Pathogenesis, prevention and  treatment of postpartum uterine disease

Pathogenesis, prevention and treatment of postpartum uterine disease

Robert O. Gilbert
Professor of Theriogenology, Associate Dean,
Academic Affairs,Ross University
School of Veterinary Medicine,Basseterre,
St. Kitts & Nevis, West Indies.
From RuVASA Proceedings 2018

Introduction

Postpartum diseases are common in dairy cows, and their incidence contributes to reduced fertility and increased risk of culling, making their prevention and management extremely important.  Reproductive efficiency has a major impact on economic success of any dairy production unit.  Control of reproductive diseases is important for maintenance of health and welfare of dairy cows, for minimizing use of antibiotics and assuring a wholesome, safe and nutritious product.  Here we will consider retained fetal membranes (RFM), puerperal metritis, pyometra, endometritis, cervicitis and purulent vaginal discharge as major postpartum uterine diseases.

Retained Fetal Membranes

Although bovine fetal membranes are normally expelled within 3 – 8 hours after delivery of the calf (Wehrend et al., 2005) retention of fetal membranes is usually defined as failure of expulsion by 24 hours.  The incidence in dairy cows is about 5 – 15% and is higher for older cows than for primipara (Joosten et al., 1987, Grohn and Rajala-Schultz, 2000).  Predisposing factors include abortion, stillbirth, multiple birth, dystocia, uterine torsion, heat stress, hydrops allantois, and periparturient hypocalcemia, low calf birthweight and premature parturition (Joosten et al., 1987) and induced calving.  RFM is associated with many infectious conditions, including brucellosis, campylobacteriosis and aspergillosis.  Nutritional causes such as overconditioning of dry cows and deficiencies of carotene, selenium and Vitamin E have been incriminated.  Cattle that have RFM once may be at greater risk of the condition after subsequent parturition (Joosten et al., 1987) and cows with RFM have a higher incidence of metabolic diseases, mastitis, metritis, and even subsequent abortion (Gröhn et al., 1990).

Clinical signs of RFM are usually obvious unless the membranes are retained within the uterus or only project into the cervix or vagina and require a vaginal examination to be detected. Cows with RFM produce less milk in the affected lactation.  This is especially true for affected first lactation cows (Rajala and Grohn, 1998).  Cows with RFM are at increased risk of developing metritis, endometritis, ovarian cysts (Grohn and Rajala-Schultz, 2000) or mastitis (Schukken, 1989, Schukken et al., 1989).  Increased risk of mastitis reinforces the importance of impaired immune function in the pathogenesis of RFM.  Cows with RFM tend to experience more days to first insemination, more days from first insemination to conception and more days open than cows without RFM (Maizon et al., 2004).

Manual removal of the retained membranes does no good and may do harm, particularly when future reproductive potential is used as the outcome (Palmer, 1932, Paisley et al., 1986, Bolinder et al., 1988).  Risco et al. (1994) observed that cows with RFM, dystocia or both, which were left untreated, had similar reproductive outcomes to untreated cows which had not suffered from these disorders.   Treatment of cows with RFM with GnRH, F2α or oxytocin is not beneficial in terms of placental release or future reproductive performance (Risco et al., 1994).  Similarly, oral administration of calcium chloride gel had no effect of subsequent metritis, days to first insemination or pregnancy to first insemination (Hernandez et al., 1999).

Many practitioners in different parts of the world still rely on intrauterine infusion of antibiotics as a treatment for RFM, despite a lack of evidence for its efficacy.  Note that antibiotic therapy, especially with tetracyclines, which have the ability to inhibit matrix metalloproteinases (zinc-dependent extracellular proteinases), may actually prolong retention of fetal membranes.  Benign neglect, without attempts at manual removal, and systemic administration of antibiotics only to cows showing fever or other signs of metritis is our current recommendation.  (Drillich et al., 2003, Drillich et al., 2006a, Drillich et al., 2006b)

The most effective strategy for prevention of RFM is to ensure that cows have continued access to feed during the prepartum period, to avoid regrouping and other forms of social stress during this period and to ensure that dietary selenium and vitamin E are adequate.  Nutritional strategies to prevent hypocalcemia are likely to be beneficial in limiting incidence of RFM.  Routine treatment of cows at calving with either prostaglandin F2α or oxytocin is not effective in preventing RFM (Stevens and Dinsmore, 1997).  Feeding of monensin has been reported to decrease incidence of RFM in multiparous cows (Melendez et al., 2006), although this effect was not noticed in another (smaller) trial (Beckett et al., 1998).  Supplementation with beta-carotene may reduce incidence of retained fetal membranes in multiparous cows (Oliveira et al., 2015).

Puerperal Metritis

Acute puerperal metritis usually occurs in the first 10 days postpartum and is characterized by an enlarged, flaccid uterus, a fetid, watery red-brown discharge and, usually, fever (Gilbert and Schwark, 1992, Sheldon et al., 2006) and other signs of systemic illness such as depression or decreased milk yield and feed intake.  Fever may follow development of other signs by a day or two (Lima et al., 2014) and is sometimes not detected (Benzaquen et al., 2007, Lima et al., 2014).  Risk of metritis is increased by RFM, obstetric complications and twin birth.  It is more common in cows that are over or underconditioned.  Feeding urea to dry cows has been implicated as a cause of postpartum uterine infection (Barnouin and Chacomac, 1992).  The condition is more prevalent in dairy cows than in beef animals and occurs with higher frequency in primiparous cows.  The lactation incidence rate of metritis is about 15-20%, but may be much higher in some herds.  Milk yield of affected cows is reduced (Galvão et al., 2010, Dubuc et al., 2011a, Wittrock et al., 2011, Giuliodori et al., 2013).  Metritis contributes to delayed conception and increased risk of culling (Wittrock et al., 2011, Giuliodori et al., 2013).   Costs of acute metritis are associated with treatment costs, increased culling, and impaired fertility.  Cows with metritis are at increased risk for other postpartum complications such as displaced abomasum and for endometritis.

Cows that have diminished food intake during the late dry period have increased risk of puerperal metritis (Huzzey et al., 2007); these cows frequently show elevated beta-hydroybutyrate or non-esterified fatty acid concentrations in peripheral blood.  They have impaired immune function, partially mediated by low intracellular glycogen content of neutrophils.  Circulating cortisol and estradiol concentrations tend to be increased immediately postpartum in affected cows (Galvão et al., 2010).  Milk yield is depressed, particularly in affected first lactation animals (Galvão et al., 2010).

Bacteria commonly involved in puerperal metritis are Escherichia coli, and the gram negative anaerobes Prevatella melaninogenica and Fusobacterium necrophorum (Santos et al., 2011, Machado et al., 2012c, Santos and Bicalho, 2012).  Specific strains of E. coli  expressing specific virulence factors seem to be implicated; E. coli are the earliest invaders and their presence increases the risk for subsequent invasion of the uterus by other pathogens (Santos et al., 2008, Sheldon et al., 2010).  Of several virulence factors expressed by metritis-causing E. coli the most important appears to be FimH, a pili adhesive protein enabling the bacteria to adhere to and colonize epithelial surfaces (Bicalho et al., 2010a).  FimH adhesion is mediated by mannose, and in vitro mannose is capable of preventing adhesion to cultured uterine epithelial cells (Sheldon et al., 2010).  However, intrauterine administration of mannose was ineffective in preventing metritis (Machado et al., 2012a).  Cows with FimH-expressing E. coli in the uterus during the first two days postpartum have impaired reproductive performance (Bicalho et al., 2012, Machado et al., 2012c) and are more likely to be infected with F. necrophorum at 8-10 days postpartum(Bicalho et al., 2012).  F. necrophorum expresses a number of virulence factors, but a leukotoxin (LKT) known to be highly toxic to bovine neutrophils appears to be of most importance.  Adhesion to bovine endothelial cells is mediated by virulence factor FomA (Kumar et al., 2015).  F. necrophorum is synergistic with Trueperella pyogenes in etiology of several conditions including abscesses, footrot, summer mastitis and calf diphtheria (Nagaraja et al., 2005) and this synergy contributes to uterine disease as well (Dohmen et al., 2000, Bicalho et al., 2012, Machado et al., 2012c).  T. pyogenes appears to be more prominent in uterine disease later in the postpartum period – endometritis, cervicitis and purulent vaginal discharge.

Diagnosis of metritis is usually uncomplicated but affected cows should be examined thoroughly to exclude peracute mastitis, abomasal displacement, pneumonia, peritonitis or other systemic disease. Traditionally, fever has been regarded as an essential component of acute puerperal metritis but it may not be prominent (Benzaquen et al., 2007).

Acute puerperal metritis usually responds favorably to systemic administration of antimicrobial drugs.  If necessary, more aggressive supportive therapy, including fluid therapy, should be instituted. Many of the E. coli involved in pathogenesis of acute puerperal metritis are antibiotic resistant, but cephalosporin antibiotics remain the best choice – for microbial sensitivity and for uterine distribution (Bicalho et al., 2010b).  Although drainage of the fetid uterine contents is intuitively appealing, the uterus is friable and may be penetrated easily by a siphon tube at this stage.  Manipulation of the uterus can result in bacteremia, and any attempt at drainage should be avoided or at least delayed until after beginning antimicrobial treatment (Gilbert and Schwark, 1992).  Many antimicrobial drugs have been found to be useful in the treatment of cows with acute puerperal metritis.  Several studies have found systemic administration of ceftiofur to be effective in advancing resolution of clinical signs (Drillich et al., 2001, Zhou et al., 2001) but not in improving fertility (Haimerl and Heuwieser, 2014).  The same is true for systemic ampicillin treatment (Lima et al., 2014).  Given concerns over antibiotic resistance and residues, some have advocated waiting two days before instituting antibiotic treatment, given a self-cure rate of approximately 30 % (Haimerl and Heuwieser, 2014)  There is no evidence that other forms of treatment such as estrogens (Risco and Hernandez, 2003) or oral calcium gels (Hernandez et al., 1999) improve clinical condition or reproductive response of cows with metritis.  Intrauterine administration of antibiotics has generally not been found to be beneficial; in one exception, high doses of oxytetracycline were used for a protracted period (Goshen and Shpigel, 2006).  Many bacteria isolated from cows with metritis are resistant to tetracycline (Santos et al., 2010).

Most cows recover promptly from toxic puerperal metritis with timely treatment, or sometimes, spontaneously (McLaughlin et al., 2012).  In rare instances, fatal liver failure (Sweeney et al., 1988) or amyloidosis (Johnson and Jamison, 1984) may be complications of puerperal metritis.  Acute puerperal metritis increases the risk of subsequent infertility (Moss et al., 2002, Elkjaer et al., 2013, Toni et al., 2015).  Cows with acute puerperal metritis are at increased risk of later purulent vaginal exudate or endometritis (Lima et al., 2014).

Effective means of preventing metritis would be extremely valuable to dairy producers.  Although reduced dry matter intake in the dry period is a major contributor to the pathogenesis, it is not clear how to avoid a reduction in voluntary intake, which occurs in some cows even in the absence of any social stressors such as group changes and by eliminating competition for bunk space by feeding cows individually (unpublished observation).  Although overcrowding affects feeding behavior (Olofsson, 1999, Proudfoot et al., 2009), there is no evidence that stocking rate affects metritis incidence (Silva et al., 2014).  Nevertheless, it seems prudent to avoid overcrowding of dry cows, frequent group changes and mixing heifers and older cows.  Hygiene plays a role in metritis prevalence, and attention should be paid to hygiene in calving pens (Schuenemann et al., 2011).  Herds using straw bedding in calving pens have lower incidence of metritis than those using other forms of bedding (Kaneene and Miller, 1994).  Recently a multivalent vaccine has been reported to reduce risk of metritis in dairy cows (Machado et al., 2014) and is currently in clinical trials.

There is some prospect of genetic selection for reduction of metritis incidence.  Some investigators have reported heritability of metritis to be as high as 0.19 and 0.26 for primiparous and second lactation cows, respectively (Lin et al., 1989).  Others have reported more modest heritability, ranging from 0.02 to 0.07 (Lyons et al., 1991, Zwald et al., 2004b, a).  We have observed large differences in metritis incidence in first lactation daughters of different bulls calving in the same year in one large herd (see Table 1).  Polymorphisms in genes encoding toll like receptors and the leptin receptor gene have been linked to metritis incidence (Oikonomou et al., 2009, Pinedo et al., 2013).  As this is currently an area of active research more concrete guidelines are likely to emerge.

Pyometra

Pyometra occurs as a specific postpartum condition in postpartum cows.  It is characterized by the accumulation of purulent or mucopurulent exudates in the uterus in the presence of an active corpus luteum in acyclic cows.  It affects about 4% of dairy cows each lactation (Akordor et al., 1986), but its incidence may be increased by routine use of GnRH in the early postpartum period (Etherington et al., 1984).  In general, ovulation is delayed in cows with significant uterine pathogen load (Sheldon et al., 2002) but if cows do ovulate in the face of ongoing uterine contamination they risk development of pyometra, as the endometrial damage may impair endogenous release of PGF2α.  Traditionally T. pyogenes have been the most common bacteria isolated from cases of pyometra (Ribeiro et al., 2015) but metagenomic methods demonstrate prevalence of F. pyogenes in affected animals (Knudsen et al., 2015).  A specific form of pyometra is also seen in cows infected with Tritrichomonas foetus (BonDurant, 1997) and is not considered further here.

The treatment of choice for pyometra is PGF2α or its analogs (de Kruif et al., 1977, Fazeli et al., 1980, Ott and Gustafsson, 1981, Paisley et al., 1986, el-Tahawy Ael and Fahmy, 2011).  Treatment results in luteolysis, behavioral estrus, expulsion of accumulated exudate and bacteriological clearance of the uterus in about 90 % of treated cases.  Recurrence of pyometra after a single treatment occurs in 9 to 13 % of cases (de Kruif et al., 1977, Fazeli et al., 1980).  First service conception rate of approximately 30% or more follows treatment, but 80 % of animals may be expected to conceive within 3 to 4 inseminations (de Kruif et al., 1977, Ott and Gustafsson, 1981).

Estrogens, in the form of estradiol cypionate of diethyl stilbestrol, have also been used for the treatment of pyometra.  (Such use is now illegal in many countries.)  It should be remembered that estrogens are luteolytic in cows.  The clinical response to estrogen therapy is poorer than that expected after treatment with PGF2α (Fazeli et al., 1980), and posttreatment conception results are poorer.  Both a higher (de Kruif et al., 1977) and a lower (Fazeli et al., 1980) incidence of cystic ovarian disease after treatment of pyometra with estrogens relative to prostaglandins, has been reported.  In one study (Fazeli et al., 1980), nitrofurazone infusion into the uterus was combined with either estradiol or prostaglandin treatment.  In both cases, the use of nitrofurazone significantly depressed posttreatment conception rates.  These data provide additional evidence against intrauterine infusion as a modality of treatment for bovine uterine disorders.

Endometritis

Endometritis (sometimes referred to as subclinical endometritis) is defined as inflammation of the endometrium.  It is a local disease and is not accompanied by systemic signs.  It typically occurs in clinically relevant form after 4 weeks postpartum.  Endometritis requires endometrial cytology (Gilbert et al., 1993, Gilbert et al., 1998, Gilbert et al., 2005, Dubuc et al., 2010b) or biopsy (Bonnett et al., 1993) for convincing diagnosis, but its presence can be inferred from the pH, protein or leukocyte esterase concentration of recovered uterine lavage fluid (Cheong et al., 2012, Denis-Robichaud and Dubuc, 2015), or more simply the appearance  or optical density (Machado et al., 2012b) of this fluid.  Transrectal ultrasonography is also useful for diagnosis, but with moderate sensitivity and specificity (Barlund et al., 2008).  The prevalence of endometritis in the immediate prebreeding period (approximately 40 – 60 days postpartum) is high in dairy cows and exerts a substantial negative effect on subsequent reproductive performance (Gilbert et al., 2005, Dubuc et al., 2010a, Cheong et al., 2011b), reducing conception to insemination and increasing pregnancy loss between 28 and 60 days after insemination.

The major risk factor for development of endometritis appears to be periparturient negative energy balance (Hammon et al., 2004, Dubuc et al., 2010b, Cheong et al., 2011a).  Acute puerperal metritis in the early postpartum period increases risk of subsequent endometritis (Cheong et al., 2011b, Lima et al., 2014).  The major bacteria associated with endometritis are the same as those implicated in the pathogenesis of puerperal metritis – E. coli, Trueperella pyogenes and the gram-negative anaerobes Prevotella melaninogenica and Fusobacterium pyogenes.  E. coli appears to be an early invader and has largely disappeared by the time endometritis is diagnosed.  T. pyogenes is more often isolated contemporaneously with the diagnosis (Bicalho et al., 2012, Machado et al., 2012c, Santos and Bicalho, 2012).

Virtually all cows show evidence of mild uterine inflammation at 2 weeks postpartum.  By 4 to 6 weeks postpartum, up to half of cows still have cytological endometritis.  Attempts to diagnose endometritis before about 4 weeks postpartum are confounded by physiological inflammation associated with endometrial remodeling.  Overall prevalence of endometritis at about 40 to 60 days postpartum is about 26 %, but herd prevalence ranges widely (5 % to over 50 %) (Dubuc et al., 2010a, Cheong et al., 2011b).

Endometritis reduces pregnancy to first AI and overall risk of pregnancy in the affected lactation (Kasimanickam et al., 2004, Gilbert et al., 2005, Cheong et al., 2011b).  The consequences of subclinical endometritis were less severe in first lactation animals; although first service conception rate was diminished by endometritis in both age groups, overall time to pregnancy was not affected in primiparous cows with subclinical endometritis (Cheong et al., 2011b).

Routine diagnosis of endometritis is seldom practical for all cows in a herd.  However, it may be useful to examine a cohort of cows (e.g. 20 cows) by endometrial cytology to obtain insight into the prevalence of the condition on a specific farm.  Then, if prevalence is high steps can be initiated to better manage transition cows to minimize periparturient negative energy balance.

Because individual cows are seldom diagnosed with endometritis, treatment is usually moot.  Kasimanickam has shown that intrauterine infusion of a specific formulation of cefapirin (Metricure®, Merck Animal Health) has beneficial effects on subsequent reproductive performance of affected cows.  This product is not available in the USA.  Several studies have examined prostaglandin administration for treatment or prevention of endometritis, without any evidence of efficacy, either for reducing incidence or improving reproduction (Galvão et al., 2009, Dubuc et al., 2011b, Haimerl et al., 2012).

Prevention of endometritis rests largely on management of dietary intake and periparturient energy balance.  Reduction of metritis incidence will reduce endometritis risk.  Calving and postpartum hygiene are important.

Cervicitis and Purulent Vaginal Discharge

Although visible purulent vaginal exudate may accompany more severe forms of endometritis, it has become clear that cows may have visible reproductive tract exudate but be free of endometritis.  It is assumed by most investigators that primary cervicitis is the major cause of a vaginal exudate in the absence of endometrial inflammation.  Several lines of evidence support this conclusion.  In pioneering work on identifying clinical findings associated with reduced fertility, LeBlanc et al. found that increased cervical diameter after 3 weeks postpartum was one factor (along with purulent vaginal discharge) predicting reduced likelihood of pregnancy (LeBlanc et al., 2002).  Indeed, identification of an enlarged cervix was recognized as a harbinger of poor fertility much earlier (Tennant and Peddicord, 1968).  It now seems likely that these cows have cervical damage, sustained during parturition, and independent of endometritis, although the two conditions can co-exist.  Dubuc et al. found that endometritis and purulent vaginal discharge had independent and additive detrimental effects on reproduction and that they had largely separate risk factors (Dubuc et al., 2010b).  Endometritis was predisposed to mainly by negative energy balance, while cervicitis/purulent vaginal discharge was most commonly a consequence of obstetrical complications, including RFM.  Both conditions occur with higher frequency in cows that have suffered from acute puerperal metritis (Galvão et al., 2010).  Direct evidence for the presence of cervicitis, diagnosed by cytology, has recently been presented by Deguillaume et al. (Deguillaume et al., 2012).  They found that cervicitis existed independently of endometritis.  Prevalence of endometritis alone in their study was 13%, cervicitis only was 11 % and 32 % of cows had both conditions.  Both contributed to reduced hazard of pregnancy, and cows with both conditions fared worse than those with either one.  Identification of cervicitis as a common postpartum disorder does not completely clarify the question of origin of purulent exudate in the vagina.  Approximately half of cows with cervicitis have purulent vaginal discharge, and vice versa (Deguillaume et al., 2012, LeBlanc, 2014).  In some cases, purulent vaginal discharge may reflect more sever endometritis.  However, the source of exudate in some cases still remains unresolved, and may indicate primary vaginitis in some animals.

Whatever the source, presence of purulent vaginal exudate is associated with reduced reproductive performance.  Presence of purulent material in the vagina may be conveniently detected by use of a dedicated instrument, the “Metricheck®.”  This device scoops mucus or exudate from the cranial vagina for examination.  Depending only on visible exudate or palpation findings will result in missing as many as 40 % of cases of purulent vaginal exudate (LeBlanc et al., 2002).

There are few effective treatment options for purulent vaginal exudate. A formulation of cephapirin specially fabricated for intrauterine administration (Metricure®) has been shown convincingly to improve reproductive performance in treated cows when administered to affected cows after 4 weeks postpartum.  Metricure is not available in the USA.  There is no evidence in favor of intrauterine infusions other than cephapirin, and they should be avoided. Although PGF2α is often used for treating purulent vaginal discharge, evidence for its efficacy is equivocal (Dubuc et al., 2011b, LeBlanc, 2014), although it may have beneficial effects on reproduction independent of endometritis / cervicitis.  Despite the weak evidence in its favor, PGF2α may be the best treatment option, especially in the USA; it avoids additional antibiotic use, is inexpensive, and has other beneficial effects on reproduction (including presynchronization for controlled breeding programs).

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