A recent increase in nocardioform placentitis serves as a good reminder for veterinarians to review the best ways to catch this infection early and how to treat it.
Causing 30 percent of perinatal loses, placental infection poses a critical concern for mares from conception to parturition.1 In her presentation at last November's West Coast Equine Reproductive Symposium in Los Olivos, Calif., Margo Macpherson, DVM, MS, DACT, of the Department of Clinical Sciences at the University of Florida Center for Veterinary Medicine, noted that the University of Kentucky reported a significant spike in nocardioform placentitis cases affecting the 2011 foal crop.
Macpherson has spent more than 10 years researching placentitis in mares. The following discussion, based in part on her November presentation, outlines the potential causes and treatments for this condition.
The placental structure, including the amnion and chorioallantois, is vital for exchanging nutrients, gases and waste products between a pregnant mare and her foal. To protect this important structure, viscous mucus produced from the cervix helps form an impermeable barrier—a cervical plug—to keep bacteria and other foreign organisms from invading the fetus' sterile environment, including the delicate placental membranes.
In some mares, however, a compromised reproductive tract can allow bacterial or fungal infection of the placenta. The result is often early embryonic loss, late-term abortion or premature birth. Foals that survive birth may be weak and die soon after parturition.
Placentitis may occur in mares of any age but most often occurs in underweight or older mares in which the conformation of the vulva allows bacterial ascension through the cervix. Previous cervical injury also may allow bacteria to breach the cervical barrier, increasing the potential for placentitis.
Infection usually congregates at the cervical star, though it can also penetrate farther, invading the entire placental structure. Once inflammation and infection spread, the mare's body produces prostaglandins, which can cause uterine contraction and abortion. Inflammation may also cause the placental tissue to thicken and pull away from the uterine lining, decreasing nutrients and oxygen to the foal. In some cases, premature separation of the placenta from the uterus leads to a "red-bag" delivery. Instead of rupturing the placenta at the cervical star, emerging foals become wrapped in the placental membranes, causing suffocation and stillbirth.
With nocardioform placentitis, infection occurs at the base of the uterine horn, not at the cervical star as in other forms of placentitis. The associated lesions most commonly occur "in the body of the placenta at the bifurcation of the horns. The affected chorion is covered by a thick, light brown, tenacious exudate. The actinomycetes associated with nocardioform placentitis do not reach the fetus, and fetal lesions are limited to those of placental insufficiency."2
Macpherson attributes the 2011 spike in nocardioform infection to Amycolatopsis species and Crossiella equi. Although these species are common in soil, as a 2012 study says, "It is not known if these bacteria are present in soil or any other place and whether mares become infected with these actinomycetes in the stall environment or in pasture."2
In this recent outbreak, abortion occurred exclusively during the last trimester of gestation and affected mostly thoroughbreds, although there were some standardbred, saddlebred and quarter horse cases. "Most of the reported cases from 2010 to 2011 involved placental lesions in term foals with relatively fewer abortions occurring," says Barry Ball, DVM, PhD, DACT, of the University of Kentucky Gluck Equine Research Center. "It is likely that some of the increased incidence of the disease was due to improved surveillance and reporting of this type of lesion by owners and veterinarians," he says.
Diagnosing placentitis can be difficult and begins with the basics—obtaining a complete mare history (including previous pregnancies) and the foaling due date. "Essentially the mare with placentitis is presenting with premature mammary gland development because she's developed a 'bag' and she's not due to foal for several weeks or months," Macpherson says. "Now you can rule out whether the mare has ascending placentitis or whether, among other causes, she's experiencing a twin pregnancy."
In addition to observing premature mammary gland development, examining the vulvar area is an important part of the general physical examination, as vulvar discharge would likely indicate placentitis, Macpherson says. "In my experimental model, where I infect mares' placental area by putting bacteria in their cervix, we see vulvar discharge before we see mammary gland development," she says. "In the clinical setting, however, we see the mammary glands come up long before we ever see the vulvar discharge. That's probably because most people aren't looking frequently at the mare's perineal region. So if she has bits of purulent material in her vulva, she swishes her tail and it's gone."
One of the primary tools Macpherson uses to diagnose placentitis is transrectal ultrasound, looking at the cervical star region for the combined thickness of the uterus and placenta (CTUP). In previous studies,3 doctors measured this region to determine what was normal at eight, nine, 10 and 11 months of gestation. They also looked at mares with placentitis and determined that affected mares would have an increase in the CTUP. "So the transrectal ultrasound can help us see if there is a change or an increase in those measurements or if there is any separation of the placenta at the cervical star region," Macpherson says. "We also look at the character of the fetal fluids to see if there are abnormal changes suggestive of an infection."
Macpherson also uses transabdominal ultrasound to look at the CTUP from a different view and help diagnose nocardioform placentitis, which results in a broad mucoid discharge and separation of the placenta. "That is something you cannot diagnose with transrectal ultrasound," she says. "Transabdominal ultrasonography gives us the best view and is also our best means of detecting twins. Finally, transabdominal ultrasound examination is a great tool for assessing fetal viability through measurement of fetal heart rate and activity level."
At the West Coast Equine Reproductive Symposium, Jennifer Ousey, BSc, MSc, PhD, research scientist at Rossdale and Partners in Suffolk, UK, discussed the use of Doppler ultrasonography to assess the equine fetus and placenta.
"A colleague of mine did not find it a useful tool," says Macpherson, "but people have postulated that there is a change of blood flow to the placenta's infected areas." This technique certainly warrants further investigation.
In addition to ultrasound, some laboratory tests may help diagnose placentitis, including mammary secretion testing for electrolytes, which are noted to change close to delivery. Doctors can also measure serum progesterone concentrations over several days of gestation. "Both of these lab tests give practitioners some information about the pregnancy's status," Macpherson says.
Among the newer diagnostic laboratory techniques is the measurement of serum amyloid A concentrations. Researchers from The Ohio State University and the University of Kentucky have shown exciting results from measuring serum amyloid A protein concentrations from normal pregnant mares4 and mares with placentitis.5,6 These inflammatory proteins may rise in conjunction with placental infections, providing a useful biomarker of disease.
Treatment of placentitis includes combating the infection, decreasing the inflammatory response and supporting and maintaining the pregnancy.
At the University of Florida, Macpherson and her colleagues have tested several treatment methodologies. Mares have been treated with combinations of antimicrobials (penicillin, gentamicin, trimethoprim sulfamethoxazole), anti-inflammatory drugs (pentoxifylline, flunixin meglumine) and altrenogest (synthetic progestin), designed to control the infection, delay premature delivery and improve the foal's health.
In her studies, Macpherson looked at various combinations of medications. "Long-term administration of trimethoprim sulfamethoxazole (TMS) and pentoxifylline (PTX) extended gestational length in mares with placentitis when compared with infected, untreated mares," she says. "However, foal survival was not improved in treated animals (TMS and PTX were present in fetal and placental tissues). When progestins (altrenogest) were added to the TMS and PTX treatment regimen, 10 of 12 mares (83 percent) delivered viable foals."
A more recent study explored the use of TMS alone or combined with anti-inflammatory agents (dexamethasone, aspirin) and progestins (altrenogest plus aspirin). In this study, Macpherson says, experimentally infected mares receiving only TMS were as likely to deliver viable foals (63 percent) as mares receiving TMS in combination with dexamethasone, aspirin and altrenogest (72 percent). "A caveat to the administration of a TMS-based therapy for mares with placentitis is that foal viability is not consistently improved with this therapy in clinical practice, as it is not consistently shown effective in vivo as it is in vitro," she says.
"We have used TMS a lot in one of the projects done at the University of Florida, where we've had a very high live-foal rate. About 83 percent of our foals survived after infection and treatment with TMS, PTX and altrenogest," Macpherson says. "TMS is a drug that has some limitations, particularly for streptococcal organisms. The No. 1 cause of placentitis is Streptococcus equi, so in order to combat it, we need a better armament of drugs."
Macpherson recently evaluated the use of a long-acting ceftiofur, a third-generation cephalosporin,7 which has excellent bacterial activity against streptococcal organisms as well as many gram-negative aerobes and some anaerobes. Ceftiofur sodium is a commonly used antimicrobial in equine practice, and its injectable formulation provides a practical method of administration.
The newer drug—ceftiofur crystalline free acid—has a broad appeal for equine practitioners not only because it is a potent antimicrobial against Streptococcus zooepidemicus but also because it is administered intramuscularly at four-day intervals and provides therapeutic drug concentrations in horses for 10 days after the second dose. In addition, studies showed that it did not cross the placenta at all, which was a big eye-opener.
"In many ways, this exciting new drug would appear to be the perfect antimicrobial treatment for mares with placentitis," Macpherson says. "But we have to continue to explore that drugs are passing the placenta and that we can use effectively."
Ed Kane, PhD, is a researcher and consultant in animal nutrition. He is an author and editor on nutrition, physiology and veterinary medicine with a background in horses, pets and livestock. Kane is based in Seattle.
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3. Kelleman AA, Luznar SL, Lester GD, et al. Evaluation of transrectal ultrasonographic combined thickness of the uterus and placenta (CTUP) in a model of induced ascending placentitis in late gestation in the pony mare. Theriogenology 2002;58(2):845-848.
4. Coutinho da Silva MA, Canisso IF, Johnson AEM, et al. Parturition increases serum amyloid A concentration in healthy pregnant mares. Clin Theriogenol 2011;3(3):355.
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7. Macpherson ML, Giguère S, Hatzel JN, et al. 2012. Disposition of desfuroylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal tissues after administration of ceftiofur crystalline free acid (CCFA) to pony mares with placentitis. J Vet Pharmacol Ther 2012 [Epub ahead of print].