Continuing Education Activity

Endometritis is inflammation of the uterine lining. It can affect all layers of the uterus. The uterus is typically aseptic, however, the proximal migration of microbes from the cervix and vagina can lead to inflammation and infection. This activity describes the background, typical clinical presentation, diagnosis, treatment, and possible complications of endometritis. It specifically highlights the role of the healthcare team in treating this disease.

Objectives:

• Identify the etiology and epidemiology of endometritis.
• Describe how to perform appropriate history, physical, and evaluation of a patient with endometritis.
• Review the treatment and management options available for patients with endometritis.
• Summarize interprofessional team strategies for improving care coordination and communication to better diagnose and treat endometritis.

Introduction

Endometritis is an infectious inflammation of the endometrium, which is the innermost uterine layer. When the inflammation extends into the muscular layer, the process is termed endomyometritis, and when it extends all the way through to the parametrium, it has been termed endoparametritis. [1] Endometritis can be either acute or chronic and may be either related or unrelated to pregnancy.

Postpartum endometritis is the most common postpartum infection. Most cases of postpartum endometritis are polymicrobial, involving both aerobic and anaerobic bacteria, and are due to the translocation of normal vaginal flora into the uterine cavity during the processes of labor and delivery. [2] Endometritis is 5-20 times more common in patients that undergo cesarean delivery (compared to vaginal delivery). [2]

Acute endometritis unrelated to pregnancy is typically classified as pelvic inflammatory disease (PID) and represents an endometrial infection present for less than 30 days. [3] It is typically due to either a sexually transmitted infection (STI) or bacterial vaginosis (BV)-causing organisms. Histologically, it is characterized by the formation of microabscesses and neutrophilic invasion. [4] Additionally, although acute salpingitis (which frequently accompanies acute endometritis in PID) is associated with tubal factor infertility due to scarring, acute endometritis alone does not appear to be associated with reduced fertility rates. [4][5]

Chronic endometritis is a more subtle chronic inflammatory condition unrelated to pregnancy, lasting at least 30 days. [3] It is characterized by the presence of plasma cells in the endometrial stroma and other signs of chronic inflammation. While symptoms are frequently mild and often go undetected by both patients and clinicians, the condition is associated with recurrent pregnancy loss and other fertility challenges. [4][6]

Etiology

Infectious endometritis results from the proximal translocation of normal bacterial flora from the cervix and vagina into the uterine cavity. It may also be due to bacteria exogenous to the genital tract.[7]

Postpartum Endometritis

During pregnancy, the thick mucus plug (along with other host factors) protects the uterine cavity from infection, and PID/endometritis is uncommon. As the cervix dilates and the fetal membranes rupture, the opportunity for bacterial colonization of the uterine cavity increases. This risk is increased further with instrumentation and insertion of foreign bodies into the uterine cavity. Bacteria is also more likely to colonize uterine tissue that has been devitalized, bleeding, or is otherwise damaged (such as during a cesarean delivery).[8] 

Risk factors for postpartum endometritis include:

• Cesarean delivery (most important risk factor)
• Infections/bacterial colonization present during labor and delivery, including intrapartum intraamniotic infection (also known as chorioamnionitis), bacterial vaginosis, Group B streptococcus (GBS), and STIs
• Prolonged rupture of membranes and/or prolonged labor
• Insertion of foreign bodies into the uterus, including multiple cervical examinations, invasive maternal/fetal monitoring devices, and manual extraction of the placenta
• Operative vaginal delivery
• Maternal factors: HIV infection, diabetes mellitus, and obesity [1][2]

Postpartum endometritis infections are usually polymicrobial, involving both aerobic and anaerobic bacteria. Some of the most common species identified include:

• Gram-positive cocci: Groups A and B Streptococci, Staphylococcus, Enterococcus
• Gram-negative bacilli:  Escherichia coli, Klebsiella, Proteus
• Anaerobic organisms: Bacteroides, Peptostreptococcus, Peptococcus, Prevotella, and Clostridium
• Others: Mycoplasma, Chlamydia[9][10]

Chlamydia is an uncommon cause of postpartum endometritis, though it is often associated with late-onset presentations. [11][12] Although rare, serious infections with Streptococcus pyogenes, Staphylococcus aureus, Clostridium sordellii, or Clostridium perfringens are associated with increased morbidity and mortality. [13][14][15]

Acute and Chronic Endometritis Unassociated With Pregnancy

Endometritis not associated with pregnancy is also due to altered endometrial microbiota. 

In acute endometritis/PID, >85% of infections are caused by STIs (primarily Chlamydia trachomatis and to a slightly lesser extent Neisseria gonorrhoeae), and/or BV-causing organisms, such as Gardnerella vaginalis. [3][5] Other potential causes include Mycoplasma genitalium, Streptococcus and Staphylococcus species, Haemophilus influenzae, Escherichia coli and anaerobes. [16] The risk of infection increases during uterine instrumentation, for example, during an endometrial biopsy or placement of an intrauterine device (IUD). [16] 

Chronic endometritis is also thought to be a polymicrobial infection. Causative organisms include Streptococcus, Enterococcus, E. coli, Klebsiella, Staphylococcus, Mycoplasma, Ureaplasma, Gardnerella, Pseudomonas, and yeasts (including Candida and Saccharomyces). [17] In addition, genital tuberculosis can result in chronic granulomatous endometritis, a condition most often seen in developing countries. [4] Unlike acute endometritis, however, Chlamydia and Neisseria infections are uncommon causes of chronic endometritis. [4]

Epidemiology

Postpartum Endometritis

Postpartum endometritis is the most common postpartum infection.[18] In patients without risk factors, following normal spontaneous vaginal delivery, the incidence is about 1% to 3%. [2] Risk factors, however, can increase this rate to a 5% to 6% risk of infection following vaginal delivery.

Cesarean delivery, on the other hand, is the most important risk factor for endometritis and is associated with a 5 to 20-fold increase in risk for postpartum endometritis when compared to spontaneous vaginal deliveries.[19][7][9][10] The risk of postpartum endometritis also depends on whether or not a cesarean delivery was performed before or after the onset of labor and whether or not the patient received appropriate prophylactic antibiotics.

A Cochrane Review noted the following frequencies of postpartum endometritis:[9]

 When left untreated, fatality rates have been estimated to be as high as 17%. [10]

Acute Endometritis

PID most commonly affects younger adults and teenagers, 15 to 29 years of age. If untreated, approximately 10-20% of people with genital chlamydia or gonorrhea infections may develop PID.

Chronic Endometritis

The true prevalence of chronic endometritis is difficult to estimate, given the generally mild presentation. In people with recurrent pregnancy loss, however, a meta-analysis of 12 studies by Pirtea et al. estimated a prevalence of nearly 30%.[6]

Pathophysiology

With postpartum endometritis, the rupture of the amniotic membranes allows the translocation of normal bacterial flora from the cervix and vagina to the usually aseptic uterus. 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 then invade the endometrium, myometrium, and perimetrium, causing inflammation and infection.

Acute endometritis associated with PID is due to ascending infection of the cervix, most often by Chlamydia trachomatis. Endocervical infections disrupt the barrier functions of the endocervical canal, allowing the infection to ascend.

Chronic endometritis is characterized by endometrial infection leading to an immune response and chronic inflammation, with significant infiltrates of endometrial stromal plasmacytes (ESPCs) and the development of micropolyposis.[4][20] Elevations in interleukin (IL)-1b and tumor necrosis factor (TNF)-alpha are also present. TNF-alpha has been shown to increase estrogen synthesis in endometrial glandular cells, which may, in turn, be responsible for the micropolyposis often seen on hysteroscopy in chronic endometritis. [4] In addition, certain genes associated with embryo receptivity and decidualization are downregulated while others associated with antiapoptotic effects and ovarian steroid receptors tend to be upregulated, suggesting a possible relationship between chronic endometritis and progesterone resistance. [4]

Histopathology

Acute and chronic endometritis can be differentiated histologically. Acute endometritis is characterized by microabscesses and neutrophil invasion of the superficial endometrial epithelium, glandular lumens, and endometrial cavity. [4] 

Chronic endometritis, on the other hand, is characterized by infiltration of ESPCs, micropolyposis (multiple small protrusions, < 1mm), edematous changes in the proliferative phase, and dissociated maturation between the stroma and epithelium known as "out-of-phase" morphology. [4][20][6] In addition, B cells accumulate in the endometrial stroma and glands.[4][20][6]

History and Physical

Postpartum Endometritis

Postpartum endometritis typically presents with fever, uterine tenderness, and lower abdominal pain, which is typically significant. Additionally, lochia may be purulent, foul-smelling, and heavier than usual due to subinvolution of the uterus (which is more common with uterine infections). [7] Generalized symptoms such as malaise, headache, and chills may also be present. On physical exam, suprapubic and uterine tenderness is typically pronounced, and additional vital sign abnormalities such as tachycardia are also common.

It is also important to maintain a high index of suspicion for maternal sepsis. In addition to fever and tachycardia, signs include hypotension, hypothermia, altered mental status, and evidence of end-organ dysfunction. [21] Endometritis caused by Group A streptococcus or Clostridium species is often particularly severe, and can quickly develop into toxic shock syndrome and/or necrotizing fasciitis. 

Acute Endometritis

Patients are typically sexually active individuals who present with lower abdominal or pelvic pain and often deep dyspareunia that is typically bilateral and has developed acutely over several days. [5][16] A slower progression of symptoms over several weeks is also possible, though less common. 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. The endometritis may also result in irregular bleeding, such as post-coital, intermenstrual, and/or heavy menstrual bleeding. Purulent vaginal discharge is also common, and a speculum exam should be performed to assess discharge, obtain samples for testing, and look for cervical friability. [16][22][16] Perihepatitis (known as Fitz-Hugh-Curtis syndrome) is also possible, which may present with right upper quadrant pain. [5]

The history should also attempt to identify common risk factors for PID, which include:

• Age < 25 
• Multiple, new, or symptomatic sex partners
• Nonbarrier contraception (e.g., oral contraceptive pills, IUDs)
• Recent IUD insertion
• History of STIs[5]

The key finding on physical exam is significant tenderness to palpation of the infected internal genital organs. In cases of endometritis, this is typically seen as significant uterine tenderness on pelvic and abdominal examinations; concurrent cervical motion tenderness and adnexal tenderness are also common. Cervical inflammation with purulent discharge is often present, and a sample should be obtained for diagnostic testing.[5][16]

Chronic Endometritis

Chronic endometritis is often asymptomatic, though it may present with some bleeding irregularities, vague pelvic discomfort, and/or leukorrhea.[4] Some of its most common presentations, however, are recurrent pregnancy loss, repeated implantation failure, and/or infertility. [4][20]

Evaluation

Postpartum and acute endometritis/PID are both primarily clinical diagnoses based on the history, physical exam, and presence of risk factors, while chronic endometritis typically relies on histologic examination and/or findings on hysteroscopy.

Postpartum Endometritis

Postpartum endometritis is primarily a clinical diagnosis, made based on history, physical exam findings, and the presence of risk factors. 

Leukocytosis is a common finding immediately postpartum (especially in those who underwent cesarean delivery). [23] Leukocytosis of 15,000 to 30,000 cells/microL, however, will almost always be present in cases of postpartum endometritis, and a CBC with differential should be ordered during evaluation. Additionally, an increasing "left shift" (i.e., bandemia > 10%) is also suggestive of infection. A urinalysis and culture should also be obtained to rule out urinary tract infections, which can have overlapping symptomatology.

Cervical and endometrial cultures are generally not indicated, as they are often contaminated and rarely change management. They may be helpful, however, if group A streptococcus or an STI is suspected. [7] Blood cultures should be obtained if patients have "alarm findings" suspicious for sepsis and/or bacteremia, such as a fever > 102 F (38.9 C), an elevated lactate, and/or tachycardia, tachypnea, or hypotension. 

Imaging is rarely helpful unless an alternative diagnosis such as 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. [24] If needed, pelvic ultrasound would be the first-line imaging modality in most cases. 

Acute Endometritis/PID

PID is typically diagnosed clinically, based on the presence of history, physical exam findings, and the presence of risk factors. A pregnancy test should always be ordered to rule out ectopic pregnancy.

Work-up should include testing for STIs and BV. The presence of Chlamydia trachomatis, Neisseria gonorrhoeae, and/or Mycoplasma genitalium are best assessed with nucleic acid amplification tests (NAAT) run on endocervical, vaginal, or urine specimens, while Trichomas vaginalis and BV can be diagnosed on microscopic evaluation of vaginal discharge using a wet prep. [16] An endometrial biopsy is generally not indicated. [16][5]

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are often elevated but are nonspecific findings. Additionally, leukocytosis is common, but white blood cell count is frequently normal in milder cases. [16][5] Additionally, patients suspected of having PID should be screened for HIV and syphilis due to similarities in risk factors. [16]

Imaging with transvaginal ultrasonography is indicated in cases of diagnostic uncertainty and when patients fail to respond to appropriate antibiotic therapy or have moderate-to-severe disease in order to rule out a pelvic abscess. CT and/or MRI may help rule out other causes of the patient's symptoms in complex cases. [16][5]

Chronic Endometritis

Chronic endometritis is frequently asymptomatic or has nonspecific clinical findings, so typically requires histologic and/or hysteroscopic diagnosis. An endometrial biopsy sample can be obtained and assessed for the presence of multiple ESPCs, either by traditional tissue staining techniques or using immunohistochemistry marker CD138. [4][20][6] 

Hysteroscopic findings associated with chronic endometritis include endometrial micropolyposis (1-2 mm protrusions from the endometrial surface) and strawberry aspects (hyperemic areas of endometrium with a central white point, found in about 65% of women with confirmed chronic endometritis). [4][6]

Treatment / Management

Postpartum Endometritis

Most patients should be treated with intravenous (IV) antibiotics, including those with moderate to severe disease, concern for sepsis, and/or patients with endometritis after a cesarean delivery. A Cochrane review on antibiotic regimens for postpartum endometritis identified IV clindamycin plus gentamicin as the most effective antibiotic regimen. [2]

The recommended regimen is:

• Gentamicin 5 mg/kg IV every 24 hours (preferred) or 1.5 mg/kg IV every 8 hours or PLUS clindamycin 900 mg IV every 8 hours 
• If GBS-positive, or signs/symptoms fail to improve within 48 hours: ADD Ampicillin 2 g IV every 6 hours (or 2 g IV loading dose, followed by 1 g every 4-8 hours) or Ampicillin-sulbactam 3g IV every 6 hours [21]

Daily gentamicin dosing is associated with a shorter hospitalization time compared with dosing every 8 hours and has been shown to be just as effective. [25] 

Significant clinical improvement in response to antibiotics typically occurs within 48 to 72 hours. If there is no clinical improvement within 24 hours, providers should consider adding ampicillin 2 g initially, followed by 2 g every 6 hours (or 1 g every 4-8 hours) for enhanced Enterococcus coverage. 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. 

IV antibiotics should continue until the patient becomes afebrile for at least 24 hours in addition to improvements in the pain and leukocytosis. At this time, there is no substantial evidence demonstrating that continuing antibiotics in oral form following clinical improvement improves significant patient-oriented outcomes.[26]

In mild cases that are identified in patients after discharge from the hospital, oral antibiotics (e.g., amoxicillin-clavulanic acid) may be carefully considered.

In low-resource settings where IV therapy is unavailable, oral and/or IM antibiotics may be considered. A 2015 review in Obstetrics & Gynecology identified the following 5 alternative non-IV regimens as appropriate for use in postpartum endometritis:

• Amoxicillin-clavulanic acid 875 mg/125 mg PO every 12 hours
• Gentamicin 4.5 g IM every 24 hours PLUS clindamycin 600 mg PO every 6 hours
• Cefotetan 2 g IM every 8 hours
• Meropenum OR Imipenem-cilastatin 500 mg IM every 8 hours
• Amoxicillin 500 mg PO every 8 hours PLUS metronidazole 500 mg PO every 8 hours [10]

Acute Endometritis/PID

Several different antibiotic regimens are recommended by the U.S. Centers for Disease Control and Prevention. [27] Oral regimens are recommended for mild-moderate cases that can be managed as an outpatient. These regimens include:

Option 1:

• Ceftriaxone 500 mg IM x1
• PLUS doxycycline 100 mg PO twice daily for 14 days 
• PLUS metronidazole 500 mg PO twice daily for 14 days

Option 2:

• Cefoxitin 2 g IM x1 
• PLUS probenecid 1 g PO x1 
• PLUS doxycycline 100 mg PO twice daily for 14 days 
• PLUS metronidazole 500 mg PO twice daily for 14 days

Option 3:

• Other parenteral third-generation cephalosporins
• PLUS doxycycline 100 mg PO twice daily for 14 days 
• PLUS metronidazole 500 mg PO twice daily for 14 days

Alternative regimens for patients with severe cephalosporin allergies include:

• Levofloxacin 500 mg PO once daily PLUS metronidazole 500 mg every 8 hours
• Moxifloxacin 400 mg PO once daily for 14 days (preferred for M. genitalium infections)
• Azithromycin 500 mg IV once daily for 1-2 doses, followed by 250 mg PO daily for a total duration of 7 days of azithromycin therapy PLUS metronidazole 500 mg PO three times daily for 12-14 days

 Indications for hospitalization include: 

• Tuboovarian abscess
• Failure of outpatient therapy (or unable to follow or tolerate the regimen)
• Severe illness, including high fever or other "alarm features"
• Surgical emergencies cannot be excluded [22][16] 

If admitted to the hospital, patients should be treated with parental antibiotics until patients show signs of clinical improvement (typically within 24-48 hours), at which time they can be transitioned to an oral regimen. Recommended parental regimens include:

• Cefoxitin 2 g IV every 6 hours OR cefotetan 2 g IV every 12 hours
• PLUS Doxycycline 100 mg PO or IV every 12 hours

Alternative regimens:

• Ampicillin-sulbactam 3 g IV every 6 hours PLUS doxycycline 100 mg PO or IV every 12 hours
• Clindamycin 900 mg IV every 8 hours PLUS gentamicin IV or IM 3-5 mg/kg every 24 hours

Chronic Endometritis

Chronic endometritis is typically treated with doxycycline 100 mg twice daily for 14 days. [4] For patients who fail doxycycline therapy, metronidazole 500mg daily for 14 days plus ciprofloxacin 400mg per day for 14 days can be used.

For chronic granulomatous endometritis, antitubercular therapy is recommended with:

• Isoniazid 300 mg per day
• PLUS rifampicin 450-600 mg per day
• PLUS ethambutol 800-1200 mg per day
• PLUS pyrazinamide 1200-1500 mg per day [4]

Differential Diagnosis

In the patient with postpartum fever and abdominal/pelvic pain, key conditions in the differential diagnosis include urinary tract infections (including pyelonephritis), pneumonia, surgical site infections, and septic pelvic thrombophlebitis. 

For patients with acute endometritis/PID, the differential diagnosis includes ectopic pregnancy, hemorrhagic or ruptured ovarian cyst, ovarian torsion, endometriosis, acute cystitis, and GI causes (e.g., appendicitis, diverticulitis, irritable bowel syndrome).

Chronic endometritis typically presents as either irregular bleeding or fertility challenges. The differential diagnosis of irregular bleeding is broad, and the American College of Obstetricians and Gynecologists (ACOG) recommends classifying abnormal uterine bleeding (AUB) according to the PALM-COEIN system, which is an acronym standing for polyps, adenomyosis, leiomyomas, malignancy, coagulopathy, ovulatory dysfunction, endometrial causes (of which chronic endometritis is one cause), iatrogenic/infectious, and not-yet-classified. [28] Infertility also has a broad differential that includes uterine factors, tubal factors, ovulatory/hormonal dysfunction, chromosomal issues, and male factor etiologies. [29]

Prognosis

If untreated, the fatality rate of postpartum endometritis is approximately 17%. [10] 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 which significantly increases the risk for tubal factor infertility. [4][5]

Evidence suggests that after treatment for chronic endometritis, fertility outcomes can improve significantly. 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 60-65% vs 6-15%). [17] Another study demonstrated that in patients with recurrent pregnancy loss and chronic endometritis, live birth rates increased from 7% prior to treatment to 56% after treatment. [30]

Complications

Approximately 1% to 4% of patients will 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.[7]

Consultations

Patients diagnosed with postpartum endometritis should be managed by clinicians experienced in treating this condition. For patients presenting to emergency departments, urgent care clinics, and primary care providers who do not practice obstetrics, referral to an obstetrician is appropriate.

Patients with fertility challenges should be referred to a Reproductive Endocrinologist/Infertility (REI) specialist.

Deterrence and Patient Education

Due to the significant increase in prevalence and mortality of endometritis after cesarean deliveries, ACOG recommends prophylactic antibiotics before all cesarean deliveries. A recent Cochrane review showed a significant reduction in the risk of postpartum infections, including endometritis, when appropriate antibiotics were given.

The regimen recommended in the ACOG Practice Bulletin on prophylactic antibiotics in labor and delivery recommends giving a first-generation cephalosporin, such as cefazolin 1 g IV administered within 1 hour prior to skin incision. [31] Additionally, evidence suggests improved outcomes in nonelective cesarean deliveries in patients who received azithromycin 500 mg IV infused over 1 hour in addition to standard preoperative prophylaxis (i.e., cefazolin). The increased risk of postpartum infection should be discussed with patients prior to cesarean delivery as part of the informed consent process. [31] 

Outside of pregnancy, endometritis is best prevented with the appropriate use of barrier contraceptives to prevent the transmission of STIs. In addition, clinicians should use appropriate technique whenever they are performing invasive gynecologic procedures, such as IUD insertions.

Pearls and Other Issues

• Endometritis is an inflammation and infection of the uterus.
• Postpartum endometritis is the most common postpartum infection.
• Endometritis should be suspected in any postpartum patient with fever and abdominal/pelvic pain. Purulent or foul-smelling lochia supports the diagnosis. Early identification and obstetric consultation are essential.
• Acute endometritis is considered part of PID, and usually coexists with salpingitis and/or cervicitis.
• Chronic endometritis is associated with recurrent pregnancy loss, repeated implantation failure, and infertility.
• Treatment in all cases is with appropriate antibiotics.
• The severity of the disease can vary. If necessary, resuscitation, including early antibiotic administration, should be the primary focus.

Enhancing Healthcare Team Outcomes

Endometritis is the most common postpartum infection. Disease severity can range from mild to severe, with treatment regimens ranging from outpatient PO antibiotics with adequate obstetrics follow-up and return precautions to inpatient hospitalization with IV antibiotics and surgery.

Patients will often present to generalists: non-obstetric primary care providers, urgent care centers, and emergency departments. Early obstetric consultation is critical. Such a consult can help aid efficient and appropriate diagnosis and treatment. If imaging is needed, ultrasonographers, radiology technicians, and diagnostic radiologists are all critical in providing an accurate diagnosis. For ideal antibiotic choice, dosing, and administration, a clinical pharmacist may help validate antimicrobial therapy against the latest antibiogram data, check for interactions, and alert the staff to the potential adverse effects. If operative intervention is required, an anesthesiologist is also necessary for a successful surgery.

To ensure that a patient with endometritis receives optimal care, an effective interprofessional approach is crucial. Prompt involvement of appropriate specialists and strong communication between providers can make a significant difference in the patient's clinical course, morbidity, and mortality. Obstetrical nurses should promptly report fevers to the managing providers, administer treatment, and educate patients. With interprofessional collaboration, patient outcomes will improve. [Level 5]