Reproduction: persistent post-breeding endometritis in Horses (Equis) | Vetlexicon
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Reproduction: persistent post-breeding endometritis

ISSN 2398-2977


Synonym(s): Susceptible mare, Problem mare

Introduction

  • Cause: failure of the normal physiological mechanisms for eliminating sperm cells and inflammatory products / debris following breeding (natural cover or AI). This failure consists of both under-activation and uncontrolled activation of normal physiological pathways.
  • Signs: intrauterine fluid accumulation detected upon ultrasonography after breeding, which if untreated persists beyond 24-48 h after breeding.
  • Diagnosis: ultrasonographical examination of the reproductive tract; supportive endometrial cytology and bacteriology and palpation of the reproductive tract (per rectum and per vaginum) to help identify underlying causes.
  • Treatment: address pre-existing problems, eg bacterial endometritis Uterus: endometritis - bacterial, prior to breeding. Limit insult to the uterus by breeding only once per estrous cycle. Then, depending on underlying cause: agents to make the uterus contract; cervical dilation; intrauterine or systemic antibiotics, immunomodulation; exercise to promote uterine clearance.
  • Prognosis: depends upon underlying cause. Prognosis improved by prompt recognition of the susceptibility of mares to persistent post-breeding endometritis, accurate diagnosis of the underlying cause, and aggressive early treatment.

Presenting signs

Acute presentation

  • When mare is examined using reproductive ultrasonography after breeding, an intrauterine fluid accumulation is detected which fails to resolve within 24-48 h post-breeding.
  • Rarely, vulval discharge may be apparent.

Geographic incidence

  • Worldwide.

Age predisposition

  • Older maiden mares (particularly with cervix which fails to dilate in estrus Cervix: fibrosis +/- some degree of uterine fibrotic degeneration Endometrium: fibrosis).
  • Older multiparous mares (particularly with pendulous uteri from which expulsion by uterine contractions of the normal inflammatory products of breeding is disrupted due to the influence of gravity, since the uterus sits lower than the cervix).

Cost considerations

  • Costs of intensive veterinary involvement to treat the problem during the acute phase in order to try and facilitate the establishment of pregnancy.
  • On-going costs of veterinary treatments to resolve/address the underlying problem across repeated estrous cycles.
  • Failure to achieve a pregnancy despite treatment. Post-breeding endometritis is the leading cause of subfertlilty in broodmares.

Pathogenesis

Etiology

  • In order to understand the etiology of persistent post-breeding endometritis, it is necessary to understand the normal physiological mechanisms which occur in the mare’s uterus following breeding, since persistent post-breeding endometritis is the failure (either underactivation or uncontrolled activation) of these mechanisms.
  • Following breeding, mares need to eliminate those sperm cells which do not pass through the utero-tubal junction into the oviduct and other debris from the uterus, in order to leave the uterus in a non-inflamed state, ready to receive the embryo when it descends into the uterus from the oviduct 5.5-6 days post-ovulation.
  • This clearance is normally achieved by a combination of lymphatic drainage, myometrial contractions (physical expulsion), and a non-specific immune response (necessary because a specific immune response with a memory would have a detrimental effect the fertility of any subsequent breedings).
  • Thus all mares undergo a transient inflammatory reaction within the uterus (endometritis) following breeding - this is a normal physiological mechanism. The inflammation is triggered by sperm cells, which activate complement in uterine secretions. This causes complement factor C5 to cleave into C5a and C5b. This cleavage acts as a chemotactic signal to polymorphonuclear leukocytes (PMNs), causing an influx of PMNs into the uterine lumen Polymorphonuclear (PMN) score table.
  • These activated PMNs bind to sperm cells, by ligand binding and possibly also by extruding their (the PMNs’) DNA to form extracellular neutrophil traps (NET). The PMNs phagocytose sperm cells and bacterial contaminants from breeding.
  • It is proposed that the activated PMNs also release prostaglandin F2α, which promotes myometrial contractions, thus physically removing inflammatory products and fluid from the uterus.
  • In normal mares, the inflammation (endometritis) subsequently subsides. Seminal plasma (i.e. the non-sperm and non-gel component of the ejaculate) has a role to play in limiting the duration of physiological post-breeding endometritis by suppressing complement activation, PMN chemotaxis and phagocytosis.
  • The use of spermatozoa with reduced seminal plasma (as in frozen/thawed semen or sperm 'packed' from fresh semen by centrifugation) results in a more marked and prolonged inflammatory response, because seminal plasma is a modulator of sperm-induced inflammation and protects viable spermatozoa from opsonization and phagocytosis.
  • In mares which are susceptible to persistent post-breeding endometritis (around 10-15% of broodmares), some part of this normal physiological mechanism of post-breeding inflammation, physical clearance and subsequent dampening of the inflammation fails (see Pathophysiology below).

Predisposing factors

General

  • Older mare, either maiden or pluriparous.
  • Mares bred with frozen/thawed semen.

Specific

  • Cervix which fails to dilate during estrus Cervix: fibrosis.
  • Pendulous uterus.
  • Failure of myometrial contractility, ie failure of physical clearance of intrauterine fluid.
  • Failure of normal suppression of normal physiological inflammatory reaction to breeding.
  • Poor lymphatic drainage, eg due to endometrial degeneration/fibrosis Endometrium: fibrosis.
  • Possibly, angiosis, ie endometrial vascular degeneration.

Pathophysiology

  • In mares which are susceptible to persistent post-breeding endometritis, one or a combination of the following factors results in a failure of the normal physiological mechanism for dealing with the insult to the uterus which breeding represents:
  • Failure of physical clearance mechanisms
    • Pendulous uterus meaning that intrauterine fluid cannot be moved towards the cervix by the contracting myometrium, due to gravity.
    • Lack of myometrial contractility.
  • Failure of suppression of the normal inflammatory reaction to breeding, by 24-48 h post-breeding.
There is no evidence that there is a failure of the normal, physiological, initial post-breeding inflammatory mechanism in ‘susceptible’ mares  - the failure is rather one of that mechanism not subsiding by 24-48 h post-breeding.
  • There is an inter-relationship between disruption of normal mechanisms of inflammation and myometrial contractility. During inflammation, nitric oxide is synthesized by inducible nitric oxide synthase. In mares susceptible to persistent post breeding endometritis, there is an increase in NO production following breeding compared to non-susceptible mares. Nitric oxide has a relaxing effect on smooth muscle, ie inhibits myometrial contractility.
  • Prolonged inflammation and prostaglandin release can cause premature lysis of the corpus luteum with resulting progesterone deficiency and embryo mortality.
  • The persistent inflammatory reaction within the uterus and the failure of normal physical clearance combine to set up a vicious cycle of intra-uterine fluid-production. The persistence of intrauterine fluid can:
    • Act as a culture medium for bacteria introduced into the uterus prior to breeding, eg due to poor perineal conformation, at the time of breeding, or post-breeding, eg during the course of intrauterine treatments. Thus, what is primarily a disruption of normal physiological mechanisms can exacerbate or progress into bacterial endometritis Uterus: endometritis – bacterial.
    • Possibly, result in a failure of a mucociliary clearance mechanism which usually promotes uterine clearance post-breeding, by overhydrating the mucus, thus disrupting its viscosity and elasticity and preventing it from functioning normally to traps particles and facilitate their clearance via carriage by ciliary cells.

Timecourse

  • Post-breeding endometritis is initiated within 30 min of breeding.
  • In normal mares, it is self-limiting by 24-48 h post-breeding
  • In ‘susceptible’ mares, it continues beyond this time frame and may persist until the embryo descends into the uterus at 5.5-6 days post-ovulation.

Diagnosis

Presenting problems

  • Failure to conceive to appropriately managed breeding with good quality semen of known fertility.
  • Detection of persistent fluid in the uterus post-breeding.
Important to distinguish persistent post-breeding endometritis which results from the disruption of normal physiological mechanisms from acute post-breeding endometritis due to venereal infection Uterus: contagious equine metritis.

Client history

  • Failure to conceive.
  • History of persistent post-breeding endometritis following previous breedings.
Assume that older, maiden mares (particularly those with cervices which fail to dilate well in estrus) will be predisposed to post-breeding endometritis. Warn owners of that probability, and of the associated costs, and treat promptly and aggressively post-breeding.

Clinical signs

Diagnostic investigation

  • The following, which may be detected prior to breeding, act as indicators of mares being likely to be susceptible to persistent post-breeding endometritis, and alert the clinician of the need to monitor such mares closely, and to treat them early after breeding:
    • Poor perineal conformation Vulva: conformation.
    • Cervix which fails to dilate in estrus.
    • Pendulous uterus.
    • Ultrasonographic detection of a particularly pronounced edema pattern in the uterus during estrus (may reflect poor lymphatic drainage).
    • Free fluid within the uterus prior to breeding; this is often sterile.
If there is any clinical suspicion of bacterial endometritis prior to breeding, this should be confirmed by cytology and bacteriology and treated prior to breeding Uterus: endometritis - bacterial.

Confirmation of diagnosis

Discriminatory diagnostic features

  • Persistent ultrasonographically detected intrauterine fluid post-breeding.

Definitive diagnostic features

  • Effective treatment is necessarily predicated on accurately assessing the underlying cause for the persistence of the persistent post-breeding endometritis, ie:
    • Cervix which fails to dilate during estrus Cervix: fibrosis.
    • Pendulous uterus.
    • Failure of myometrial contractility.
    • Failure of suppression of normal physiological inflammatory reaction to breeding.
    • Poor lymphatic drainage, eg due to endometrial degeneration/ fibrosis Endometrium: fibrosis.
    • Possibly, angiosis, ie endometrial vascular degeneration.

Histopathology findings

Differential diagnosis

Treatment

Initial symptomatic treatment

  • There is a window of opportunity between 4 h after breeding (when sperm cells have reached the safety of the oviduct) and 4 days post-ovulation (before the embryo descends into the uterus at 5.5-6 days post-ovulation) in which intrauterine treatments can be administered.
  • Because the cervix closes quickly under the influence of progesterone once ovulation occurs, treatments designed to promote uterine clearance are generally more successful when administered prior to ovulation.
  • The time available for treatment prior to ovulation can be extended by using semen with known good longevity and breeding early in relation to ovulation. It is generally more successful to assess mares suspected of being susceptible to persistent post-breeding endometritis soon (4-6 h) after breeding, and to initiate treatment immediately, than to leave assessment until later and carry on treating in the days post-ovulation.

Standard treatment

Depending upon identification of underlying predisposing factors...

  • Improve physical clearance of inflammatory debris from the uterus:
    • Large volume uterine lavage using isotonic solutions, eg 1-2 l warmed lactated Ringer’s solution, repeat until fluid comes back clear.
    • Mucolytic agents, eg acetylcysteine 30% solution, 150 ml infused into the uterus and left for 24 h before lavage with lactated ringer’s solution or saline.
    • Ecbolic agents to make uterus contract:
      • Oxytocin Oxytocin 10-25 iu IV or IM every 4-6 hours until the fluid is cleared.
      • Long-acting oxytocin (carbetocin) 175 µg IV. 
      • Prostaglandin F2α analogue cloprostenol Cloprostenol sodium 250 µg IM. Do not use prostaglandins after ovulation as they may cause luteolysis.
    • Dilate cervix manually.
    • Encourage mares to move around/exercise, particularly immediately after lavage and ecbolic treatment.
  • Address concurrent bacterial endometritis Uterus: endometritis - bacterial.
  • Correction of anatomical defects, for example by Caslick's procedure Vulva: Caslick operation, can prevent bacterial contamination, air aspiration and ascending inflammation.
  • Use of antibiotics controversial as one study showed that uterine lavage and oxytocin were as effective at treating bacterial endometritis as intrauterine antibiotics:
    • Intrauterine antibiotic treatments (usually once off). Choose an antibiotic based on known or anticipated sensitivity, which will not irritate the endometrium, eg Ceftiofur Ceftiofur 1 g diluted in 20 ml of sterile water for injection, in accordance with medicines regulations.
    • Some advocate use of systemic antibiotics which penetrate the uterus.

Any time the cervix is breached, eg to perform a lavage, there is a risk of introducing contamination/infection, which may warrant associated antibiotic treatment.

Antibiotics will not work in the presence of exudate, so if significant volumes of uterine fluid present lavage uterus before instilling antibiotics.

Immunomodulation

  • Modulation of the inflammatory response associated with mating using the following agents has been reported:
    • Dexamethasone Dexamethasone 50 mg IV injected intravenously at the time of breeding.
    • Prednisolone Prednisolone 0.1 mg/kg PO BID for 4 days, beginning 48 h before breeding.
Take great care using steroids in mares which have concurrent bacterial endometritis as immunosuppression can exacerbate infection.
An ecbolic drug should always be used concurrently with dexamethasone, as its use may decrease myometrial contractions through suppression of cyclo-oxygenase-2 and subsequent block of prostaglandin F2α.
Take great care in using steroids in mares with a history of or likely predisposition to laminitis Foot: laminitis. Warn owners!
  • Intrauterine infusion of platelet rich plasma (recently been reported to modulate the exacerbated inflammatory response in mares susceptible to post-breeding endometritis).
  • Intrauterine infusion of stem cells is an evolving treatment which has been shown to reduce endometrial inflammation and potentially improve endometrial quality.
  • Immunostimulants which help to restore homeostatic local inflammatory mechanisms (mares susceptible to post-breeding endometritis have been reported to express higher levels of pro-inflammatory cytokines and lower levels of interleukin-10 (which inhibits production of pro-inflammatory cytokines) in their uteri compared to non-susceptible mares:
    • Cell wall extract of Mycobacterium phlei (Settle, Bioniche Animal Health).
    • Suspension of Propionibacterium acnes (Eqstim, Neogen Corp).

Monitoring

Subsequent management

Treatment

  • Treatments, particularly the use of ecbolic agents, may need to be repeated during the window of opportunity until 4 days post-ovulation, depending on response to initial treatment.

Prevention

Prophylaxis

  • Breed early in the estrous period and avoid the use of frozen semen in susceptible mares where possible.

Outcomes

Prognosis

  • Depends upon underlying predisposing factors.

Expected response to treatment

  • Resolution of persistent post-breeding endometritis: clearance of intrauterine fluid, dampening of exacerbated inflammatory response.
  • Mares may show different post-breeding responses in different cycles and different years.

Reasons for treatment failure

  • Unable to clear uterine fluid before embryo descends into the uterus 5.5-6 days post-ovulation.

Further Reading

Publications

Refereed Papers

  • Recent references from PubMed and VetMedResource.
  • Canisso I F, Stewart J & Coutinho da Silva M A (2016) Endometritis: managing persisitent post-breeding endometritis. Vet Clin North Am Equine Pract 32 (3), 465-480 PubMed.
  • Reghini M F et al (2016) Inflammatory response in chronic degenerative endometritis mares treated with platelet-rich plasma. Theriogenology 86, 516-522 PubMed.
  • Woodward E M et al (2015) Inflammatory mechanisms of endometritis. Equine Vet J 47 (4), 384-389 PubMed.
  • Bucca S et al (2008) The use of dexamethasone administered to mares at breeding time in the modulation of persistent post-breeding induced endometritis. Theriogenology 70, 1093-2000 PubMed.
  • Maischberger E, Irwin J, Carrington S & Duggan V (2008) Equine post-breeding endometritis: A review. Ir Vet J 61 (3), 163-8 PubMed.
  • Fumoso E A et al (2007) Immune parameters in mares resistant and susceptible to persistent post-breeding endometritis: effects of immunomodulation. Vet Immunol Immunopath 118, 30-39 PubMed.
  • Causey R C (2006) Making sense of equine uterine infections: The many faces of physical clearance. Vet J 172, 402-421 PubMed.
  • Troeddson et al (2005) Components in seminal plasma regulating sperm transport and elimination. Anim Reprod Sci 89, 171-186 PubMed.
  • Trodesson M H T et al (2001) Effect of periovulatory prostanglandin F2α on pregnancy rates and luteal function in the mare. Theriogenology 55, 1891-1899 PubMed.
  • LeBlanc M M et al (1998) Differences in uterine position of reproductively normal mares and those with delayed uterine clearance detected by scintigraphy Theriogenology 50, 49-54 PubMed.
  • Troeddson M H T (1997) Therapeutic considerations for mating-induced endometritis. Pferdeheilkunde 13, 516-520 VetMedResource.
  • Pycock J F & Newcombe J R (1996) Assessment of the effect of three treatments to remove intrauterine fluid on pregnancy rates in the mare. Vet Rec 138, 320-323 PubMed.
  • Katila T (1995) Onset and duration of uterine inflammatory response of mares after insemination with fresh semen. Biol Reprod Mono 1 (6), 515-517 FAO Agris.
  • Troedsson M H T (1995) Uterine response to semen deposition in the mare. In: Proc Society of Theriogenology. San Antonio, Texas, USA. pp 130-135 Scopus.
  • Kotlainen T, Huhtinen M & Katila T (1994) Sperm induced leucocytosis in the equine uterus. Theriogenology 41, 629-636 PubMed.

Further Reading