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Equine Spring 2006 (Vol 1, No 1)

Mare Reproductive Loss Syndrome

by Manu M. Sebastian, DVM, PhD, William V. Bernard, DVM, Terrence D. Fitzgerald, PhD

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    Abstract

    Mare reproductive loss syndrome (MRLS), an epidemic of equine abortion that occurred in Central Kentucky during spring 2001, affected mares both in early and late gestation. In addition to reproductive abnormalities, fibrinous pericarditis and unilateral uveitis were common. Although the syndrome recurred with significantly less intensity in spring 2002, the estimated economic losses associated with MRLS approached $500 million. Clinically, the abortions and stillbirths were explosive and often associated with premature placental separation. Microbiologic and pathologic characteristics included frequent fetal isolation of nonhemolytic Streptococcus and Actinobacillus spp, fetal pneumonia, placentitis, and funisitis. Epidemiologic surveys during 2001 identified high numbers of Eastern tent caterpillars in the mares' environment as one of the risk factors. Subsequent investigations confirmed that these caterpillars caused MRLS, although the abortigenic factor(s) in these caterpillars remains unidentified.

    In spring 2001, an epidemic of equine abortions occurred in Central Kentucky. Abortions occurred in either early or late gestation and were called early fetal loss and late fetal loss, respectively.1,2 Although the abortions were heavily concentrated in Central Kentucky, a similar syndrome occurred in southern Ohio, West Virginia, and Tennessee. The syndrome was later called mare reproductive loss syndrome (MRLS) and recurred with significantly less intensity in spring 2002.1-5 Several breeds were involved, but Thoroughbreds were affected the most. The combined economic losses in the 2 years were approximately $500 million.6 Epidemiologic investigations conducted during this period documented extremely high numbers of Eastern tent caterpillars in the farms affected by MRLS.7,8

    Clinical Syndrome

    Early Fetal Loss

    Early fetal losses were first noted during routine reproductive ultrasonographic examinations,7,9,10 with the majority of more than 1,500 fetal losses occurring between 48 and 171 days of gestation.11 Vulvar discharge and/or protrusion of fetal membranes occurred occasionally; however, a lack of clinical signs was the norm. Ultrasonographic findings included lack of a heartbeat, a slow heartbeat, and/or reduced or absent movement of the fetus.7,9,10 Allantoic and amniotic fluids were highly echogenic, with amniotic fluid being more echogenic than allantoic fluid.7,9,10

    Late Fetal Loss

    Epidemiologic surveys indicated approximately 1,216 abortions or loss of late-term fetuses during the 2001 season. More than 500 of these late-term aborted fetuses were submitted to the University of Kentucky Livestock Disease Diagnostic Center during a 5-week period from April through May12; this was a 32% increase over the same period the previous year.9 Abortions occurred during the last trimester, usually during the last month of gestation, with the fetuses being aborted near or at term. A high percentage (32%) of these submissions were diagnosed with premature placental separation; dystocia (11%) was also commonly diagnosed.13 During the 2002 season, 164 late-term fetuses were submitted.12

    Typical clinical signs of late fetal loss included dystocia, foaling while standing, premature placental separation, and an overall description of explosive parturition.7,14 Foals delivered at term were stillborn or typically in cardiovascular collapse with clinical signs of asphyxia. These foals frequently died shortly after birth despite attempts at resuscitation and intensive care.15 An unusual finding in many of these sick foals was bilateral hyphema. Blood cultures were rarely positive; alpha Streptococcus and Actinobacillus spp were cultured most frequently.16

    In 2001, an unusually high number of mares with fi­brinous pericarditis and unilateral uveitis were seen in Central Kentucky; not all of these mares were pregnant. For example, over a 2-month period coinciding with the reproductive losses, 38 cases of fibrinous pericarditis were diagnosed in Central Kentucky. Before 2001, only one or two cases repetitions were diagnosed per year in this area. The clinical signs associated with fibrinous pericarditis included marked muffling of heart sounds, tachycardia, jugular vein distention, and peripheral edema. Pericardial fluid collected from affected mares was classified as a sterile exudate. Actinobacillus spp were the principal isolates from eight of 10 untreated, terminally affected horses and three of 10 clinically affected horses.17 Some patients responded to antibiotic and long-term steroidal therapy.18 In 2002, fewer than 15 cases of pericarditis were reported in the area.17,18

    At the same time that the number of cases of fibrinous pericarditis was increasing during the MRLS outbreak in 2001, approximately 40 cases of unilateral uveitis were reported in the same area. There was no age, breed, or sex predilection associated with the development of this condition, which occurred peracutely with profound exudative ophthalmitis. The ophthalmologic findings included corneal edema and exudate in the anterior and posterior chambers. The affected eyes were refractory to treatment, and blindness ensued.19 Fewer cases of unilateral uveitis were reported in 2002.9

    Associated Pathologic Findings

    The typical pathologic lesion associated with early fetal loss was bacterial placentitis. The consistent state of autolysis of fetal submissions precluded specific anatomic localization of the inflammatory changes.20,21

    Gross lesions associated with late fetal loss included a pale brown placenta, an intact cervical star, a yellow edematous umbilical cord, hyphema, placental thickening, and edema.13,20,21 Histopathologic changes included placentitis, funisitis (i.e., inflammation of the umbilical cord), and fetal pneumonia. A characteristic lesion of funisitis (Figure 1) was identified in fetuses aborted in the later stages of gestation. Funisitis was consistently confined to the amniotic portion of the umbilical cord. The umbilical cord lesion consisted of neutrophil and bacterial aggregates, which were typically confined to the coelomic space in the subchorionic stroma. Placental inflammation was vascular or perivascular. The placentitis of MRLS was distinguishable from the typical ascending placentitis originating at the cervical star or from hematogenous placentitis with involvement of chorionic villi.20,21 There was no single pathognomonic lesion identified in cases of MRLS. Bacteriologic isolation found 10 different species from fetuses that were aborted in late gestation. Most bacterial isolates were non-b-hemolytic Streptococcus (51%) and Actinobacillus (13%) spp.16

    Initial Investigation into Possible Causes

    Although it was initially thought that there might be an infectious cause of MRLS, this was rapidly discounted because there were no clinical signs noted in the aborting mares and the classical point source outbreak suggested an environmental source toxin. Subsequently, a variety of potential toxins were considered and most of these were eliminated (Table 122-24,26).

    In 2001, Eastern tent caterpillars were spatially and temporally related to the outbreak of MRLS. Because Eastern tent caterpillars are commonly found on wild black cherry tree leaves that contain cyanogenic compounds and these caterpillars can convert the compounds to cyanide, a popular theory was that cyanide caused MRLS.25 This theory was intensively investigated but was discounted because administration of high levels of cyanide to pregnant mares failed to cause abortion.26

    Experimental Induction of the Syndrome

    In 2002, MRLS was reproduced in small pasture plots by exposing 10 pregnant mares to Eastern tent caterpillars or their frass (i.e., excrement); seven of 10 mares aborted.27 In a group of nine mares exposed to Eastern tent caterpillar frass, seven aborted. Although three of 10 pregnant mares on control pasture plots aborted, it was noted that some migration of the Eastern tent caterpillars occurred across the control pasture plots. The results of these studies provided the first experimental evidence that exposure of mares to Eastern tent caterpillars can cause MRLS. This study was repeated with improved control of Eastern tent caterpillars, and only mares exposed to the caterpillars aborted.28

    In a second study,29 five early-term mares were gavaged with either Eastern tent caterpillars or frass, and an additional five control mares received water by the same route. All mares were treated for 10 days and maintained in stalls (to prevent exposure to grass). Four of five mares treated with 50 g of Eastern tent caterpillars aborted within 8 to 13 days, whereas no mares in the control group aborted. The results of this study were consistent with a causal role of Eastern tent caterpillars in cases of MRLS and ruled out involvement of Kentucky hay or pasture grasses.

    In a third study,30 six late-term mares were gavaged with 50 g of Eastern tent caterpillars collected from the upper peninsula of Michigan. Five mares served as controls. All six of the mares gavaged with the Eastern tent caterpillars from Michigan aborted, whereas none of the control mares aborted. The results of this study showed that Eastern tent caterpillars from states other than Kentucky can cause fetal loss in late-term mares.30

    A series of additional studies28, 31-33 have been conducted to determine whether other types of caterpillars can induce abortion, which component of Eastern tent caterpillars is responsible for inducing abortion, and the effects of freezing the caterpillars on induction of MRLS. The results of these studies (Table 2) indicate that Eastern tent caterpillars, but not forest tent or gypsy moth caterpillars, induce abortion in mares; that the abortifacient factor is in the exoskeleton of Eastern tent caterpillars; and that irradiation but not freezing reduces the ability of Eastern tent caterpillars to induce abortion.

    Discussion

    The MRLS epidemic that struck Central Kentucky during spring 2001, followed by additional cases in spring 2002, was a previously unreported disease process that had several unique features:

    • An association with ingestion of or exposure to Eastern tent caterpillars
    • A unique clinical pattern and presentation of reproductive loss and, to a lesser extent, pericarditis and uveitis
    • Lack of premonitory signs before the reproductive loss
    • The explosive nature of the abortion, with premature placental separation
    • Clinical signs of illness in the foals, including hyphema and progressive asphyxia
    • Distinctive microbiologic findings
    • Distinctive pathologic/histopathologic findings

    The initial epidemiologic surveys conducted in Central Kentucky suggested that Eastern tent caterpillars might be involved in the pathogenesis of MRLS.7,8 The explosive nature of the Eastern tent caterpillar population in 2001 and, to a lesser degree, in 2002 coincided with unprecedented losses in the Kentucky horse pop­ulation. Although associations between Eastern tent caterpillars and fetal losses had not been previously reported, the results of subsequent studies have confirmed a causal rela­tionship between Eastern tent caterpillars and MRLS.27-29,30 The precise factor in Eastern tent caterpillars that initiates MRLS has not been elucidated; however, the factor appears to be contained in the cuticle or integument of the caterpillar.31 Filtration of Eastern tent caterpillars to particles smaller than 45 microns and irradiation reduce but do not totally ameliorate the abortifacient nature of the caterpillars.28 The following do not cause abortion: cyanide or related compounds,26,32 a related "hirsute" caterpillar, or the closely related laboratory-raised forest tent caterpillar (Table 228,31-33).32 Current theories regarding initiation of MRLS include the possibility that the setae of Eastern tent caterpillars serve as carriers of a toxin, enteric bacteria, other integumentary toxins, or possibly a product released by integumentary glands of the caterpillars. The role of bacteria in MRLS remains controversial because it is not clear whether the bacteria identified with abortions are primary or secondary.

    The nature of the abortions experienced during the MRLS outbreaks was unique in the lack of premonitory signs in affected mares. Mares that aborted in late gestation occasionally exhibited mild colic or restlessness before abortion. In addition, the abortions were explosive unless the foal was late term and dystocia ensued. The sick foals appeared to have rapid-onset, short-term asphyxia. Hyphema, although not commonly identified otherwise, was a frequent clinical finding in the sick foals during the outbreaks.

    Histopathologic features of the placentas of affected mares also appear to be unique to this syndrome. There was no evidence of an ascending or hematogenous route of bacterial entry into the placenta. Although the port of bacterial entry into the placenta in mares aborting during late gestation remains unclear, the microscopic lesions of the allantochorion were confined to the coelomic space in the subchorionic stroma and thus are closely associated with blood vessels. This finding suggests that there may be vascular involvement.32,34

    Bacterial culture of tissue in both early and late fetal losses indicated that Actinobacillus and Streptococcus spp were associated with the abortion or placentitis. This is unique in that these organisms are rarely associated with these conditions in horses. These bacteria are likely normal inhabitants of the equine gastrointestinal tract and are a previously uncommon finding in equine abortion.16

    The gross pathologic findings associated with early fetal losses were not specific, as indicated by autolysis of samples submitted. Although there was no evidence of funisitis in these fetuses, as occurred in fetuses aborted late in gestation, the microbiologic findings were similar to those identified with late fetal losses. No single pathologic finding was pathognomonic for MRLS or late fetal loss; however, funisitis was a characteristic lesion noted in fetuses lost in late gestation. The specific pathogenesis of the funisitis is unknown. It has been suggested that inflammatory cells may migrate from the umbilical cord vessels to the superficial layers of the umbilical cord. This migration of cells may be a result of chemotactic factors within the amniotic fluid.32,34

    The placentitis characteristic of late fetal loss was clearly differentiated from ascending placentitis. In the placentas of horses with MRLS, histo­pathologic lesions were not observed on the chorionic surface, as occurs in ascending placentitis. The histo­pathologic lesions identified in the placentas of horses with MRLS are suggestive of vascular involvement, with the inflammatory lesions of the allantochorion found primarily in the coelomic, subchorionic stroma closely re­lated to stromal blood vessels.32

    The fibrinous pericarditis and uveitis identified during spring 2001 were associated with the MRLS outbreak; however, these conditions were rarely identified in mares with either early or late fetal losses. Similarly, unilateral uveitis was not observed in mares with either early or late fetal losses.19 The incidence of pericarditis during the MRLS outbreak of 2001 was 30 times higher than the normal prevalence in Central Kentucky.17 The unilateral nature of the uveitis appears to be unique because there are no reports of unilateral uveitis epidemics in the medical literature.19 Neither unilateral uveitis nor fibrinous pericarditis was reproduced in the MRLS studies.

    The initial popular theory that cyanide originating as a result of an interaction between Eastern tent caterpillars and cherry tree leaves caused MRLS was ruled out in summer and fall 2001.26,32 Subsequent studies27,28 de­termined that Eastern tent caterpillars with or without their frass were directly associated with induction of MRLS and that Eastern tent caterpillars, but not their frass, were a causal agent.29 The results of other studies30 indicated that Eastern tent caterpillars from regions other than Central Kentucky are abortigenic.

    The suggestion that placental detachment might occur in utero (intact cervical stars) was introduced through an additional Eastern tent caterpillar feeding trial.32 The results of that study suggest a scenario in­volving placental detachment, hypoxia, fetal death, and abortion. This, in turn, suggests that the abortifacient acts at the uteroplacental interface.32

    Other studies31 using separated anatomic components of Eastern tent caterpillars found the integument of the caterpillar likely to contain the abortifacient because only mares administered the integument aborted. Thus a component or structural portion of the integument is involved in initiating MRLS. Autoclaved Eastern tent caterpillars did not cause abortions, suggesting that the abortifacient is heat labile and that bacteria associated with the caterpillars are not the cause of MRLS. The latter conclusion is supported by the fact that ethanol-treated Eastern tent caterpillars remained capable of inducing abortion. Although the role of a virus was not ruled out by either of these studies, the results of a study33 using irradiated Eastern tent caterpillars determined that an Eastern tent caterpillar virus is not involved in MRLS. Another Malacosoma sp (i.e., forest tent caterpillar) in Kentucky did not cause abortion in mares.32 However, these forest tent caterpillars were raised in the laboratory on a commercial diet, whereas the Eastern tent caterpillars used in all studies were caught in the wild.

    Currently, two hypotheses are considered to be plausible as investigations continue into the cause of MRLS:

    • Bacteremia or septicemia is induced by penetration of the mucosa of the gastrointestinal tract by the caterpillar setae (i.e., hairs)
    • A toxin carried or deposited in the environment by the caterpillar initiates the syndrome

    1. Harrison LR, Bolin DC, Donahue JM, et al: Kentucky equine abortion storm and related conditions. Proc Ann Meet Am Assoc Vet Lab Diagnosticians:90, 2001.

    2. Harrison LR: Kentucky abortion storm and related conditions. Proc US Anim Health Assoc:105, 227-229, 2001.

    3. Harrison L, Giles R, Williams N, et al: Mare reproductive loss syndrome: Pathologic observations. Vet Pathol 39:630, 2002.

    4. Powell DG: Mare reproductive loss syndrome (MRLS). Equine Dis Q 9(4)2-, 2001.

    5. Gratez K: Deadly spring. Horse 18(7):30-40, 2001.

    6. Mitchell E: Price tag on MRLS in Kentucky: $300.5 million. Blood-Horse Dec 22, 2001.

    7. Dwyer RM, Garber LP, Traub-Dargatz JL, et al: Case-control study of factors associated with excessive proportions of early fetal losses associated with mare reproductive loss syndrome in Central Kentucky during 2001. JAVMA 222:613-619, 2003.

    8. Cohen ND, Donahue JG, Carey VJ, et al: Case-control study of early-term abortions (early fetal losses) associated with mare reproductive loss syndrome in Central Kentucky. JAVMA 222:210-217, 2003.

    9. Riddle WT, LeBlanc MM: Update on mare reproductive loss syndrome. Proc Symp Am Coll Theriogenol:85-99, 2003.

    10. Riddle WT: Clinical observation associated with early fetal loss in mare reproductive loss syndrome during the 2001 and 2002 breeding season. Proc 1st Workshop Mare Reprod Loss Synd:12-14, 2002.

    11. Morehead JP, Blanchard TL, Thompson JA, et al: Evaluation of early fetal losses on four equine farms in Central Kentucky: 73 cases (2001). JAVMA 200:1828-1830, 2002.

    12. University of Kentucky: Mare reproductive loss syndrome. Accessed July 2005 at www.uky.edu.

    13. Cohen ND, Carey VJ, Donahue JG, et al: Descriptive epidemiology of late-term abortions associated with the mare reproductive loss syndrome in Central Kentucky. J Vet Diagn Invest 15:295-297, 2003.

    14. Brown S: Field and clinical observations related to late fetal loss in mares affected with mare reproductive loss syndrome. Proc 1st Workshop Mare Reprod Loss Synd:14-15, 2002.

    15. Byars TD, Seahorn TL: Clinical observations of mare reproductive loss syndrome in critical care mare and foals. Proc 1st Workshop Mare Reprod Loss Synd:15-16, 2002.

    16. Donahue JM, Sells S, Giles RC, et al: Bacteria associated with mare reproductive loss syndrome. Proc 1st Workshop Mare Reprod Loss Synd:27-29, 2002.

    17. Bolin DC, Donahue M, Vickers ML, et al: Microbiologic and pathologic findings in an epidemic of equine pericarditis. J Vet Diagn Invest:38-44, 2005.

    18. Slovis NM: Clinical observations of the pericarditis syndrome. Proc 1st Workshop Mare Reprod Loss Synd:18-20, 2002.

    19. Latimer C: Endophthalmitis syndrome: Springs 2001, 2002. Proc 1st Workshop Mare Reprod Loss Synd:26-28, 2002.

    20. Williams NM, Bolin DC, Donahue JM, et al: Gross and histopathological correlates of MRLS. Proc 1st Workshop Mare Reprod Loss Synd:29, 2002.

    21. Williams NM: Mare reproductive loss syndrome: Pathologic findings. Equine Dis Q 10(4)2-, 2002.

    22. Schultz CL, Bush LP: The potential role of ergot alkaloids in mare reproductive loss syndrome. Proc 1st Workshop Mare Reprod Loss Synd:60-63, 2002.

    23. McDowell K, Allman R, Henning J: Phytoestrogens and estrogenic activity in white clover samples from no-loss and high-loss fields during mare reproductive loss syndrome. Proc 1st Workshop Mare Reprod Loss Synd:63-65, 2002.

    24. Newman K: Review of mycotoxins as a possible cause of mare reproductive loss syndrome. Proc 1st Workshop Mare Reprod Loss Synd:66-68, 2002.

    25. Fitzgerald TD, Jeffers PM, Mantella D: Depletion of host-derived cyanide in the gut of the Eastern tent caterpillar, Malacosoma americanum. J Chem Ecol 28(2):257-268, 2002.

    26. Harkins JD, Dirikolu L, Sebastian M, et al: Cherry trees, plant cyanogens, caterpillars, and the mare reproductive loss syndrome (MRLS): Toxicological evaluation of a working hypothesis. Proc 1st Workshop Mare Reprod Loss Synd:68-74, 2002.

    27. Webb BA, Barney WE, Dahlman DL, et al: Induction of mare reproductive loss syndrome by direct exposure of susceptible mares to Eastern tent caterpillar larvae and frass. Proc 1st Workshop Mare Reprod Loss Synd:78-79, 2002.

    28. Webb BA, Barney WE, Dahlman DL, et al: Eastern tent caterpillars (Malacosoma americanum) cause mare reproductive loss syndrome. J Inst Physiol 50:185-193, 2004.

    29. Bernard WV, LeBlanc MM, Webb BA, et al: Evaluation of early fetal loss induced by gavage with Eastern tent caterpillars in pregnant mares. JAVMA 225:717-721, 2004.

    30. Sebastian M, Williams N, Harrison L, et al: Clinical and pathological features of experimentally induced MRLS late-term abortion with Eastern tent caterpillar. Proc 1st Workshop Mare Reprod Loss Synd:80-81, 2002.

    31. Herbert K: Outside of caterpillar might be linked to MRLS. Horse 20(1):16, 2003.

    32. Sebastian M: Pathobiology of late-term aspects of mare reproductive loss syndrome [PhD dissertation]. University of Kentucky, 2004.

    33. Sebastian M, Bernard W, Harrison L, et al: Experimental induction of mare reproductive loss syndrome with irradiated Eastern tent caterpillar to assess whether the primary pathogen in mare reproductive loss syndrome is a toxic molecule or a microorganism. Proc Workshop Equine Placenta:27-28, 2003.

    34. Sebastian M, Harrison L: Placental pathology in late-term abortions of 2002 mare reproductive loss syndrome. Vet Pathol 42, 717, 2005.

    References »

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