
• Option 2:
  • Cefoxitin 2 g intramuscularly once with probenecid 1 g orally once 
  • + doxycycline 100 mg orally twice daily for 14 days 
  • + metronidazole 500 mg orally twice daily for 14 days[28]
• Option 3:
  • Other parenteral third-generation cephalosporins (eg, ceftizoxime or cefotaxime) 
  • + doxycycline 100 mg orally twice daily for 14 days 
  • + metronidazole 500 mg orally twice daily for 14 days[28]
• Alternative regimens for patients with severe cephalosporin allergies include:
  • Levofloxacin 500 mg orally once daily or moxifloxacin 400 mg orally once daily (preferred for M. genitalium infections) for 14 days 
  • + metronidazole 500 mg every 8 hours for 14 days 
  • Azithromycin 500 mg intravenously once daily for 1 to 2 doses, followed by 250 mg orally daily + metronidazole 500 mg orally twice daily for 12 to 14 days[28]

Indications for inpatient hospitalization include: 

• Tubo-ovarian abscess
• Failure of outpatient therapy or inability to follow or tolerate the outpatient regimen
• Severe illness, nausea, vomiting, or oral temperature >101 °F (38.5 °C) 
• Surgical emergencies (eg, appendicitis) cannot be excluded[28]

Inpatient parenteral antibiotics until patients show signs of clinical improvement (eg, decreasing fever and abdominal tenderness), typically within 24 to 48 hours, after which they can be transitioned to an oral regimen. Recommended parental regimens include:

• Cefoxitin 2 g intravenously every 6 hours or cefotetan 2 g intravenously every 12 hours
• + Doxycycline 100 mg orally or intravenously every 12 hours[28]

Alternative parenteral regimens:

• Ampicillin-sulbactam 3 g intravenously every 6 hours + doxycycline 100 mg orally or intravenously every 12 hours
• Clindamycin 900 mg intravenously every 8 hours + gentamicin intravenously or intramuscularly 3 to 5 mg/kg every 24 hours

Chronic Endometritis

Chronic endometritis is typically treated with doxycycline 100 mg orally twice daily for 14 days.[5] For patients who fail doxycycline therapy, metronidazole 500 mg orally daily for 14 days plus ciprofloxacin 400 mg orally daily for 14 days can be used.

For chronic granulomatous endometritis, antitubercular therapy is recommended, including:

• Isoniazid 300 mg per day
• + rifampicin 450 to 600 mg per day
• + ethambutol 800 to 1200 mg per day
• + pyrazinamide 1200 to 1500 mg per day[5]

Postpartum Endometritis

Most patients should be treated with intravenous antibiotics, including those with moderate to severe disease, concern for sepsis, or endometritis after cesarean delivery. A Cochrane review on antibiotic regimens for postpartum endometritis identified the following clindamycin plus gentamicin regimen as the most effective:[4](A1)

• Gentamicin 5 mg/kg intravenous every 24 hours (preferred) or 1.5 mg/kg intravenous every 8 hours or + clindamycin 900 mg intravenous every 8 hours 
• If group B Streptococcus-positive or signs and symptoms fail to improve within 48 hours, add any of the following:
  • Ampicillin 2 g intravenous every 6 hours or
  • Ampicillin 2 g intravenous loading dose, followed by 1 g every 4 to 8 hours
  • Ampicillin-sulbactam 3 g intravenous every 6 hours[25]

For those that do not improve within 72 hours, providers should broaden their differential diagnosis to include other infections such as pneumonia, pyelonephritis, and pelvic septic thrombophlebitis. Intravenous antibiotics should be continued until the patient remains afebrile for at least 24 hours, alongside improved pain reduction and resolution of leukocytosis. No substantial evidence demonstrates that continuing antibiotics in oral form following clinical improvement improves significant patient-oriented outcomes.[30][4] An oral antibiotic regimen may be carefully considered in patients with mild symptoms that are identified after discharge from the hospital (ie, late-onset postpartum endometritis).[15](A1)

Differential Diagnosis

In addition to acute endometritis, the differential diagnosis of pelvic pain includes ectopic pregnancy, hemorrhagic or ruptured ovarian cyst, ovarian torsion, endometriosis, tubo-ovarian abscess, acute cystitis, renal stones, and gastrointestinal causes (eg, appendicitis, diverticulitis, irritable bowel syndrome).[26]

Frequent presenting symptoms of chronic endometritis frequently are abnormal uterine bleeding (AUB) or fertility challenges. The differential diagnosis of irregular bleeding is broad. The American College of Obstetricians and Gynecologists (ACOG) recommends classifying AUB according to the PALM-COEIN system, which is an acronym standing for polyps, adenomyosis, leiomyomas, malignancy, coagulopathy, ovulatory dysfunction, endometrial causes (eg, acute or chronic endometritis), iatrogenic (eg, anticoagulant medication, hormonal contraceptives), and not-yet-classified.[31] Infertility also has a broad differential that includes uterine factors, tubal factors, ovulatory or hormonal dysfunction, chromosomal issues, and male factor etiologies.[32]

In patients with postpartum fever, differential diagnoses include surgical site infections, UTIs, pyelonephritis, mastitis, pneumonia, sepsis, peritonitis, and septic pelvic thrombophlebitis.[15][1]

Prognosis

If untreated, the fatality rate of postpartum endometritis is approximately 17%.[14] In well-developed countries, however, the prognosis is typically excellent with appropriate treatment. Acute endometritis alone has an excellent prognosis; however, it is frequently present with salpingitis, significantly increasing the risk for tubal factor infertility.[5][6] Evidence suggests that fertility outcomes can improve significantly after treatment for chronic endometritis. For example, in a study looking at fresh day 3 embryo transfer cycles, live birth rates were significantly higher in treated versus untreated patients, approximately 60% to 65% versus 6% to 15%, respectively.[11] Another study demonstrated that in patients with recurrent pregnancy loss and chronic endometritis, live birth rates increased from 7% before treatment to 56% after treatment.[33]

Complications

Acute endometritis, particularly PID-associated, may lead to infertility, chronic pelvic pain, and ectopic pregnancy. Additionally, the ascending infection may develop into a tubo-ovarian abscess.[26] Complications of chronic endometritis include fertility issues (eg, recurrent pregnancy loss and repeated implantation failure) and AUB.[7] Approximately 1% to 4% of patients with postpartum endometritis can have complications such as sepsis, abscesses, hematomas, septic pelvic thrombophlebitis, and necrotizing fasciitis. Surgical intervention may be necessary if the infection has produced a drainable fluid collection.[22]