Placenta: placentitis in Horses (Equis) | Vetlexicon
equis - Articles

Placenta: placentitis

ISSN 2398-2977


Introduction

  • Cause: bacterial or fungal infection of the placenta, route of infection may be ascending or hematogenous in origin.
  • Signs: vaginal discharge, premature udder development; subsequent abortions or weak foals.
  • Diagnosis: culture discharge, utero-placental assessment via ultrasound, gross placental evaluation, histopathology.
  • Treatment: antibiotics, anti-inflammatories, tocolytics. 
  • Prognosis: guarded.

Presenting signs

  • Signs usually occur in late gestation (6 months to term).
  • Initial signs of placentitis: may not see any signs prior to abortion, or may see purulent vulvar discharge and/or premature lactation.
  • Abortion, stillbirth, or premature delivery of a weak, septic or otherwise compromised foal will occur if placentitis not treated.

Acute presentation

  • Worldwide, although specific etiologic agents are more prevalent in certain areas.

Age predisposition

  • Older, multiparous, poorly conditioned broodmares with poor perineal conformation are more likely to develop placentitis.

Breed/Species predisposition

  • Placentitis is more common in Thoroughbreds Thoroughbred, due primarily to perineal conformation.

Cost considerations

  • Placentitis causes severe economic loss to the equine industry. 
  • In addition to the loss of foals due to abortions Abortion: overview, the foals that do survive are less likely to have productive performance careers.

Pathogenesis

Etiology

  • Of 954 placentas submitted to the University of Kentucky Livestock Disease Diagnostic Center (USA) over a two year period, 236 had placentitis.
  • Only bacteria and fungi were isolated from the cases of placentitis: neither equine herpesvirus nor equine viral arteritis virus were isolated from any cases of placentitis.
  • In descending order of prevalence, the most commonly encountered pathogens associated with equine placentitis were Streptococcus zooepidemicus Streptococcus spp Placenta: placentitis - bacterial, Leptospira spp Leptospira interrogans, Escherichia coli Escherichia coli, a nocardioform actinomycete, fungi, Pseudomonas aeruginosa Pseudomonas aeruginosa, S. equisimilis, Enterobacter agglomerans, Klebsiella pneumoniae Klebsiella pneumoniae and alpha-hemolytic Streptococcus Streptococcus spp.
  • Infectious agents may reach the placenta by either the ascending caudal reproductive tract route or the hematogenous route. 
  • All of the above pathogens with the exception of Leptospira spp cause placentitis via the ascending route. Leptospira spp placentitis lesions are due to hematogenous infection.
  • The route of infection of the nocardioform organism is unknown. Nocardioform placentitis Placenta: nocardioform placentitis 01 - pathologyPlacenta: nocardioform placentitis 02 - pathology is a specific type of placentitis that is characterized by a solitary lesion at the cranial body/base of the horns that is covered with a brownish-tan mucoid material and culture of gram-positive filamentous branching bacteria. Several of the nocardioform isolates (formerly unclassified bacteria) have been classified and published with the names Crossiella and Amycolatopsis.
  • Mare reproductive loss syndrome (MRLS) Reproduction: mare reproductive loss syndrome  may be associated with placentitis. One study identified placentitis or funisitis in 44% of MRLS cases, while another study found that about 10% of the cases of MRLS exhibited placentitis.

Predisposing factors

General

  • Body conformation Vulva: conformation: poor perineal conformation predisposes the mare to ascending reproductive tract infections by compromising the vulvar and vestibular seal.
  • Body condition Body condition scoring: mares with a poor body score condition are more likely to have poor perineal conformation, and thus more likely to develop placentitis.
  • Breed: Thoroughbred Thoroughbred mares are more susceptible to placentitis, due to their perineal conformation.
  • Season Female: reproductive cycle - normal: the elevated levels of estrogen found in the lush forage of spring time pastures may cause cervical dilation and subsequent ascending cervical infection and placentitis.
  • Age: older, multiparous mares (particularly those with a history of dystocia Reproduction: dystocia and resulting perineal conformation changes) are at an increased chance of developing placentitis.
  • Environment: mares should not be allowed to come into contact with urine or urine contaminated feed, water or bedding from leptospirosis Leptospirosis host species (wildlife, rodents or cattle).

Pathophysiology

  • Placentitis due to ascending cervical infections (of either bacterial or fungal origin) is characterized by infection in the cervical star area that extends a variable distance along the body of the placenta.
  • The lesions exhibit necrosis of chorionic villi, exudative material on the chorion, and infiltration of mononuclear inflammatory cells throughout the chorioallantoic membrane.
  • This disruption of the chorion causes a loss of placental function and subsequent fetal death or premature delivery.
  • Nocardioform actinomycetes induce a characteristic chronic placentitis and late-term abortions.  The lesion is frequently located at the base of the uterine horn, where the affected area is usually thickened and the chorionic surface is covered with brown, sticky, mucoid material. This loss of functional placental surface area causes weak or stillborn foals.
  • Leptospira spp may induce acute to chronic diffuse placentitis (usually between 6 and 9 months of gestation), although infection more commonly results in direct fetal death without placentitis. 
  • When placentitis is present, infection results in disruption of the interdigitation of the chorion with the endometrium and the subsequent loss of placental function.

Diagnosis

Presenting problems

Diagnostic investigation

  • After a complete history has been obtained a thorough physical exam should be performed.
  • A vaginal speculum exam may be conducted Vagina and cervix - manual examination, but a digital exam should not be performed, as premature parturition can be easily induced at this point.
  • Culture and cytology of discharge should be performed:
    • After aseptic preparation of the vulva and perineum, a guarded uterine culturette is passed through a sterile vaginal speculum Vagina: speculum 01Vagina: speculum 02
    • If discharge can be visualized, this exudate is sampled with the swab. 
    • If no discharge is evident at this time, the vaginal portion of the cervix should be gently sampled. 
    • Cytologic examination and bacterial and fungal culture should be performed. 
  • Transrectal ultrasonographic evaluation of the feto-placental unit should be performed.  
  • Fetal biophysical profiling, consisting of evaluations of the fetal heart rate, breathing patterns, movements and echogenicity of allantoic and amniotic fluid compartments should be conducted to determine the health status of the fetus.
  • Utero-placental thickness should be evaluated transrectally, measuring the combined thickness of the uterus and placenta lateral to the area of the cervical star.  The following are abnormal values for the combined thickness of the uterus and placenta:
    • Up to gestational day 270: >7 mm.
    • Day 271-300: >8 mm.
    • Day 301-330: >10 mm.
    • Day 331-term: >12 mm Placenta: utero-placental thickness - ultrasound.
  • Various endocrine/biochemical measurements have been tested as an adjunct to diagnosing placentitis in the mare:
    • Progestins:
      • In the normal mare, plasma progestins are low until about 3 weeks before parturition, and then rise before decreasing abruptly in the last 24 h before parturition.
      • Sequential monitoring of progestin levels (which can be tested by using commercial progesterone assays such as RIA and ELISA because progestins cross react with progesterone) may be useful in mares with placentitis.
      • In the acute stages of placentitis, mares may be monitored 4 times within 48 h, and in the more chronic stages monitoring may be carried out 3 times weekly.
      • A premature rise in progestin levels (more than 3 weeks before the expected parturition date) may be indicative of placental pathology and fetal stress; whereas a premature (more than 24 h before expected parturition date) decline in progestin levels once they have risen may indicate impending abortion.
    • Plasma estradiol:
      • May be used as an indicator of fetal-placental compromise.
      • Levels of <500 ng/mg between 150 and 280 days of pregnancy have been associated with compromised or dead foals.
    • Serum amyloid A (SAA) Serum amyloid A:
      • Increases in response to infection and therefore in response to placentitis, but is not specific for placentitis. Sequential sampling may be useful to monitor response to treatment.
  • The fetus and the placenta should be submitted for culture and histopathology in all cases of abortion.
  • In births associated with premature/dysmature foals Reproduction: prematurity / dysmaturity, a high suspicion of placentitis should be considered and the placenta should be submitted to the diagnostic lab as soon as possible after expulsion.

Confirmation of diagnosis

Discriminatory diagnostic features

  • Histopathology is the method for diagnosis of placentitis, with inflammatory cell infiltration and villous necrosis being hallmark signs.
  • Bacterial and fungal culture yield involved agents in cases of confirmed placentitis in approximately 70% of submitted cases.
  • Leptospirosis Leptospirosis induced placentitis is diagnosed via the detection of leptospires by immunofluorescence (FAT), generally by testing the fetal kidney in cases of abortion or by testing urine obtained from a mare or neonatal foal suspected of being infected.
  • Nocardioform placentitis is diagnosed on the basis of the characteristic gross pathology and isolation of a gram-positive branching bacillus from the placental lesion or presence of these bacilli in histologic sections.

Gross autopsy findings

  • The placenta should always be systematically examined for any signs of placentitis or other abnormalities Placenta: twinning 03 - pathology.
  • Bacterial and fungal placentitis are both characterized by chronic focal or focally extensive lesions at the cervical area of the placenta:
    • These lesions are thickened and often a brownish tan color. 
    • Focal lesions around the area of the cervical star are indicative of ascending placentitis of either bacterial or fungal etiology Placenta: ascending placentitis 01 - pathologyPlacenta: ascending placentitis 02 - pathology.
  • Nocardioform actinomycetes induce a characteristic focal mucoid placentitis:
    • The lesion is frequently located at the cranial portion of the body of the placenta with frequent extension to the base of the uterine horn, where the affected area is usually thickened, and the chorionic surface is covered with brown, sticky, mucoid material Placenta: nocardioform placentitis 01 - pathologyPlacenta: nocardioform placentitis 02 - pathology.
  • Abortions due to infection with Leptospira spp are due to either fetal infection by the leptospires directly → death of the fetus or by placentitis-induced death of the fetus:
    • Direct fetal infection by the leptospires → death and subsequent abortions in the majority of cases.
    • The placenta in these cases may look grossly normal or have hemorrhages/mottling diffusely and randomly spread over the entire chorionic surface of the placenta. 
    • In severe cases, the placenta will be thick, heavy and edematous, and the chorionic surface may be covered with brown mucoid material. 
    • Cystic adenomatous hyperplasia of the allantois may be occasionally observed.  
  • Other abnormal but non-pathogenic appearances of the placenta include:
    • Bullous edema of the placenta, which has been observed by one of the authors but was not associated with a prolonged gestation or any fetal problems Placenta: bullous edema 01 - pathologyPlacenta: bullous edema 02 - pathologyPlacenta: bullous edema 03 - ultrasound.
    • Plaques on the amnion, which may be seen infrequently - this condition is not associated with placentitis or any other pathology and is considered a variation of normal Placenta: plaques - pathology.

Histopathology findings

  • Bacterial placentitis occurring around mid-gestation will → acute diffuse placentitis with infiltration of neutrophils in the intervillous spaces or focal necrosis of the chorionic villi.
  • Bacterial placentitis occurring in late gestation is characterized by chronic focal or focally extensive lesions at the cervical area of the placenta. These lesions exhibit necrosis of chorionic villi, eosinophilic material on the chorion and infiltration of mononuclear inflammatory cells in the intervillous spaces, stroma of villi, chorion, allantois and vascular layer.
  • Nocardioform placentitis is characterized by necrosis of the chorionic epithelium with blunting and necrosis of the villi:
    • Mononuclear cells and neutrophils can be seen infiltrating the stroma and villi, and the chorionic surface and intervillous areas are covered with an amorphous eosinophilic material. 
    • Gram stains reveal variable numbers of gram-positive branching filamentous bacteria.
  • Leptospira spp induce acute to chronic diffuse placentitis:
    • Infection and resulting abortions generally occur at 6-9 months of gestation.
    • Spirochete organisms are abundant in the placental secretions and stromal tissues Placenta: leptospiral placentitis - microscopy.
    • Mild to moderate necrosis of the chorionic villi can be seen and infiltrates of mixed inflammatory cells can be seen in the villous and/or chorionic stroma. 
    • Vasculitis Vasculitis and edema in the chorionic stroma and vascular layers are also often observed.
  • Fungi generally induce chronic focally extensive placentitis at the area of the cervical star in the late gestational period - histologic pathology includes extensive necrosis of the chorionic villi, neovascularization in the chorionic stroma, infiltration of inflammatory cells in the villi and chorionic stroma and fungal hyphae in the necrotic debris.

Differential diagnosis

Treatment

Initial symptomatic treatment

  • Therapeutic goals include elimination of the infectious agents, reduction of the inflammatory response and reduction of the increased myometrial contractility which is caused by the ongoing inflammation.
  • These goals are achieved through antibiotics Therapeutics: antimicrobials, non-steroidal anti-inflammatories Therapeutics: anti-inflammatory drugs and tocolytic agents.
  • Antibiotics Therapeutics: antimicrobials: generally, broad-spectrum antibiotic coverage to combat both gram-positive and gram-negative organisms is desired. Effective treatments include:
    • Trimethoprim-sulfadiazine Sulfadiazine with trimethoprim (15 mg/kg PO BID).
    • Gentamicin Gentamicin (6.6 mg/kg IV SID) and penicillin Penicillin G (20,000 U/kg IM or IV q6-12h).
    • Ceftiofur Ceftiofur (2.2 - 4.4 mg/kg IM SID).
    • Little is known about the placental penetration of antibiotics in horses, but antibiotic therapy with trimethoprim-sulfadiazine Sulfadiazine with trimethoprim, penicillin Penicillin G and gentamicin Gentamicin is considered to be efficacious based on the detection of adequate concentrations (achieved the minimum inhibitory concentration against pathogenic causes of placentitis) of these antibiotics in allantoic fluid.
    • There have been no controlled studies that support the use of one of these antimicrobials over the others in cases of equine placentitis.
  • Anti-inflammatories Therapeutics: anti-inflammatory drugs:
    • The bacteria or bacterial products elicit a cell-mediated immune response in which pro-inflammatory cytokines from macrophages are released. 
    • These cytokines, such as PGE2 and PGF2±, cause uterine contractions. 
    • Prevention is based on mediating the inflammatory response with:
      • Flunixin meglumine Flunixin meglumine (1.1 mg/kg BID).
      • Phenylbutazone Phenylbutazone (4 mg/kg BID).
      • There is an apparently low likelihood for perinatal NSAID administration to → premature closure of the ductus arteriosus in the neonate, as cyclooxygenase inhibitors decrease the levels of circulating prostaglandins in the fetus, which are necessary to maintain ductus arteriosus patency. However, the benefits of NSAID administration are generally considered to far outweigh the risks.
      • Pentoxyphylline (7.5 mg/kg PO BID) is a xanthine derivative that is thought to exert anti-inflammatory/cytokine effects as well as to improve oxygenation of the placenta through an increased deformability of the red blood cells. There is theoretical support for its use in cases of equine placentitis, but the clinical benefit has been unclear.
  • Tocolytic agents: the goal is to prevent or disrupt uterine contractions and premature labor. Drugs used include:
    • Clenbuterol Clenbuterol hydrochloride (0.8 µg/kg): clenbuterol, a beta-sympathomimetic agent, causes acute tocolysis with a duration of up to 120 min in the horse. However, a recent study demonstrated that length of gestation did not differ among control mares and mares that were treated once daily with clenbuterol → the suggestion that clenbuterol has limited usefulness in delaying premature parturition.
    • Progesterone Progesterone supplementation is thought to aid in myometrial quiescence by the inhibition of the formation of gap junctions, which facilitate myometrial contractions, and it may antagonize the abortigenic effects of prostaglandins released by the uterus in response to placentitis. Progesterone supplementation options include:
      • Altrenogest Altrenogest (0.044-0.088 mg/kg PO SID or divided).
      • Progesterone Progesterone in oil has also been used.

Subsequent management

Treatment

  • The mare with signs indicative of placentitis should be treated in attempt to treat the infection and prevent premature parturition.
  • The length of time for which treatment should be continued is a matter of debate. Some clinicians and authors recommend treating for 10-14 days, whereas others suggest continued treatment until the foal is born for fear that stopping therapy may be followed by a recurrence of symptoms. Some authors and clinicians recommend intermittent treatment throughout the remainder of the pregnancy.
  • Prolonged antibiotic and NSAID therapy may cause gastrointestinal side effects.
  • Prolonged treatment with exogenous progestin may disrupt the normal mechanisms of parturition. Some authors therefore recommend stopping progestin therapy at 320 days gestation, even if it has been continued until then.
  • Treatment decisions should be based on response to treatment and foetal viability, determined by monitored regularly using a combination of clinical examination, placental ultrasound and endocrine/biochemical measurements.
  • Weak foals born prematurely due to placentitis should be assumed to be septic and aggressive treatment initiated Foal: neonatal septicemia syndrome.

Prevention

Control

  • Use clean, minimally contaminated breeding techniques.
  • Select broodmares with satisfactory perineal conformation and Caslicks index.
  • Feed mares to maintain good body condition throughout pregnancy and lactation.
  • Avoid having mares with a history of placentitis graze in pastures of lush grasses or legumes in late gestation.

Prophylaxis

  • Perform Caslicks vulvoplasty surgery Vulva: Caslick operation or other procedures to improve perineal conformation post-breeding.

Outcomes

Prognosis

  • The prognosis for the fetus in cases of placentitis is generally guarded. However, with early intervention and appropriate antibiotic, anti-inflammatory and progestin therapy, delivery of a live, term foal can be achieved in some cases.
  • The prognosis for the live foal born prematurely due to placentitis is also guarded - these foals are often weak and should be assumed to be septic and treated as such Foal: neonatal septicemia syndrome.
  • The prognosis for the mare experiencing placentitis is generally good, although postpartum uterine health should be monitored by ultrasound examination and uterine lavage or ecbolic therapy initiated as needed.

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • El-Sheikh Ali H, Legacki E L et al (2019) Equine placentitis is associated with a downregulation in myometrial progestin signalling. Biol Reprod 101 (1), 162-176 VetMedResource.
  • Wynn M A A, Ball B A et al (2018) Changes in maternal pregnane concentrations in mares with experimentally-induced, ascending placentitis. Theriogenology 122, 130-136 PubMed.
  • Canisso I F, Ball  BA et al (2017) Changes in maternal androgens and oestrogens in mares with experimentally-induced ascending placentitis. Equine Vet J 49 (2), 244-249 PubMed.
  • Canisso I F, Ball B A et al (2014) Serum amyloid A and haptoglobin concentrations are increased in plasma of mares with ascending placentitis in the absence of changes in peripheral leukocyte counts or fibrinogen concentration. Am J Reprod Immunol 72 (4), 376-385 PubMed.
  • Crabtree J (2012) Peripartum problems in mares. 1. Prepartum problems. In Pract 34 (7), 400-410 VetMedResource.
  • Christensen B W et al (2006) Nocardioform placentitis with isolation of Amycolatopsis spp in a Florida-bred mare. JAVMA 228 (8), 1234-1239 PubMed.
  • Macpherson M L (2005) Treatment strategies for mares with placentitis. Theriogenology 64, 528-534 PubMed.
  • Cattoli G, Vascellari M, Corro M  et al (2004) First case of equine nocardioform placentitis caused by Crossiella equi in Europe. Vet Rec730-731 PubMed.
  • Bolin D C, Donahue J M, Vickers M L et al (2004) Equine abortion and premature birth asso