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Contents

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

Post-partum uterine disease has a detrimental effect on dairy cow fertility; affected cows require more serves per conception, have reduced conception rates and are more likely to be culled for infertility. Furthermore, the detrimental effects on fertility remain even after clinical resolution of disease. There are many factors that influence a cow's resistance to or development of post-partum disease, and the key drivers determining disease outcome are uterine microbial load, regulation of inflammation and immune responses peripherally and at a local level, production pressure, and metabolic (energy) status. These factors are intricately interlinked, which makes assessment of their individual effects difficult. It is clear, however, that the period surrounding calving is a key transition phase and events during this time point will influence uterine disease outcome and subsequent fertility. Good peripartum management and accurate diagnosis are critical to facilitate the use of the most effective treatment and limit the negative impact of post-partum uterine disease on fertility. If we can improve our understanding of the underlying causes of disease, then we can identify ‘at risk’ animals and implement management and breeding strategies to prevent uterine disease or reduce its severity. Thus, this article aims to summarize the key factors that drive uterine disease in the post-partum dairy cow.


Introduction

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

The resolution of post-partum uterine infection and inflammation has been identified as one of the most important events that has to happen for the successful establishment of pregnancy in dairy cattle (Walsh et al. 2011). A meta-analysis on the effects of metritis on fertility found that it resulted in the extension of calving to conception intervals by approximately 19 days and a reduction in conception rate to first service of 20% (Fourichon et al. 2000). Furthermore, conception rates remain approximately 20% lower in animals that previously suffered from uterine infection even after clinical resolution of the disease; a further 3% of animals remain infertile and are culled from the herd (Borsberry and Dobson 1989). This reduction in fertility is partly mediated by the disruption of ovarian and uterine function in cows with uterine disease. In a study of normal post-partum cattle with no clinical risk factors for uterine disease, such as retained foetal membranes or dystocia, 75% of the animals had increased numbers of pathogenic bacteria in the uterus on day 7 post-partum. In these cows, the first post-partum dominant follicle grew slower and produced less oestradiol, and in the animals that ovulated, the corpus luteum (CL) was smaller and produced less progesterone (Table 1; Williams et al. 2007). Following administration of Escherichia coli lipopolysaccharide (LPS) in vivo, fewer cows ovulate and the structure and function of the CL are suppressed (Williams et al. 2008a; Herzog et al. 2012). Furthermore, within the uterus, bacterial infection may disrupt the mechanisms of prostaglandin (PG)-induced luteolysis in cyclic cows and therefore contribute to prolonged luteal phases by switching endometrial PG synthesis away from PGF2α towards PGE2 (Williams et al. 2008b; Herath et al. 2009a). The effects of uterine infection and inflammation on uterine and ovarian function are mediated via the disruption of endocrine function by innate immune molecules primarily involved in the recognition of pathogens, and these mechanisms have been comprehensively reviewed (Williams et al. 2008b; Sheldon et al. 2009a,b; Gilbert 2011).

Table 1. Mean ± SEM (a) follicle diameter and plasma oestradiol concentrations on days 13 and 15 post-partum and (b) corpus luteum (CL) diameters and plasma progesterone concentrations on days 24 and 26 post-partum in animals with high vs low uterine pathogen load
  1. Values differ between groups within day *p < 0.05, **p < 0.01. Adapted from Williams et al. 2007.

(a)
Day post-partum1315
Bacterial loadHighLowHighLow
Follicle diameter (mm)10.9 ± 0.412.4 ± 0.7*12.5 ± 0.513.8 ± 0.5*
Plasma E2 (pg/ml)1.0 ± 0.22.7 ± 1.1*1.6 ± 0.32.0 ± 0.3**
(b)
Day post-partum2426
Bacterial loadHighLowHighLow
CL diameter (mm)18.8 ± 1.125.1 ± 0.6*21.5 ± 1.126.7 ± 1.7*
Plasma P4 (ng/ml)1.6 ± 0.45.6 ± 1.6*1.1 ± 0.65.0 ± 1.8*

The incidence of uterine disease varies across individual herds, but on average, 20–40% of dairy cows develop acute clinical uterine disease within a week of calving that persists in 20% of animals as endometritis, and approximately 30% of cows suffer from subclinical endometritis (Sheldon et al. 2009a,b). In addition, clinical endometritis is shown to persist beyond 60 days post-partum in approximately 25% cows that previously had purulent cervico-vaginal discharge and occurs in over 10% of animals who were previously found to be healthy (Gautam et al. 2010).

Despite many years of research, trends suggest that the incidence of post-partum uterine disease is increasing (Williams et al. 2008b). There are a number of factors that could be contributing to a higher incidence of uterine disease, including improved disease diagnosis and the detrimental effects of genetic selection for milk production at the expense of fertility and animal health (Sheldon et al. 2009a,b). Nonetheless, with the removal of milk quotas within the EU by 2015 and the predicted expansion in dairy production that will occur in some European regions, the pressures on the individual dairy cow will only become greater. Thus, following a long period of effort in characterizing post-partum uterine disease and understanding its pathogenesis, particularly in relation to the effect on fertility, the focus has now changed and researchers are more concerned with identifying the factors that cause uterine disease in the dairy cow. If we can improve our understanding of the underlying causes of disease, then we can identify ‘at risk’ animals and implement management and breeding strategies to prevent uterine disease or reduce its severity and duration. This article aims to summarize the key factors that drive uterine disease in the post-partum dairy cow and will particularly focus on the influence of the microbial population, the cows immune response to infection and metabolic and production pressure.

Peripartum Events and the Definition of Uterine Disease

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

There are a number of risk factors for post-partum uterine disease in dairy cattle; cows having dystocia, retained placenta, twins or stillbirths and various metabolic disorders are more likely to develop uterine disease than other cows (Lewis 1997; Potter et al. 2010).

Recent work has demonstrated that different risk factors result in different manifestations of uterine disease; those risk factors that increase uterine trauma and bacterial contamination such as twinning and dystocia are more likely to result in purulent vaginal discharge (PVD) in the absence of endometrial inflammation, whereas risk factors that reflect immune suppression or metabolic imbalance in the peripartum period, such as low body condition score or hyperketonaemia, are more likely to result in endometrial inflammation (cytological endometritis; Dubuc et al. 2010b). Furthermore, PVD and cytological endometritis both result in a reduced risk of pregnancy but the effects are cumulative in cows that have both conditions at the same time, suggesting that the effects have different origins (Dubuc et al. 2010a).

Definitions of post-partum uterine disease based on the key clinical features proposed by Sheldon et al. (2006) have been widely accepted by both researchers and clinicians. The clinical features assessed at specific time points after calving include an evaluation of the signs of systemic illness, the presence or absence of pyrexia, the size of the uterus and the character and smell of uterine discharge detected in the vagina. Evaluation of vaginal mucus has been shown to be indicative of the number and type of bacteria present in the uterus and is correlated with circulating concentrations of acute-phase proteins, which are markers of inflammation (Williams et al. 2005). Furthermore, cows with PVD have reduced reproductive performance (LeBlanc et al. 2002; Williams et al. 2005; Dubuc et al. 2010a). Therefore, mucus assessment is valuable as a quick, on-farm measure of uterine disease. However, it is not clear whether mucus present in the vagina accurately reflects the inflammatory status of the endometrium, and over-reliance on mucus assessment may result in false diagnoses. Indeed, <40% of animals with clinical endometritis also had cytological endometritis, as determined by increased numbers of neutrophils (Dubuc et al. 2010a). Furthermore, the presence of cervicitis is not indicative of the presence of endometritis and endocervical inflammation in the early post-partum period results in reduced pregnancy rates (Deguillaume et al. 2012). These findings highlight the importance of including cytological assessment in the routine investigations of uterine health status in dairy cattle.

In summary, the events around calving may not only increase the risk of uterine disease but will also determine the type of uterine disease a cow will develop. This will in turn influence how well individual animals respond to treatment and their resultant fertility. Good peripartum management and accurate diagnosis will facilitate the use of the most effective treatment and limit the negative impact of post-partum uterine disease on fertility.

Uterine Microbial Population

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

The bovine uterine lumen is readily contaminated with a wide spectrum of microorganisms during the peripartum period and supports the growth of a variety of aerobic and anaerobic bacteria. Many organisms isolated from the uterus are opportunistic and are successfully eliminated from the uterus by the host defence. Thus, the microbiome of the uterus fluctuates throughout the weeks following calving in cycles of contamination, clearance and recontamination (Griffin et al. 1974).

The bacteria that contaminate the uterine lumen have traditionally been categorized according to their pathogenicity within the uterus, and the severity of uterine inflammation is dependent on both the type, and number, of bacteria present (Williams et al. 2007). Uterine disease is most commonly associated with the presence of Escherichia coli, Trueperella pyogenes (formerly known as Arcanobacterium pyogenes), Fusobacterium necrophorum and Prevotella species. The most commonly isolated bacterium is E. coli, which dominates the uterine flora in the first few days after calving (Hussain et al. 1990; Huszenicza et al. 1999) and appears to increase the susceptibility of the uterus to subsequent infection with T. pyogenes (Fig. 1; Williams et al. 2007). Animals infected with E. coli or T. pyogenes on day 10 post-partum have a higher risk of being diagnosed with abnormal vaginal discharge and a higher risk of infection with the same bacterial species on day 24 post-partum (Werner et al. 2012). In addition, the presence of E. coli virulence factors in the uterus within the first 3 days of calving is strongly associated with the subsequent development of metritis and clinical endometritis, but is not associated with uterine disease when detected at later stages of lactation (Bicalho et al. 2012). Specific strains of E. coli have been shown to be particularly pathogenic to bovine endometrial cells and stimulate a host cell immune response via the TLR4 pathway (Sheldon et al. 2010), and virulence genes associated with adhesion and invasion of endometrial cells and subsequent uterine disease have been identified (Bicalho et al. 2012). In contrast, the presence of specific virulence genes of T. pyogenes isolates recovered from the uterus of post-partum dairy cows was not related to the ability to induce clinical metritis, suggesting that the type of T. pyogenes may not be a causative factor in the development of post-partum uterine disease, but instead the synergism between T. pyogenes and other bacteria may be more important (Silva et al. 2008).

image

Figure 1. Uterine (□) Escherichia coli and (■) Trueperella pyogenes growth density from uterine lumen swabs collected 7, 14, 21 and 28 days postpartum, for cows categorized as high (n = 50) uterine pathogen growth density on day 7 postpartum. Bacterial growth density differed significantly between E. coli and T. pyogenes within day *p < 0.05. Adapted from Williams et al. 2007.

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The majority of studies investigating the microbial populations of the bovine post-partum uterus have examined only those that are detectable by culture. Whilst these studies have reliably demonstrated the pathogenic relevance of many organisms, they may have underestimated the complexity of the uterine microbiome, as <1% of the organisms in many environments can be readily cultured under standard laboratory conditions (Amann et al. 1995; Whitman et al. 1998). Culture-independent techniques enable the identification of bacterial species that are clinically significant by treating samples in such a way as to ensure the community profiles are generated solely from DNA contained within viable bacteria (Rogers et al. 2009). Characterizing profiles of bacterial communities may help us to further understand what constitutes a healthy or disease community (Rogers et al. 2010). Indeed, a recent study by Santos et al. (2011) applied culture-independent methods to the analysis of the post-partum uterine microbiome and found that the bacterial diversity between healthy and metritic cows was much greater and more complex than described following traditional culturing techniques. Furthermore, although E. coli and T. pyogenes have previously been highlighted as being key modulators of uterine disease, gene sequences related to these organisms were not found using culture-independent techniques. The authors suggest that this could be influenced by the sampling time point used (day 10 post-partum) as E. coli is commonly isolated from the bovine uterus very early post-partum, whereas T. pyogenes is predominant from day 15 post-partum onwards (Santos et al. 2011). However, it is also possible that even though E. coli and T. pyogenes predominate following culture, as a proportion of the entire microbial population, their contribution may not be as significant as others. This observation opens the door to the possibility of using these emerging technologies to gain a much greater understanding of the complexities and interactions within the uterine microbial population. It may also lead to further insight into the intricate host–pathogen interactions that are important in the establishment of uterine disease.

The Bovine Immune Response

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

After calving, contamination of the uterine lumen with bacteria affects the majority of dairy cattle (Griffin et al. 1974; Williams et al. 2007), and whilst some cattle can efficiently eliminate these bacteria, approximately 25–30% of animals have a persistent inflammatory response and are subfertile as a result (Gilbert et al. 2005; Sheldon et al. 2009a,b). The endometrium is the first line of defence against bacteria that ascend the female genital tract after parturition (Herath et al. 2009a,b). As well as providing a physical barrier to infection, the endometrium has an important role in innate immunity, and this has been well characterized in a number of reviews (Sheldon et al. 2009a,b; Sheldon and Bromfield 2011; Turner et al. 2012).

The bovine uterine response to bacterial contamination is partly mediated by the recognition of pathogen-associated molecular patterns (PAMPs) via the Toll-like receptor (TLR) pathway. Endometrial cells respond to bacterial LPS via TLR4 and consequently produce a range of cytokines and chemokines (Sheldon and Roberts 2010; Sheldon et al. 2010; Cronin et al. 2012). In addition, responses to PAMPs that bind TLR1, TLR2, TLR5 and TLR6 have also been reported in pregnant cow endometrium and in human endometrial cell lines (Young et al. 2004; Silva et al. 2012).

In most cows, these processes lead to clearance of bacterial infection and epithelial repair after which the inflammatory response is reduced or switched off. In cows with uterine inflammatory disease, the extent and/or duration of response is not controlled properly with detrimental effects on uterine and ovarian function (LeBlanc 2012). Indeed, a greater endometrial pro-inflammatory response during the first-week post-partum, as demonstrated by increased endometrial expression of TLR4 and a higher IL-1/IL-10 ratio, is associated with persistent endometritis and subfertility (Herath et al. 2009a,b).

As well as the local immune response in the uterus, abnormal peripheral immune function before and after calving predisposes cows to uterine disease (Lewis 1997). Cows classified as having a good immune response (based on their antibody and cell-mediated immune responses to known antigens) had a reduced incidence of post-partum diseases, including metritis, within 30 days after parturition, and the authors suggest that breeding for enhanced immune responsiveness will decrease disease incidence (Thompson-Crispi et al. 2012). Endometritis is also associated with impairment of neutrophil function that starts before parturition (Hammon et al. 2006). It has recently been hypothesized that individual variation in the immune regulation of pregnancy and parturition and the reversal of these changes in the post-partum period are important drivers of susceptibility to uterine infections (Hansen 2013). The ability to identify animals with suboptimal immune function before or soon after calving would provide an opportunity to put in place preventative strategies to reduce the incidence of uterine (and other) disease thereby improving fertility.

Metabolic and Production Pressure

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

The majority of health problems in dairy cows occur in the periparturient period, and this is thought to be due to the physiological imbalances that result from the adaptations to lactation (Ingvartsen 2006). Notably, the establishment of uterine infection takes place around the same time as peak milk yield and the incidence of uterine disease is greater in high-yielding animals. In one study, 73.3% cows producing more than the median value of 35 kg milk/day suffered from metritis or endometritis compared with only 45.2% of cows producing <35 kg milk/day (Fig. 2; Crowe and Williams 2012). This relationship is thought to be due to the influence of negative energy balance (NEB), with cows producing larger quantities of milk having a more pronounced energy deficit in the post-partum period. The interactions between metabolism, inflammation and fertility are comprehensively reviewed by LeBlanc (2012) who concluded that NEB contributes to immune dysfunction, a major factor in the establishment of reproductive tract inflammatory disease. Hammon et al. (2006) suggested that uterine disease was associated with NEB that starts before calving and continues through to early lactation and found that cows with severe NEB had impaired neutrophil function. Furthermore, severe NEB was associated with an increased expression of inflammatory genes in the endometrium 2 weeks after calving (Wathes et al. 2009). These data suggest that NEB compromises immune function, which may influence the susceptibility of dairy cows to uterine disease and impair their ability to resolve post-partum uterine contamination. Indeed, cows with uterine disease experienced a greater degree of NEB indicated by higher non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHBA) around calving (Galvão et al. 2010). Other studies, however, have reported contrasting results. Burke et al. (2010) found that animals with endometritis had similar profiles of NEFA and glucose as healthy animals, and neither NEFA or BHBA during early lactation was found to have an association with metritis (Valergakis et al. 2011) or subclinical endometritis (Senosy et al. 2012) suggesting that energy status, as determined by metabolite concentrations, is not a risk factor for uterine disease.

image

Figure 2. Incidence of uterine disease in animals producing more (high yielders) or less (low yielders) than the median herd value of 35 kg of milk per day. *p < 0.05. From Crowe and Williams 2012

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The reasons for the disparity between these studies are not clear. Metabolic status and NEB are the result of a combination of factors including milk yield, dry matter intake, body condition and parity, so it is possible that differences in any of the factors contributing to NEB may affect disease outcome. Heavier cows are 3.6 times more likely to have a purulent vaginal mucus score on day 14 post-partum (Williams et al. 2009), and advancing parity has been associated with higher milk yield and an increased risk of endometritis and culling for reproductive failure (Lee and Kim 2006). In a recent study, cows with clinical endometritis had a higher milk yield than healthy herd mates (Giuliodori et al. 2013).

It is clear that NEB can affect immune function in the post-partum dairy cow, and whilst this may contribute to an increased risk of developing uterine disease, the data are contrasting which makes it difficult to reach a conclusion on the effect of NEB on uterine disease.

Conclusion

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References

Many factors influence resistance to, and development of, post-partum uterine disease in dairy cattle. The key drivers that determine disease outcome are as follows: production pressure, metabolic (energy) status, microbiological load and regulation of inflammation and immune responses. These factors are intricately interlinked, which makes assessment of their individual effects difficult. It is clear, however, that the period surrounding calving is a key transition phase and events during this time point will control uterine disease outcome and subsequent fertility.

Specific strains of E. coli have been shown to be pathogenic to bovine endometrial cells, and the predominance of E. coli within the first few days after calving increases the risk of metritis and endometritis and reduces fertility. Furthermore, animals that are known to have suboptimal immune status or be under metabolic stress in the period around calving are more likely to suffer from uterine disease. These different contributors result in different manifestations of uterine disease with some increasing the risk of PVD and others more likely to cause cytological endometritis. The disease type will in turn influence the cow's response to treatment and her subsequent fertility.

Whilst prompt and accurate diagnostics are key in ensuring that sick animals are treated efficiently and correctly, it is critical that we understand the influence of the drivers of uterine infection, so that we can accurately identify those at risk very early post-partum or even before calving, so that we can reduce the incidence or severity of uterine disease and increase fertility in the dairy herd.

References

  1. Top of page
  2. Contents
  3. Introduction
  4. Peripartum Events and the Definition of Uterine Disease
  5. Uterine Microbial Population
  6. The Bovine Immune Response
  7. Metabolic and Production Pressure
  8. Conclusion
  9. Acknowledgements
  10. Conflict of interest statement
  11. Author contributions
  12. References
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