How To Decide What Treatment Options Are Best For PMIE?

Post-mating induced endometritis (PMIE) 

Post-mating-induced endometritis (PMIE), a noninfectious inflammatory condition of the uterus, is one of the most common reproductive abnormalities encountered.^1-2 PMIE refers to the accumulation and retention of inflammatory fluid in the uterus for more than 48 hours after breeding.^3-5 Mares with fluid present in the uterus 48 hours after breeding are considered susceptible to developing PMIE. Mares free of inflammation 48 hours post-breeding are considered resistant to PMIE. Failure to evacuate intrauterine fluid and the inflammation that follows leads to reproductive inefficiency and significant economic loss to the mare owner.^6-7

Mares with PMIE typically appear normal (i.e., no intrauterine fluid is seen on ultrasound, and negative findings on endometrial culture and cytology). In some cases, mares with PMIE will develop exuberant edema as estrus progresses. Mares at risk for PMIE are often older (older than 15 years) have poor vulva conformation or a pendulous uterus, and have a Kenney biopsy score of 2 or greater.^8-9 A thorough history is often the most rewarding element of a diagnostic workup for identifying mares prone to developing PMIE; mares with a history of recurring embryonic loss, or failure to conceive are at higher risk for developing PMIE.¹⁰ Additionally, if a mare has developed PMIE in previous seasons, problems with fluid clearance will likely continue in the future.  

One of the key differences in differentiating PMIE from infectious endometritis is that mares with PMIE have normal endometrial culture and cytology results prior to breeding.¹⁰ PMIE is an inflammatory response to the spermatozoa, not an infectious event. Mares being treated for PMIE typically do not require antibiotic intervention, as an active infection is not present.¹⁰ The use of antibiotics in the treatment of PMIE should be considered only if the uterus is inoculated with significant and known quantities of bacteria during the breeding or treatment period. Examples include semen with high levels of bacteria or contamination during a uterine lavage.  

The goal of treating mares with PMIE is to assist in clearing the inflammatory fluid from the uterine lumen and to decrease inflammation in the endometrium.¹⁰ The severity of PMIE varies greatly, and not every mare needs to receive all available treatments. The practitioner should develop a treatment plan for each mare that results in the elimination of the intrauterine fluid within 48 hours after ovulation.  

Treatment Options: Removal of inflammatory products from the uterus 

Oxytocin  (10–20 IU, IM or IV, every four to six hours) is the first line of defense and is administered to most mares with PMIE.^11-13. Oxytocin induces progressive uterine contractions capable of clearing intrauterine fluid. Mares with a small volume of fluid in the uterine lumen and an open cervix may be treated successfully with oxytocin alone. Administration of more than 20 IU of oxytocin can cause the myometrium to spasm and prevent the normal myometrial waves associated with uterine clearance.¹²  

An alternative ecbolic agent is prostaglandin F2α (PGF2α) which can cause prolonged uterine contractions as compared to oxytocin (five hours vs. 40 minutes, PGF2α vs. oxytocin) A dosage of 250 μg of cloprostenol sodium can be administered intramuscularly, to aid in the clearance of intrauterine fluid.^14-16 In the author’s experience, the vast majority of mares will respond to oxytocin and cloprostenol sodium similarly, with effective fluid clearance after treatment. However, in the author’s clinical program, there are mares that repetitively have not cleared fluid following oxytocin treatment and will effectively clear this fluid with cloprostenol sodium treatment. Administration of cloprostenol sodium prior to ovulation can be effective at clearing uterine fluids. However, administration post-ovulation results in altered corpus luteum development, reduced systemic progesterone concentrations and reduced pregnancy rates.¹⁶ 

Acupuncture, both in its traditional needle form and through electrical stimulation, has been anecdotally suggested to improve uterine fluid evacuation. While many of these reports appear promising, a controlled, blind clinical study did not show an advantage of acupuncture in treating fluid post-breeding compared with traditional therapies like oxytocin.¹⁶ However, it should be noted that the number of mares treated was small, and the acupuncture points treated may have differed between previous anecdotal evidence and this controlled study.^17,18 

If fluid remains following oxytocin or prostaglandin administration, or in cases of moderate to severe PMIE (more than 2 cm fluid depth), uterine lavage is typically performed.¹⁵ Uterine lavage removes the spermatozoa and prevents further inflammation, while also removing the inflammatory cells and mediators from the uterine lumen. The uterus can be lavaged with either lactated Ringer’s solution or sterile physiologic saline as soon as four to six hours after breeding without adversely affecting pregnancy rates.¹⁹   

Recent work in 2020 compared a routine uterine lavage at either one hour or four hours post deep-orn insemination.²⁰ Pregnancy rates were found not to differ in a controlled study of normal mares.²⁰. These findings indicate that within one-hour post-deep horn insemination, the spermatozoa required for fertilization are protected in the mare’s oviduct. A follow-up study indicated that subfertile mares had a higher pregnancy rate after a uterine lavage one-hour post-deep horn insemination compared with four hours.²⁰. This increase in pregnancy rates may be due to removing the stimuli (spermatozoa) for continued inflammation from the uterus quickly and shifting focus to decreasing inflammation post-mating.  

It is important to note that the suggested adjustment in time from breeding to lavage from four hours to one hour was specifically focused on mares bred by deep-horn insemination and not using a routine body insemination.²⁰ 

An interesting finding associated with increased development of PMIE was stall confinement during breeding management.¹⁷   In one study, mare confinement in 12-by-12-foot stalls during breeding management was associated with up to 78% of susceptible mares accumulating fluid post-breeding.¹⁷ The use of lunging at a trot for 15 minutes (at six, 12, 24, 30, 36, 48 hours post-mating) in the 48 hours post-breeding dramatically reduced the rate of fluid retention by 66% in susceptible mares after breeding.¹⁷  Exercise, when possible, is a simple tool to aid in uterine fluid evacuation in the peri-ovulatory period.¹⁷  

Modulation of inflammation 

Dexamethasone, a glucocorticoid, can be used to modulate inflammation during the breeding process. Bucca et al. (2008) showed that administration of dexamethasone (50 mg IV at the time of breeding) resulted in increased pregnancy rates in mares that had at least three risk factors for developing PMIE (abnormal reproductive history, positive endometrial culture, more than 2 cm endometrial fluid prior to breeding, abnormal perineal conformation, abnormal cervix, post-breeding endometrial fluid  between 1.5 and 2 cm, post-foaling vulvoplasty, abnormalities of the reproductive tract, or post-breeding fluid persisting more than 36 hours after mating).²¹ 

This enhancement in pregnancy rates is likely due to the alteration of pro-inflammatory cytokines after breeding in mares.²² Because dexamethasone alters inflammation in abnormal mares, there is no effect on pregnancy rates when administered to normal mares. Lower doses of dexamethasone were not shown to be as effective in reducing inflammation after breeding,²³ and long-term dexamethasone administration was associated with ovulation failure in some mares.²⁴ Daily administration of prednisolone (0.1 mg/kg every 12 hours) four treatments before breeding and one treatment at time of breeding was associated with an increase in pregnancy rates^.25 

The majority of NSAIDs have shown a lack of clinical improvement in PMIE and have been associated with increased incidence of anovulatory follicle formation.^26-27 Administration of firocoxib, a COX-2-selective anti-inflammatory drug, was shown to modulate inflammation in mares prone to PMIE when administered from ovulation induction until 24 hours after artificial insemination. Treatment resulted in decreased migration of white blood cells into the uterine lumen and reduced inflammatory mediators. The dose of firocoxib used in this study was 0.2 mg/kg, compared with the more commonly used dose of 0.1 mg/kg, once daily (after a single loading dose of 0.3 mg/kg).²⁸  

Bacterial cell wall extracts have been investigated for their effects on the uterine immune system and enhancement of pregnancy rates. While most of the work is focused on clearance and treatment of infectious endometritis, a study in 2012 evaluated the immune response to spermatozoa. Mares were treated with 1.5 mg Settle^TM IV 24 hours prior to insemination. Overall, a downregulation of IL-1 mRNA was found in this population of susceptible mares six hours after AI.²⁹ Large-scale clinical trials showing alterations in pregnancy rates using bacterial cell wall extracts are limited in the treatment of PMIE. 

Mucolytics and Chemical Curretage 

Not uncommonly, the lavage effluent from mares with PMIE contains excessive quantities of mucus.³⁰ Chronic uterine inflammation often results in exuberant mucus production, which may manifest as a thick mucus layer overlying the endometrium.  Mucolytic agents such as N-acetylcysteine, or other agents focusing on stopping mucus production, including dimethyl sulfoxide (DMSO) or kerosene, can be used with beneficial effects in some mares. N-acetylcysteine disrupts disulfide bonds in mucus, making it less viscous. Infusion of 3.3% N-acetylcysteine (30 mL of a 20% solution diluted in 150 mL pf saline solution) has been associated with an increase in pregnancy rates in mares that have excessive mucus accumulation.³¹   

Infusion of a 30% solution of DMSO into the uterus  has been associated with improvement in biopsy grade, and treated mares tend to have an increased pregnancy rate.³² Although intrauterine infusion of kerosene is associated with severe endometritis and necrosis of the luminal epithelium, 50%of treated mares with a category II or III biopsy score became pregnant on the subsequent cycle and carried foals to term.³³ It is believed that  severe inflammation and necrosis result in the removal of mucus and exudate from the uterine epithelium.³³ Kerosene treatment typically consists of infusion of 50 to 500 mls of kerosene undiluted into the uterus. Typically, lower volumes are used during diestrus and larger volumes during estrus to account for an open vs. closed cervix. Uterine lavage and ecbolics are used 12 to 18 hours later to remove residual kerosene and debris from the uterus. 

Platelet-Rich Plasma 

Platelet-rich plasma (PRP) is a filtrate of whole blood plasma with a high concentration of platelets. PRP contains various growth factors and cytokines that act in an anti-inflammatory manner throughout the body. This therapy has become more common to reduce PMIE inflammation and fluid accumulation post-breeding.^34-39 Common time points to use PRP are 48 and 24 hours prior to breeding and six and 24 hours post-breeding. 

Summary

Multiple treatments have been utilized to treat PMIE in the horse. The clinician is faced with the challenge of how to select these treatment options in clinical practice. Overall, as the severity of PMIE increases, the treatments required to manage fluid retention and uterine inflammation increase. The best approach to treating mares with PMIE is to obtain a thorough history, perform serial examinations, and optimize the treatment regimen for each individual mare.   

References

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About the Author

Ryan A. Ferris | DVM, MS, DACT

Dr. Ferris graduated from veterinary school at Washington State University in 2007. Ryan completed an internship in equine surgery, medicine and reproduction at the Equine Medical Center of Ocala in 2008. Followed by a residency in Equine Reproduction at Colorado State University. He received a MS in Clinical Science from Colorado State University, passed the board examinations for the College of Theriogenologists and was an assistant professor at Colorado State University from 2010-2017. In 2018 Dr. Ferris and his family moved to Western Oregon and established Summit Equine, Inc. Summit Equine is a referral equine reproduction and sports medicine practice. Reproduction services offered include breeding management (fresh, cooled or frozen), embryo transfer, problem mare evaluations, oocyte aspiration, stallion collections for fresh, cooled or frozen semen and evaluation of problem stallions. Interests: Bacterial and fungal endometritis, biofilm, embryo transfer, oocyte pick up and intracytoplasmic sperm injection.