Commentary
Chronic endometritis is a controversial and complex condition
encountered by reproductive specialists. In the infertile population,
the prevalence of chronic endometritis has been estimated to between
2.8- 37.0% but as high as 56.8% in one study, compared to around 10%
in the general population undergoing hysterectomy for benign
pathology.1,2 The overwhelming prevalence of chronic
endometritis in infertile women suggests that both infectious and
non-infectious etiologies must be considered as causative factors. The
pathologic diagnosis of chronic endometritis requires the identification
of plasma cells on histologic sections of endometrial samples. Plasma
cells present within the endometrium are often associated with reactive
stroma, increased lymphocytic infiltrate, lymphoid aggregates and
disordered glandular architecture; however, these changes are not
required to render a diagnosis of chronic
endometritis.3 When present, chronic endometritis has
been implicated in reduced reproductive potential, primarily through
decreased embryo implantation and recurrent miscarriage. Several studies
have suggested that treatment with antibiotics may improve subsequent
reproductive outcomes in women with chronic endometritis, making
screening and diagnosis essential to improving outcomes. However, even
with appropriate antibiotic therapy, cure rates for chronic endometritis
are approximately 32.3% after a single course of antibiotics, which
supports the hypothesis that non-infectious causes are also a common
cause of this condition.4 This evolving understanding
of causative factors is central to the complexity of managing chronic
endometritis. One of the increasingly important etiologies for chronic
endometritis is retained products of conception (RPOC) which can
propagate a persistent inflammatory milieu within the endometrium.
Retained products of conception occur in up to 17.8% of first trimester
pregnancy losses.5 For the vast majority of women,
RPOC will be spontaneously expelled from the uterus without further
surgical intervention. However, with expectant management the median
time to sonographic resolution has been reported to be upwards of 111
days (median: 84, IQR: 50-111).6 In the infertile
population, management strategies that help to expedite subsequent
attempts at conception are often preferred so interventions such as
misoprostol, mifepristone, and operative hysteroscopy are routinely
recommended. Furthermore, prolonged retention of pregnancy tissue and
blood products within the uterine cavity is not without its own risk as
the miscarried tissue may act as culture media for genital tract
pathogens resulting in infection and inflammation that can have
deleterious reproductive consequences.
Increasingly, the concept of an impaired inflammatory state of the
endometrium (IISE) has been used to describe both infectious and
non-infectious etiologies that have traditionally been consolidated into
the catch-all of “infectious chronic endometritis”.7 Microbial pathogens, but also trauma, ischemia, and
foreign bodies are potent activators of the body’s inflammatory
response. Depending on the nature of the inciting event, IISE can be
classified as transient, repeated, or persistent. Acutely, inflammation
is a consequence of activation of the innate immune system for
immediate, non-specific host defense and is a transient event. However,
over-activation of pro-inflammatory pathways and/or failure to
transition to a post-inflammatory state may make the endometrium
susceptible to repeated and eventually persistent impaired inflammatory
states. This repetitive or prolonged inflammatory state may alter the
microenvironment of the endometrium and increase susceptibility to
pathogens leading to further inflammation - a vicious cycle.
Our group has recently reported on a series of 111 women without a
history of chronic endometritis who underwent operative hysteroscopy for
retained products of conception and found that nearly 1 in 4 women
(23.4%) had evidence of chronic endometritis on histopathology.8 Miscarriage, in and of itself, is an acute
inflammatory event with a broad range of cytokines being released and
immune cells being recruited to and developing within the endometrium.
However, as previously mentioned, most women will spontaneously pass the
products of conception allowing the endometrium to transition to a
post-inflammatory state. When the products of conception do not pass
completely, the resulting RPOC serves as a foreign body within the
endometrium that may serve to stimulate a persistent inflammatory
environment. Viewing chronic endometritis through the lens of a
persistent or recurrent impaired inflammatory state helps to
conceptualize this novel finding and may explain why a large percentage
of women fail to respond to treatment with antibiotics despite
appropriately targeted therapy. More importantly, it raises questions
about how to optimally manage retained products of conception to prevent
the damage to the endometrium from prolonged inflammatory stimuli.
In our study cohort, the median time from sonographic diagnosis of RPOC
to operative hysteroscopy was 11 days (IQR: 6-20). Despite this
relatively short interval to surgical management, diagnostic of chronic
endometritis (i.e. presence of plasma cells) were present in some of the
tissue specimens as detailed above. This raises consideration of whether
passive management strategies that increase the latency between
diagnosis to resolution of RPOC may prolong the inflammatory process
within the endometrium. This may have the potential to cause long term
deleterious reproductive outcomes and enhance susceptibility to
microbial infection. While more work is needed to better understand
optimal management strategies to minimize persistent inflammation, we
believe hysteroscopic management is one option that affords patients an
opportunity for timely and targeted resolution to retained tissue that
may have downstream beneficial reproductive consequences.
Until now, management of retained products of conception has focused on
evacuating the tissue either through surgical intervention or through
the use of prostaglandin E1 analogues and/or anti-progestins. Reframing
our understanding of chronic endometritis as a persistent impaired
inflammatory state that may have non-infectious etiologies invites the
possibility of novel therapeutic adjuncts beyond antibiotic therapy.
Synthetic glucocorticoids, for example, have been used in the management
of reproductive failure for their potent and broad-spectrum
anti-inflammatory and immunosuppressive properties. 9It is possible that their ability to dampen inflammation within the
endometrium perioperatively may be of added benefit beyond simple
resection of the retained tissue. Of course, further studies are needed
to better characterize their utility and safety as a percentage of
patients with RPOC may also have an infectious etiology that warrants
antibiotic therapy.
If we are to treat chronic endometritis effectively, it is incumbent
that we reframe our understanding of the condition beyond an infectious
pathogen resulting in infiltrative plasma cells within the endometrium.
Allowing for both infectious and non-infectious etiologies to be
causative agents in impaired inflammatory states of the endometrium
(IISE) increases our ability to identify conditions or events that may
have deleterious reproductive outcomes. Retained products of conception,
by nature of the inflammatory and then ischemic processes preceding
them, may result in recurrent and eventually persistent inflammatory
damage to the endometrium. Optimal management strategies for RPOC, with
a focus on timely resolution and the potential for anti-inflammatory
adjuncts, require further attention and study. Only then may we stand a
chance to unravel this complex and likely multifactorial condition that
we still refer to singularly as “chronic endometritis”.