Nocardioform Placentitis Linked to Rise in Foal Deaths

A rise in the frequency of foal deaths attributed to nocardioform placentitis has sparked a renewed wave of research efforts from equine reproductive specialists and veterinarians in Central Kentucky who hope to shed light on the condition that has so far thwarted any attempts to define its nature.   

As of Feb. 5, the University of Kentucky Veterinary Diagnostic Laboratory had reported 34 equine deaths in Fayette County alone. Six deaths were reported in Woodford County, six in Bourbon County, two in Scott County, and one in Harrison County, and Shelby County. The reported fatalities are not limited solely to the Thoroughbred population. 

"This is something that is certainly happening now," said Dr. David Horohov of the University of Kentucky's Gluck Equine Research Center. "Some people are using the word 'epidemic.' It is above what we normally see, so it is unusual. Is it catastrophic? Certainly if you are the owner of the mare that aborted, yes it is. In terms of all the farms in the area? No, it's not at that level, thankfully." 

The elevation in deaths—namely, abortions and stillbirths in pregnant mares—attributed to the condition is the third such identifiable rise to occur over the past decade in Central Kentucky. Previous studies were conducted by the UKVDL in 2011 and 2016-17 when similar spikes were seen among the equine population. In 2011 alone, 94 abortions were attributed to nocardioform placentitis, and 229 placentas were submitted to the research lab and subsequently diagnosed as infected. 

"It actually goes farther back than that," explained Dr. Stuart Brown, who is a partner at the Hagyard Equine Medical Institute and serves as chairman of the Gluck Equine Research Foundation. "We had the first major spike in 2000, the year before we had MRLS (Mare Reproductive Loss Syndrome). We talked a lot about it at the time, and that was the first time where we really delved into the questions of what was the mucoidy-type placentitis that we were starting to recognize? A lot of foaling people were actually identifying it and bringing in placentas to the vets and asking them to identify it. We began to do microbiological cultures on a lot of those placentas and recover these 'nocardioform' bacteria. That's a broad-based classification, really, because that nocardioform reference is really a group of bacteria, not a specific bacteria. 

"Since that time, we've had this occurrence in 2011, the one in 2016, and the one we're experiencing now. There are two particular strains of organism we tend to associate with the impact on late pregnancy, and that's Crossiella equi and the Amycolatopsis species. Those two are differentiated out in the Nocardia family of soil-resident organisms that we associate with that kind of placentitis."

According to research conducted by the UKVDL, nocardioform placentitis was first identified in Central Kentucky in the mid-1980s. It is defined as a "unique form of bacterial placentitis affecting late gestation mares, causing abortion, stillbirth, or foals born alive but compromised." While the foal is not directly infected in utero by the bacteria, the infection disrupts the delivery of nutritional support from the placenta to the foal. The results can range from abortion, to stillbirth, to early delivery of an undersized and/or underdeveloped foal. 

"It's characterized by finding the infection down at the bottom of the placenta where we associate as the ventral surface of the placenta," Brown said. "It is dependent in the uterus, so it tends to be at the base of the horns or in the body of the uterus, way down low at the lowest part of the mare's abdomen. That's differentiated again from the typical type of placentitis we usually see in late pregnancy which we call ascending placentitis. In those cases, the fetus gets really big and the uterus gets pulled really far forward. Since horses are quadrupeds, when the baby gets bigger in the mare, it pulls the reproductive tract forward and stretches the cervix. Sometimes we get what we call cervical discontinuity, so there is an opportunity for bacteria to get out of the mare's vagina, into the cervix, and then gain access to the placenta. We see a really specific pattern in the caudal part or back of the placenta where it meets the cervix in those cases. 

"In these cases (nocardioform placentitis), we can differentiate them because we see the surface of the placenta and the lowest and most dependent part of the uterus is where we associate finding the separation between the placenta and the wall of the uterus. Some of these cases we've described and that we see now can be quite dramatic. It can range from being one to two centimeters of separation to, for example, I have a mare I'm working on now for a client who is almost 10 centimeters. That is almost five inches of separation in exudate, the fluid that fills the space between the mare's placenta and uterus. When that happens and it is severe enough to cause that large of a separation, the nutrient supply to the fetus is interrupted. They're born smaller in stature, they have low body weights, a lot of times their bones are incompletely ossified, and that is because the placental supply of nutrients has been interrupted, so their development is impeded." 

Though placentitis in other forms can be relatively common among mares in late term, the location of the nocardioform placentitis within the mare's uterus makes it distinct from its cousins and can render the condition difficult to diagnose. The condition can be treated if identified early enough, but Brown and Horohov said the key word is "early." In many cases, an infected mare can present no symptoms at all. The only superficial sign that could help with early detection is when a mare develops mammary glands and begins to lactate, sometimes four to eight weeks out from her due date. 

"There aren't any obvious frank signs that will tell you a mare is developing this," Horohov said. "The bagging-up as they will do can occur in some cases, but it can occur for other reasons as well. Some are also relying on doing abdominal ultrasounds to look for evidence of placental separation. Again, that isn't specific for nocardioform placentitis, but it is suggestive something is going on and could mean the pregnancy is at risk." 

If the infection is caught, the delivery of sulfa drugs (Sulfonamides)—the usual antibiotic recourse for treating bacterial infections—has proven effective with bacteria showing little or no resistance.

While the foal is negatively affected by the contraction of nocardioform placentitis, a point that has puzzled scientists is that mares often experience an absence of issues and usually pass the infection through their systems with ease. There is no pattern when a mare might contract the condition. Indeed, a mare can be adversely affected in one season and never contract the virus again. In a study conducted by Dr. Barry Ball of the Gluck Center in 2016, Brown said mares appeared curiously unaffected by the artificial introduction of the nocardioform placentitis bacteria into their systems. 

"This organism is very slow-growing. It takes three days to grow on a normal microbiological plate. Dr. Ball did three different studies after the 2016 outbreak where he tried to infect mares with the organism by putting it in the semen extenders that he did or in the mare at the time of breeding, and we could never reproduce it. Out of the study he did with 20 mares, 19 of them got pregnant. The mares cleared it relatively efficiently, and it didn't impact their ability to get in foal. None of the mares got 'dirty,' either. If you came back and cultured in those mares, they didn't show any signs of the bacteria." 

"What Dr. Ball tried to develop was an experimental model for it where we could ask questions like, 'What effect does this or that have on the susceptibility of the disease progression,' so we could then better diagnose and treat the condition," echoed Horohov. "In reality, it's near impossible just to expose these mares to bacteria. Interestingly enough, there was no evidence the mares in his experiment even made antibodies to the bacteria, which suggests they were so effective in eliminating the bacterial challenge that the immune system itself wasn't even involved. So for this condition to happen, there has to be a tipping point in addition to having the bacteria that creates the disease." 

With the symptoms of the infection undetectable, another factor frustrating research efforts is that the means of transmission for nocardioform placentitis is also yet to be determined. Researchers have struggled to define a set of risk factors that could help to identify why the Thoroughbred population and those horses residing in Central Kentucky comprise the largest at-risk population. In the past decade, one of the only correlations they have been able to observe with the rise of chronic nocaridoform placentitis is that the recurrence of specific environmental conditions appears to coincide with high infection rates. 

"The problem is we don't know really what we're dealing with," Horohov said. "The basic ideology of the disease, how the horses acquire it, the pre-supposing factors, how to identify mares early enough on so that we can prevent the adverse affects we see, are all issues that are wide open to investigation. We've tried to take a holistic approach, if you will, to the disease, and we have funded projects in the past. 

"One of those was under Dr. Ball, who looked at gene expression in the placentitis-affected placenta to see the effect it had on the affected genes and to see if there were characteristic patterns of expression that could be identified. That's given some us some interesting leads in our work now. Dr. Ball also identified an association between climatic conditions and the subsequent occurrence of these conditions. A hot, dry summer and early fall seem to be predisposing factors, but we don't know why. What concerns me is that the last major outbreak was in 2011, then 2016-17, and here we are again in 2020. The timeline is shortening, and we seem to think that it is associated with hotter summers, and one thing that everyone is predicting is we may see hotter, dryer summers going forward. There is an urgency to this—not because it is a catastrophic occurrence now, but it is a rather foreboding thing that we are seeing it more frequently and at a higher occurrence than we are accustomed to. Work needs to be done." 

Building on the experiments and results attained by their colleagues, Horohov and those on the team at the Gluck Center are in the process of collecting blood samples from mares suspected to be infected with nocardioform placentitis. Their hope is they will be able to develop a LYSA assay (lyophilisation solubility assay) that will help them identify whether a mare is producing antibodies to fight the infection. In addition, they will return to the question of gene expression posed by Dr. Ball in 2016, using both placentas and blood samples to look for changes in gene expression in the circulation cells that could be an indication that things are going on inside the mare that are associated with placentitis. 

While nocardioform placentitis has occurred in other states within the U.S., as well as other countries, there is some solid ground to be found in the quagmire of questions. According to Brown, Kentucky represents a unique control group for the team researching the condition. The density of the Thoroughbred horse population, the quality of farm management, and the access to pathology experts at the top of their fields have created a perfect mélange in which researchers, vets, and horsemen can disseminate their findings quickly across the industry. 

"One thing the Gluck Center and the diagnostic lab are trying to do is work with the farms in the area and the vets and the managers to try and work together to capture as much information as we can," Brown said. "Some of that might be at the molecular level, and we will look at cytokine expression in those mares to try and understand that in the family where this organism comes from there, and if there are other organisms that are slow-growing that we do know something about. That way we can think about what we know about the way those organisms behave that might give us some clues as to how to identify this at-risk population. 

"It's about sharing that information and working with research teams. For example, we've developed an informational sheet for people assessing their mares anonymously, and they can provide that data allowing the diagnostic lab and the research team at the Gluck Center to engage with those practitioners and work with them to collect samples, or if those mares haven't foaled, gained access to a lot of placentas so we can examine those. One thing we have talked about is activating funds at the Gluck Center that will allow us to do all of the histological examinations of the placentas that would contribute to our work but wouldn't cost the horse owner anything." 

"We're in a bit of a Catch-22," said Horohov, aware of the fact that the data set required for the research of the disease is unfortunately foal fatalities. "In this case, we're allowing nature to give us the opportunity to ask these questions, and this is our best chance right now to ask these questions.

"For example, we've developed an informational sheet for people assessing their mares anonymously, and they can provide that data allowing the diagnostic lab and the research team at the Gluck Center to engage with those practitioners and work with them to collect samples, or if those mares haven't foaled, gained access to a lot of placentas so we can examine those."

While conditions at the moment are not ideal, in past years of foal deaths researchers have seen a general trend in which deaths spike at the beginning of the season, reaching a peak in January or February. After that point, data has shown a precipitous decline. The question of why this occurs is just one more unknown variable in an already stymieing query.  

"It concerns me when I see some headlines about this that it makes one think all the foals are being born with this, and that is not the case," Brown said. "We are certainly seeing a higher number, but we are also seeing a higher number of foalings that appear to be normal. We're seeing more widespread distribution of the nocardioform placentitis both within herds and across herds in different pockets in Central Kentucky. That is what we need to understand and identify where are we seeing it more prominently. We want to support the industry using the resources we have along with our time and expertise to help solve this problem. 

"That's where we are now, trying to gather more information. Part of what we're doing is putting all the pieces together so we can solve the mystery and make sense out of this. The density in the population of horses we have here, coupled with the factor that we work for the Thoroughbred industry, raises the level of investigation because of the intensity of management we have. Things don't get pushed off to the side and dismissed. We strive to understand, and we want to address health issues on the highest level. The more we understand, the more we can manage away from risk factors and avoid bad outcomes."