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 Animal Reproduction Science 8283 (2004) 295306

Postpartum uterine health in cattle

I.M. Sheldon a, , H. Dobson b
a Department of Veterinary Clinical Sciences, Royal Veterinary College, University of London,
Hawkshead Lane, North Mymms, Hatfield AL9 7TA, UK
b Department of Veterinary Clinical Science, University of Liverpool, Leahurst,

Neston, South Wirral CH64 7TE, UK

Abstract
Uterine health is often compromised in cattle because postpartum contamination of the uterine
lumen by bacteria is ubiquitous, and pathogenic bacteria frequently persist causing clinical dis-
ease. The subfertility associated with uterine infection involves perturbation of the hypothalamus,
pituitary and ovary, in addition to the direct effects on the uterus, and appears to persist even after
clinical resolution of the disease. Absorption of bacterial components from the uterus can prevent
the follicular phase LH surge and ovulation. In addition, the first postpartum dominant follicle has a
slower growth rate and secretes less estradiol at the end of the growth phase. There are also localised
ovarian effects of high uterine bacterial growth density, because fewer first dominant follicles are
selected in the ovary ipsilateral than contralateral to the previously gravid uterine horn. Thus, it is
important to diagnose and treat uterine disease promptly and effectively. Examination of the con-
tents of the vagina for the presence of pus is the most useful method for diagnosis of endometritis.
The character and odor of the vaginal mucus can be scored and this endometritis score is corre-
lated with the growth density of pathogenic bacteria in the uterus, and is prognostic for the likely
success of treatment. The challenge for the future is to design prevention and control programs
to reduce the incidence of disease, and understand how the immune and endocrine systems are
integrated.
2004 Elsevier B.V. All rights reserved.
Keywords: Bovine; Postpartum; Uterus; Disease; Ovary

1. Introduction

Postpartum uterine health is more likely to be compromised and clinical disease more
common in cattle than other ruminants, such as sheep (Borsberry and Dobson, 1989;
Regassa and Noakes, 1999; Sheldon et al., 2002c). The risk factors for uterine infections
Corresponding author. Tel.: +44-1707-666282; fax: +44-1707-666239.

E-mail address: msheldon@rvc.ac.uk (I.M. Sheldon).

0378-4320/$ see front matter 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.anireprosci.2004.04.006
296 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306

Table 1
Risk factors for the establishment of uterine bacterial disease in cattle (Markusfeld, 1987; Hussain et al., 1990;
Noakes et al., 1991; Peeler et al., 1994; LeBlanc et al., 2002)
Uterine damage
Stillbirth, twins, dystocia, caesarean section operation
Retained placenta
Delayed uterine involution
Metabolic conditions
Milk fever, ketosis and left displaced abomasum
Balance between pathogenicity and immunity
Disruption of neutrophil function
Type of bacterial flora in the uterine lumen
Progesterone or glucocorticoid administration; early formation of a corpus luteum
Level of hygiene of the environment, cows or calving boxes may be less important

are well established (Table 1), but programs for disease prevention are not. The likelihood
of dystocia or caesarean section may be reduced by careful sire selection, and metabolic
diseases controlled by appropriate nutrition during the dry period and early lactation. How-
ever, the incidence of uterine infection has not changed appreciably over the last 30 years
(Griffin et al., 1974; Sheldon et al., 2002c).
Uterine bacterial infections are important because they disrupt not only the function of
the uterus, but also the ovary and the overarching higher control centres in the hypothala-
mus and pituitary. The inflammatory and immune response to uterine bacterial infection
compromises animal welfare as well as causing subfertility and infertility. Thus, for vet-
erinarians, the diagnosis and treatment of uterine disease is a key component of fertility
control programs. Understanding the mechanisms underlying the effect of uterine bac-
terial contamination and the associated immune response on bovine reproduction is an
important challenge for reproductive biologists in the 21st century (Sheldon and Dobson,
2003).

2. Postpartum uterine health

Before parturition the uterine lumen is sterile and if bacterial invasion occurs, there is
usually resorption of the fetus or abortion (Semambo et al., 1991). During parturition, the
physical barriers of the cervix, vagina and vulva are compromised providing the opportunity
for bacteria to ascend the genital tract from the environment as well as the animals skin and
feces. Indeed, bacterial contamination of the uterine lumen is almost ubiquitous in cattle
(Fig. 1) and notably greater than in other mammals including ruminants such as sheep
(Elliot et al., 1968; Gier and Marion, 1968; Regassa and Noakes, 1999; Sheldon et al.,
2002c). The reasons for the species differences are not clear, as sheep and cattle inhabit
similar environments and the progress of uterine involution is similar (Regassa et al., 2002;
Sheldon et al., 2003). Surprisingly, the level of hygiene of the environment during and
immediately after parturition appears to have little effect on the qualitative or quantitative
uterine bacterial flora (Noakes et al., 1991).
 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 297

Elliot et al (1968)
100 Griffin et al (1974)
Sheldon et al (2002)
Williams et al (unpublished data)
Percent animals with uterine bacteria

80

60

40

20

0
0 10 20 30 40 50 60
Day postpartum

Fig. 1. Proportion of uteri contaminated with bacteria during the first 60 days postpartum drawn from the data of
Elliot et al. (1968), Griffin et al. (1974) Sheldon et al. (2002b) and Williams, Dobson and Sheldon (unpublished
data).

Uterine bacterial contamination in cattle is a dynamic situation, with regular contami-

nation, clearance of bacteria and spontaneous re-contamination during the first few weeks
after parturition, rather than just contamination at the time of calving (Griffin et al., 1974).
Indeed, the proportion of uteri contaminated with bacteria changes little during the first
2 weeks after parturition (Fig. 1). The uterine bacterial contamination is non-specific and
involves a wide range of bacterial species (Griffin et al., 1974; Sheldon et al., 2002c). Based
on the published literature, bacterial isolates can be categorised according to their potential
pathogenicity within the uterus as recognised uterine pathogens associated with uterine en-
dometrial lesions, although Kochs postulates have not been fulfilled for these organisms;
potential pathogens frequently isolated from the bovine uterine lumen and cases of en-
dometritis, but not commonly associated with uterine lesions; or, opportunist contaminants
transiently isolated from the uterine lumen and not associated with endometritis (Laven
et al., 2000; Sheldon et al., 2002c). The recognised uterine pathogens most often associ-
ated with clinical disease are Arcanobacterium pyogenes, Escherichia coli, Fusobacterium
necrophorum and Prevotella melaninogenicus. Indeed, A. pyogenes, F. necrophorum and P.
melaninogenicus act synergistically to enhance the likelihood and severity of uterine disease
(Griffin et al., 1974; Ruder et al., 1981; Olson et al., 1984; Bonnett et al., 1991). Among
their effects, A. pyogenes produces a growth factor for F. necrophorum, F. necrophorum
produces a leukotoxin, and P. melaninogenicus produces a substance that inhibits phagocy-
tosis. The qualitative and quantitative uterine bacterial contamination is dependent on the
balance between bacterial contamination and the animals defence mechanisms.
298 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306

The innate immune system is principally responsible for combating bacterial contami-
nation of the uterus by a range of anatomic, physiological, phagocytic and inflammatory
defences. The vulva, vestibule, vagina and cervix act as physical barriers to bacteria as-
cending the genital tract. Physiological barriers include the copious amounts of mucus
secreted by the vagina and cervix, particularly during estrus. The main phagocytic barrier is
provided by the invasion of neutrophils in response to bacterial challenge, and the inflam-
matory barriers include the non-specific defence molecules such as lactoferrin, defensins
and acute phase proteins. Neutrophils are the earliest and most important phagocytic cell
to be recruited from the peripheral circulation to the uterine lumen, killing internalised
bacteria and contributing to the formation of pus when the phagocytes die. However, the
functional capacity of neutrophils is reduced after parturition in many cattle (Zerbe et al.,
2000); and this may predispose to the establishment of uterine disease. Later, macrophages
are likely to be important in the uterine immune response. Immune cells detect bacterial
components such as endotoxin and peptidoglycan via toll-like receptors, which activate
down-stream signalling to stimulate the release of cytokines including tumour necrosis
factor-alpha (TNF ), and interleukins (IL-1, IL-6, IL-8) (Beutler et al., 2003). These cy-
tokines cause pyrexia, and provide a positive feedback loop to further increase immune
cell mobilization. Pro-inflammatory cytokines released in response to bacterial infection or
tissue turnover, also stimulate hepatic secretion of acute phase proteins. Thus, peripheral
plasma acute phase protein concentrations increase around parturition and then decrease
with the concomitant elimination of bacterial contamination and uterine involution (Sheldon
et al., 2001).
The postpartum return of ovarian cyclic activity impinges on the uterine immune response.
In particular, luteal phase concentrations of progesterone suppress the immune response
making the uterus mores susceptible to bacterial infection (Lewis, 2003). Early ovulation
after parturition and establishment of a progesterone phase before elimination of uterine
bacterial contamination predisposes to the establishment of pyometra (Olson et al., 1984).
Similarly, in postpartum beef cows, intrauterine infusions of A. pyogenes and E. coli when
progesterone concentrations were basal did not cause uterine infections, whereas all cows
developed infections when the bacteria were infused after the onset of luteal function and
progesterone concentrations had begun to increase (Del Vecchio et al., 1994). In addition,
an early ovulation and formation of a corpus luteum after calving (<19 days versus >32
days) increased the risk for prolonged luteal cycles before service in dairy cattle (Opsomer
et al., 2000). Conversely, it is difficult to establish experimental uterine infections when
estrogens dominate the uterus (Seals et al., 2003). However, the mechanisms underlying
these observations are not clear. For example, peripheral blood or uterine neutrophil cell
function in cattle is not consistently upregulated by exogenous estradiol, nor suppressed by
progesterone (Subandrio et al., 2000).
It is important to differentiate between the contamination of the uterine lumen with a
range of bacteria and the persistence of pathogenic bacteria with the establishment of uter-
ine disease, which might be described as uterine infection. Metritis is a severe inflammatory
reaction involving all layers of the uterus: endometrium, submucosa, muscularis and serosa
(BonDurant, 1999). Clinically, metritis is characterised by pyrexia (39.5 C) up to 10
days postpartum with a fetid purulent vulval discharge, often associated with delayed in-
volution of the uterus. The incidence of metritis using this definition was 18.5% in dairy
 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 299

cattle (Drillich et al., 2001). However, there is a wide variation between farms with the in-
cidence ranging up to 40% (Markusfeld, 1987). Endometritis is a superficial inflammation
of the endometrium, extending no deeper than the stratum spongiosum (BonDurant, 1999).
Histologically, there is some disruption of the surface epithelium, infiltration of inflamma-
tory cells and vascular congestion. However, clinically endometritis is characterised by the
presence of pus in the vagina, 21 days or more postpartum, and often associated with de-
layed uterine involution (Sheldon and Noakes, 1998). Using this definition of the presence
of purulent vaginal mucus, the incidence of endometritis is about 1020% in dairy cattle
(Borsberry and Dobson, 1989; LeBlanc et al., 2002).

3. Effect of uterine health on fertility

Infection causes damage to the uterine tissues and features of endometrial damage such
as increased inflammation in the stratum compactum are associated with poor reproductive
performance (Bonnett et al., 1993). Similarly, the presence of A. pyogenes or anaerobic
bacteria is a risk factor for reduced fertility. Endometritis causes infertility at the time the
uterine infection is present and subfertility even after successful resolution of the disease.
In typical studies the conception rate is about 20% lower for cows with endometritis, the
median calving to conception interval 30 days longer and there are 3% more animals culled
for failure to conceive (Borsberry and Dobson, 1989; LeBlanc et al., 2002). Furthermore,
cows with a purulent cervical discharge have lower submission rates (McDougall, 2001).
As well as the effects on fertility, uterine infection is associated with lower milk yields
particularly if associated with retained placenta (Esslemont and Kossaibati, 2002; Sheldon
et al., 2004). The financial losses associated with uterine infection are dependent on the cost
of treatment, reduced milk yield, and subfertility. In the UK, the direct costs of treatment and
reduced milk yield of a cow with uterine disease were 62, and the indirect costs of a longer
calving interval, increased culling rate, extra inseminations and lower estrus expression
were 69 per cow (Esslemont and Kossaibati, 2002). The direct costs of uterine disease
were estimated at 725 per 100 cows per annum for 21 dairy herds where data was recorded
intensively between 1989 and 1999 (Esslemont and Kossaibati, 2002). There are 2.2 106
dairy cows in the UK (http://statistics.defra.gov.uk/esg/publications/auk/2002/default.asp),
and projecting the direct costs of uterine disease on a national basis would represent a cost
of 16 million.

4. Effect of uterine health on ovarian function

The subfertility associated with uterine infection involves disruption of ovarian function
as well as the effects of uterine damage, and appears to persist even after clinical resolu-
tion of the disease. Presumably uterine damage disrupts the luteolytic mechanism to cause
the prolonged postpartum luteal phases, as determined by progesterone profiles, associated
with retained placenta (odds ratio (OR) 3.5), metritis (OR 11.0) or endometritis (OR 4.4)
(Opsomer et al., 2000). However, these epidemiological studies also indicate that uterine
infection is a risk factor for delayed ovulation (OR 4.5) (Opsomer et al., 2000). Similarly,
300 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306

Table 2
Endometritis clinical score
Description Score

Mucus character
Clear or translucent mucus 0
Clear or translucent mucus containing flecks of white pus 1
<50 ml exudate containing <50% white or cream pus 2
>50 ml exudate containing 50% white, cream or bloody pus 3
Mucus odor
No unpleasant odor 0
Fetid odor 3
The vaginal mucus is scored for character and odor using the given descriptions. The two scores are summed to
give the endometritis score.

when endometritis was monitored by clinical evaluation (see later and Table 2) and ovarian
function by transrectal ultrasonography, fewer cows with endometritis score 6 compared
with scores <3 ovulated the first postpartum dominant follicle (8% versus 40%, n = 113,
P < 0.05). Furthermore, ovarian function is perturbed in cattle with greater uterine bacterial
contamination after parturition (Sheldon et al., 2002c). The first postpartum dominant folli-
cle has a slower growth rate and secretes less estradiol at the end of the growth phase (Fig. 2).
The mechanisms underlying these observations are multi-level, affecting the hypothalamus,
pituitary and ovary.
Examination of the effect of uterine infection on hypothalamic and pituitary function
has focussed on the role of endotoxin, which is a component of Gram-negative bacterial
cell walls. Indeed, endotoxin can be absorbed from the postpartum uterine lumen into the
peripheral circulation and plasma endotoxin concentrations are increased in cows with spon-
taneous postpartum uterine infections (Peter et al., 1990; Mateus et al., 2003). Spontaneous
uterine infection does not appear to alter the first postpartum transient increase in FSH con-
centration and follicle wave emergence (Sheldon et al., 2002c). However, infusion of E. coli
endotoxin into the uterine lumen of heifers prevents the expected pre-ovulatory LH surge
and ovulation, causing persistence of follicular cysts (Peter et al., 1989). Indeed, high doses
of endotoxin perturb the follicular phase rise in peripheral plasma estradiol concentration
and the LH surge in a range of species, and the sheep has been used as a model to study
the underlying mechanisms (Karsch et al., 2002). Endotoxin inhibits pulsatile LH secretion
from the pituitary, suppressing hypothalamic GnRH secretion and reducing the pituitary
responsiveness to endogenous or exogenous GnRH pulses. However, in some animals, en-
dotoxin blocks the pre-ovulatory increase in peripheral plasma estradiol concentration even
in the face of normal LH pulsatility (Battaglia et al., 2000). This observation suggests that
there may also be direct effects of endotoxin on the ovary.
A further indication that there may be direct effects of uterine infection on the ovary is the
unequal distribution of postpartum follicular growth in cattle. There are fewer animals with
a follicle >8 mm diameter in the ovary ipsilateral to the previously gravid uterine horn than
the contralateral ovary (26.1% versus 49.6%, n = 284, P < 0.001), between 14 and 28 days
postpartum (Sheldon et al., 2000). This could be a carry over effect of pregnancy, but at least it
is not due to the regressing corpus luteum of pregnancy (Sheldon et al., 2002a). Furthermore,
 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 301

Fig. 2. Mean S.E.M. (a) first dominant follicle diameter, and (b) plasma estradiol concentrations between day
7 and 16 postpartum for cows in which there was a standard (, n = 50) or high (, n = 20) uterine bacterial
contamination on day 7 as determined by collection of uterine lumen swabs for aerobic and anaerobic culture
and semi-quantitative evaluation of the number of bacterial colonies. Within a day, values differ between bacterial
contamination category P < 0.05, P < 0.01, P < 0.001. Graphs redrawn from Sheldon et al. (2002b,c).

these ovarian differences decline with increasing interval postpartum, in parallel with uterine
involution and elimination of bacterial contamination. These observations are of interest
because although less frequent, the presence of a dominant follicle in the ovary ipsilateral to
the previously gravid uterine horn is a marker of subsequent fertility (Bonnett et al., 1993;
Sheldon et al., 2000). It is likely that this improved fertility associated with the presence of a
dominant follicle in the ovary ipsilateral to the previously gravid uterine horn reflects uterine
health. When uterine bacterial growth density is high at 7 or 21 days postpartum, fewer first
or second dominant follicles are selected in the ipsilateral than the contralateral ovary,
respectively, compared with animals that have a lower uterine bacterial growth density
(Sheldon et al., 2002c). We hypothesise, therefore, that the immune response to uterine
infection has a localised effect on ovarian function. It may be that the larger previously gravid
uterine horn can contain more bacteria or that the greater uterine venous vasculature delivers
302 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306

more bacterial products to the ipsilateral ovary. A range of pro-inflammatory molecules,

including the cytokines TNF , IL-1 and IL-6, are released by immune cells in response
to bacterial products such as endotoxin (Miller et al., 1997). So, bacterial products may
exert their effect on the bovine ovary directly or via these intermediaries. Indeed, TNF
suppresses granulosa and theca cell estradiol secretion in vitro (Spicer, 1998).

5. Management of postpartum uterine health

Irrespective of the mechanisms underlying the subfertility caused by uterine infection, it

is important for veterinarians to diagnose and treat uterine disease promptly and effectively.
Diagnosis of metritis within the first 10 days postpartum is associated with the presence
of pyrexia, fetid pus within the uterine lumen, vagina or discharging from the vulva, and
delayed uterine involution. Solely monitoring the rectal temperature of dairy cows to diag-
nose metritis is less reliable than including an examination for abnormal uterine discharge
because pyrexia is not consistently associated with pathogenic bacteria in the uterine lumen
(Sheldon et al., 2004). The most important line of treatment for metritis is parenteral an-
tibiotic. Although oxytetracycline is widely used, it is not the optimum treatment because
there is evidence for bacterial resistance to this antimicrobial and high concentrations of
the antibiotic are required to inhibit bacterial growth (minimum inhibitory concentration,
MIC) when tested in vitro (Sheldon et al., in press). Indeed, cephalosporins have the lowest
MIC values when tested against recognised pathogenic bacteria collected from the uterus
of cows with clinical disease. Furthermore, dairy cows at risk of metritis are less likely to
develop disease if treated with ceftiofur (Risco and Hernandez, 2003).
The most accurate method for diagnosis of endometritis is examination of the contents
of the vagina for the presence of pus (Bretzlaff, 1987; Sheldon and Noakes, 1998; LeBlanc
et al., 2002). The vagina can be examined manually, withdrawing the mucus for inspection
or by using a vaginoscope, which allow inspection of the mucus flowing out of the cervix.
However, manual vaginal examination is probably more practical and even using simple
techniques to clean the vulva before inspection does not cause uterine bacterial contamina-
tion or inflammation (Sheldon et al., 2002b). The character and odor of the vaginal mucus
can be scored to produce an endometritis clinical score. Vaginal mucus is assessed for color,
proportion and volume of pus, and odor resulting in an endometritis clinical score ranging
from 0 to 6 (Table 2). The endometritis clinical score reflects the bacterial growth density
of recognised uterine pathogens (r > 0.44, P < 0.01), but not other bacteria (Williams and
Sheldon, 2003). Thus, the endometritis clinical score is a useful indicator for veterinarians
of the presence and growth density of pathogenic bacteria contaminating the postpartum
uterine lumen (Fig. 3). In addition, endometritis clinical score is prognostic for the likely
outcome of treatment (Sheldon and Noakes, 1998). The success rate for cure of endometritis
over a 2-week period is 44% if the vaginal mucus is purulent with a fetid odor, but 78% if
there are only flecks of pus in the mucus. Interestingly, the mucus containing only flecks of
pus (score 1) has similar numbers of bacteria to clear, normal mucus (score 0) 3 or 4 weeks
postpartum and may reflect the healing stages of uterine infection.
The rationale for the choice of treatment for endometritis has been widely discussed
(Bretzlaff, 1987; Sheldon, 1999). Briefly, administration of prostaglandin F2 is the treat-
 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306 303

Fig. 3. Higher endometritis clinical score is associated with greater mean S.E.M. bacterial growth density of
recognised pathogenic (), but not potential pathogenic ( ) or opportunist contaminant () bacteria in the uterine
lumen. Endometritis score based on evaluation of vaginal mucus character and odor (see Table 2). Uterine bacterial
growth density determined by collection of uterine lumen swabs for aerobic and anaerobic culture, identification
of bacterial colonies and semi-quantitative evaluation of the number of colonies on the plate as follows: 0: no
growth; 1: <10 colonies; 2: 10100 colonies; 3: 101500 colonies; and 4: >500 colonies (Noakes et al., 1991).
Bacterial growth density differs significantly from endometritis score 0, within pathogenicity group P < 0.01,
P < 0.001 (Williams, Fischer, England, Noakes, Dobson and Sheldon, unpublished observations).

ment of choice for cases of endometritis in which a corpus luteum is present. Whereas, in
the absence of a corpus luteum, a range of intrauterine treatments have been administered
including antiseptics and antibiotics. Estradiol at doses of 510 mg per animal has been used
therapeutically for postpartum endometritis and is as effective as prostaglandin F2 (Pepper
and Dobson, 1987; Sheldon and Noakes, 1998); both are superior to the spontaneous re-
covery rate of untreated animals. However, the interval from treatment to conception was
longer with estradiol treatment than prostaglandin F2 or intrauterine antibiotic (Sheldon
and Noakes, 1998).

6. Conclusions

In cattle, postpartum contamination of the uterine lumen is ubiquitous, and persistence

of pathogenic bacteria commonly causes clinical disease. The consequence is subfertility
associated with delayed ovulation after parturition, persistence of the corpus luteum once
it forms, and lower conception rates. Thus, effective diagnosis and treatment of uterine
disease is essential in reproductive control programs. The challenge for the future is to
use our knowledge of the risk factors for uterine disease to design prevention and control
programs to reduce the incidence of disease. Uterine infections not only damage the uterus,
304 I.M. Sheldon, H. Dobson / Animal Reproduction Science 8283 (2004) 295306

but also suppress hypothalamic GnRH and pituitary LH secretion, and have localised effects
on ovarian function. The mechanisms underlying the effects of infection on the reproductive
tract involve the immune or inflammatory response. Conversely, the reproductive endocrine
environment can modulate the immune response and understanding the integration of the
immune and endocrine systems is an important emerging discipline.

Acknowledgements

The authors work is supported by the Wellcome Trust (Project Grant No. 064155), the
Biotechnology and Biological Sciences Research Council (BBSRC, Grant No. S19795),
the Royal College of Veterinary Surgeons Trust, and a Royal Veterinary College Internal
Grant.

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