Chapter 50
Postpartum Uterine Infection
Colin Palmer
Department of Large Animal Clinical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
Introduction
The postpartum period is one of the most important periods in a cow’s reproductive life and is a key area for veterinarians to address in terms of prevention, diagnosis, and appropriate treatment of uterine diseases and their sequelae. Most reproductive problems in cattle occur during this period, although the ultimate goal must be to have the cow calve normally and proceed through the postpartum period with as few problems as possible.
Uterine infections are a frequent disorder during the postpartum period. Dairy cattle seem to be more susceptible than beef cattle, or are more likely to be presented for examination on an individual or herd basis. The reason for this may be that dairy cattle are under more production stress; are more intensively housed and therefore exposure to pathogenic strains of bacteria is more likely; are observed more closely, facilitating diagnosis; and resume ovarian cyclicity sooner than beef cattle, which alters local uterine immune function.
The proportion of cattle developing uterine disease varies greatly, even between what outwardly appear to be similar farms in the same geographical region. Milk production, hygiene, and other management factors probably explain most of the variability. Overall, 20–40%, or more of dairy cattle may develop one or more uterine diseases during lactation,1 resulting in economic loss due to decreased milk production, impaired fertility, premature culling, and death. Uterine disease is not new yet the incidence seems to be increasing. A reasonable explanation may be heightened awareness and improved diagnostic capabilities facilitated by advanced statistical and herd management software that only now enables us to realize the true economic impact of uterine disease.
Predisposing factors
Prolonged calving, twins, dystocia, and retained fetal membranes (RFM) are often implicated as predisposing factors for uterine infection.2,3 The three principal postpartum uterine infections, metritis, endometritis and pyometra, are generally considered separately in the literature and have been shown to have additional distinct risk factors which support the conjecture that they are separate conditions.4 To put this in perspective, not all cows that develop metritis will later be diagnosed with endometritis. However, a relationship still exists as cows afflicted with metritis are approximately twice as likely to develop endometritis.5,6 Additional risk factors for endometritis include parity, season and body condition score, ketosis, and milk production.3,5
Cows that developed metritis ate 2–6 kg less feed than their healthy contemporaries 2–3 weeks prior to showing signs of metritis7 and spent significantly less time feeding during the last 3 weeks before calving.8 It is plausible that a relationship exists between appetite and impaired immune function that begins weeks before calving.9 Decreased dry matter intake, increased serum nonesterified fatty acid, and β-hydroxybutyrate concentrations impair neutrophil function enabling the development of metritis.10
Retained placenta or RFM is usually implicated as a cause of uterine infection and with good reason. The odds of a cow with RFM developing metritis are six times greater than that of her unaffected herd mate, far greater than other conditions.11 Calving areas, bedding, and overall farm hygiene should also be considered, but are surprisingly far less important than other risk factors for metritis.12
Pathophysiology
During the first 6 weeks after calving the uterus undergoes the normal process of sloughing and regeneration of the endometrium known as involution.13 Typically, lochia is passed until approximately 23 days postpartum and progresses from thick, mucoid and bloody to purulent discharge.14 Practically all cows have bacterial infection of the uterus during the first 2 weeks postpartum;15 however, the perpetuation of infection depends on the presence of substrate, the degree of bacterial contamination, and the various uterine defense mechanisms.16 Pathogenic organisms must adhere to the mucosa, multiply on the surface, or penetrate the epithelium. Some bacteria produce compounds that directly promote disease or the growth of other bacteria.1 Elevated progesterone and estrogen concentrations in late gestation effectively suppress the immune system of the dairy cow and this carries onward through the first 3 weeks of the postpartum period.9,17 Both hormones are capable of modifying the expression of hormone receptors in immune cells and both, especially progesterone, reduce the secretion of prostaglandins from stromal cells stimulated by Gram-negative cell wall lipopolysaccharide (LPS). Furthermore, metabolic substances such as insulin-like growth factor (IGF)-1 and numerous other proteins have been shown to have immunomodulatory properties in the endometrium.17 During and around the time of parturition the physical barriers to genital infection – the vulva, vagina and cervix – are compromised enabling entry of bacteria into the uterus. Throughout the immediate postpartum period the pattern of infection, clearance, and reinfection occurs repeatedly.13,14 A variety of bacterial species may be cultured from the uterus during the postpartum period; however, virulent strains of Trueperella pyogenes, capable of causing disease alone or in combination with the Gram-negative anaerobes Fusobacterium necrophorum and Prevotella melaninogenicus, are most frequently encountered.14 Until recently the microbial flora of the postpartum uterus has been characterized exclusively by bacterial culture. Metagenomic DNA extracted from the uterine fluid of postpartum dairy cows and amplified using polymerase chain reaction (PCR) technology has provided evidence of a more diverse and complex microbiota than previously described. Many clone sequences belonged to groups of bacteria that had not yet been cultured and there were distinct differences in the types of bacteria between healthy cows and those diagnosed with metritis. Fusobacteria, Bacteroidetes and Proteobacteria represented the majority of clones from metritic cows; however, Escherichia coli and T. pyogenes were not detected, probably because sampling was performed 10 days after calving.18
Escherichia coli is a common culture isolate from the uterus, but tends to be more prevalent earlier in the postpartum period;13,14 T. pyogenes is prevalent more than 2 weeks after calving.18 Infection with E. coli during the puerperal period may predispose to infection with other bacterial species.1,17,19–21 Until recently the true significance of E. coli beyond that of an opportunistic pathogen was debatable; however, six E. coli virulence factors were significantly associated with a higher risk of infected cows developing metritis, providing strong evidence that E. coli should be considered a primary uterine pathogen.22
Trueperella pyogenes is responsible for the most severe damage to the endometrium, facilitated by a cytotoxin pyolysin capable of destroying endometrial cells.17 Although not consistently isolated together, a synergistic relationship exists between T. pyogenes, F. necrophorum, and P. melaninogenicus facilitated by the production of growth-promoting factors and substances shown to limit neutrophil chemotaxis and phagocytosis.14 Damage to the endometrium interferes with the establishment and maintenance of early pregnancy and inflammatory mediators will reduce the number of trophectoderm cells around the embryo.1,23 Uterine infections also impair the growth of dominant follicles, impair ovulation, and are associated with lowered plasma estradiol and progesterone concentrations,21,24–26 and have been associated with prolonged luteal phases and cystic ovarian disease.27
Defining uterine infections
Uterine infections primarily are named for the severity, extent and characteristics of the inflammatory reaction. However, since inflammation is associated with normal involution, it is important to consider the number of days since calving to determine if the degree and severity of signs are consistent with disease.
Metritis
Metritis is defined as inflammation of the uterine wall including the endometrium, muscular layers, and serosa. Metritis differs greatly from endometritis both histologically and clinically. Unfortunately, the term “metritis” is commonly misused when referring to both of these conditions. Researchers and clinicians should make an effort to use the correct terminology to mitigate confusion.
Most cases of metritis occur within 1–2 weeks of calving. The most common and severe presentation, referred to as puerperal or toxic metritis, occurs within the first 2 weeks after calving and is characterized by a fetid, watery, brown uterine discharge and severe systemic illness. Affected animals are usually depressed, anorexic, dehydrated, and febrile (body temperature >39.5 °C). The uterus is palpably enlarged, flaccid, and lacks longitudinal rugae or ridges typical of a normal postpartum uterus. If metritis occurs in the absence of systemic illness, then the condition may be referred to as simply metritis28 or as acute postpartum or acute puerperal metritis.29,30
Multiparous cows with puerperal metritis consume less feed and produce less milk and are more likely to be culled than their healthy herdmates, but these effects are apparently not realized in primiparous cows.31,32 Uterine inflammatory conditions with purulent exudate occurring beyond 2 weeks after calving are difficult to distinguish from normal uterine involution. The current belief is that the severity of metritis decreases with time and that a proportion of these cases will persist as endometritis.33
Endometritis
Endometritis is defined as inflammation limited to the endometrium. Histologically, evidence of inflammation should not extend beyond the stratum spongiosum.34 Endometrial inflammation involves disruption of the epithelium, increased blood flow, edema, and an influx of inflammatory cells, mostly neutrophils and lymphocytes.9
Endometritis has been further subcategorized as clinical and subclinical disease. Diagnostic signs associated with clinical endometritis are obvious to the eye and include purulent or mucopurulent (50% pus, 50% mucus) discharge visible at the vulva or present within the cranial vagina.35 With respect to subclinical endometritis, purulent or mucopurulent uterine discharge is not evident, yet infection and inflammation persist. Examination of cellular material harvested directly from the uterine lumen and endometrium is used to assess the level of inflammation.
Neutrophils are the first and most significant inflammatory cell involved in endometritis, but are also foremost during normal uterine involution. The inflammatory cell response in cases of subclinical endometritis is widely believed to be quantifiably more severe than that associated with normal involution yet milder than clinical endometritis. However, despite supposed differences in volume of neutrophils, fluid, mucus and other debris, it is doubtful that the negative impact on reproductive performance is any less severe. Because it is so difficult to differentiate real disease having a negative impact on reproductive performance from normal uterine involution, diagnostic indicators must be evaluated relative to the number of days after calving. The current dogma among many of those who study endometritis is that attempts to diagnose endometritis should be delayed until after the first month post calving.
Dubuc et al.4 have provided evidence that clinical and cytological endometritis may be distinct manifestations of reproductive tract disease. When endometrial cytology was assessed in cows presenting with vaginal discharge typical of clinical endometritis, only 38% and 36% of cows examined at, respectively, days 35 and 56 postpartum also had evidence of cytological endometritis. Cows having each of these conditions experienced a negative effect on reproductive performance; moreover, when they were present in the same cow the detrimental effect on reproductive performance was additive. The source of the vaginal discharge was speculated to be the cervix, specifically cervicitis. Another plausible reason for the disparity in findings was that cytological preparations prepared from material harvested from the uterine body might not be representative of inflammatory cell accumulations in the uterine horns. These authors proposed that purulent vaginal discharge was a more descriptive and accurate term for vaginal discharge previously considered diagnostic for clinical endometritis. Furthermore, cows with purulent vaginal discharge responded to antibiotic treatment deposited within the uterus. This finding suggests that there is much more to learn regarding the inflammatory response of the postpartum uterus, cervix, and vagina.
Pyometra
Pyometra is defined as the accumulation of pus within the uterine lumen facilitated by a closed cervix and the presence of a corpus luteum.28,36 The persistence of a corpus luteum is the key feature distinguishing pyometra from closely related endometritis and ensures that the cervix remains closed and there is absence of myometrial contractions to expel the pus into the vagina. Furthermore, the persistence of a progesterone-dominant state ensures that immune defenses remain inactive. Prolongation of the luteal phase may be attributed to increased concentrations of luteotrophic prostaglandin (PG)E2 associated with endometrial bacterial infection.37 Endometrial cells exposed to E. coli LPS, T. pyogenes exotoxin, and bovine herpesvirus 4 preferentially secrete PGE2 rather than PGF2α.
However, extension of the luteal phase is not exclusive to pyometra and may occur under the right conditions in cases of endometritis.1 Pyometra is relatively rare in comparison to metritis and endometritis,33 but will persist indefinitely until luteolysis occurs. Cows that ovulate when pathogenic bacteria are still present in the uterus are predisposed to the development of pyometra.38 An example of iatrogenically induced pyometra is the use of gonadotropin-releasing hormone (GnRH) to advance ovarian cyclicity in postpartum cows without a follow-up injection of PGF2α.
Diagnosis
Metritis
A complete physical examination is the most effective way to diagnose puerperal metritis. Typically, the individual cow is presented because she has failed to pass her placenta, is off her feed, is “sickly,” or is experiencing decreased milk production, or all four. Systemic signs such as depression, dehydration, anorexia, and body temperature above 39.5 °C in any cow occurring within 1–2 weeks of calving should warrant further examination of the uterus and its contents. Not all sick cows with metritis will have a fever and not all cows with a fever in the immediate postpartum period will have metritis, so herdspersons should be instructed to observe postpartum cows carefully rather than simply flagging cows with elevated body temperatures for further examination. Transrectal palpation of the uterus is a useful tool for evaluating uterine size, tone and texture, and to facilitate the expulsion of fluid by gentle massage. The presence of a fetid, reddish brown, watery discharge in addition to the aforementioned systemic signs can be considered diagnostic for metritis. Normal lochia is reddish brown to white and lacks a significant odor. In cases of metritis the uterus is also very large and flaccid without longitudinal ridges (also known as rugae) indicative of normal postpartum uterine contraction. However, assessment of uterine size and tone is subjective. Clinicians should strive to gather experience by palpating otherwise normal postpartum cows so the that abnormal becomes apparent when presented. Other common clinical findings are leukocytosis with or without a left shift and ketosis. Displacement of the abomasum may be diagnosed simultaneously and will present additional clinical signs specific to this condition.
Endometritis
The diagnosis and treatment of endometritis has been controversial. Researchers and practitioners constantly struggle with appropriate case definitions and ultimately with determination of treatment effectiveness. A perfect diagnostic test must identify all cows at risk of impaired reproductive performance due to both clinical and subclinical endometritis and must offer an immediate answer.
Diagnosis was once based solely on transrectal uterine palpation. Enlarged uterine horn(s), asymmetry of the uterine horns, thickness of the endometrium, and the presence of a palpable uterine lumen and/or palpable fluid within the lumen were attributed to this condition. One of the most significant obstacles to overcome when diagnosing endometritis has been to establish the most appropriate time to examine cows for evidence of disease. In recent years there has been a concerted effort to establish diagnostic protocols to facilitate an accurate diagnosis. Measures of reproductive performance including pregnancy rate, calving to first service interval, first-service conception rate, service per pregnancy, and overall conception rate have been used to retrospectively determine diagnostic thresholds. Understanding that uterine involution involves sepsis and an inflammatory process yet is a normal physiologic process is critical. Realizing that impairment of reproductive performance caused by complicated or delayed uterine involution explains the majority of cases of endometritis is paramount. Even in cows experiencing a normal postpartum period, the uterine horn diameter does not reach the pregravid size of 4–5 cm until 25–30 days after calving.39 LeBlanc et al.35 reported the results of a large-scale study involving 1865 dairy cows examined between 27 and 33 days in milk. One of the objectives was to investigate and validate diagnostic criteria for endometritis. Uterine characteristics including location of the uterus, symmetry of the uterine horns, uterine horn diameter, evidence of a palpable uterine lumen, and thickness of the uterine horn wall were assessed by transrectal palpation. None of the palpable uterine characteristics were associated with the relative pregnancy rate. Use of transrectal palpation of the uterus as the principal method for diagnosing endometritis should be avoided as it is far too subjective and imprecise. From a pragmatic point of view, far too many cases of endometritis will be missed, potentially leaving a number of diseased animals at risk for impaired reproductive performance if left untreated.
