Advances in Bovine Reproduction and Embryo Technology

Reproductive tract defense and disease in postpartum dairy cows

Stephen J. LeBlanc
a,
*, Takeshi Osawa
b
, Jocelyn Dubuc
c
a
Population Medicine, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
b
Iwate University, Morioka, Japan
c
Facult de Mdecine Vtrinaire, Universit de Montral, C.P. 5000, Saint-Hyacinthe, Qubec, J2S 7C6, Canada
Received 10 May 2011; received in revised form 3 July 2011; accepted 5 July 2011
Abstract
This paper briey reviews recent data and concepts on the development and mitigation of infection and inammation in the
reproductive tract of dairy cows during the rst 2 mo after calving. The incidence of metritis is typically between 10 and 20%, of clinical
endometritis or purulent vaginal discharge (PVD) approximately 15%, and of subclinical or cytological endometritis a further 15%.
Worse postpartum negative energy balance is associated with more severe or prolonged uterine inammation. Changes in feed intake,
expression of genes for pro-inammatory cytokines, notably interleukin (IL) 1, IL6 and IL8, circulating concentrations of beta-
hydroxybutyrate (BHBA) or nonesteried fatty acids (NEFA), and innate immune function precede both metritis and endometritis by
several weeks. Infections with Escherichia coli and Arcanobacterium pyogenes are associated with both metritis and PVD. There are
new data to suggest that specic virulence factors in E. coli associated with adherence may be important in metritis and PVD.
Cytological endometritis and PVD are overlapping but largely distinct conditions, and there are emerging data that cervicitis exists both
concurrent with and separate from endometritis. Much remains to be learned about what initiates and sustains harmful inammation of
the reproductive tract. Such information is necessary to develop effective treatments for the various forms of disease and, more
importantly, to develop means to prevent endometritis and cervicitis. In particular, vaccination against specic uterine pathogens and
interventions to modulate innate immune response appear to be important avenues for investigation. Presently, commonly recommended
best management practices for cows in the transition period are likely to be helpful to mitigate the risk of reproductive disease.
2011 Elsevier Inc. All rights reserved.
Keywords: Metritis; Endometritis; Uterus; Uterine inammation; Purulent vaginal discharge; Cattle
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
2. Origins of reproductive tract disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
3. Immune defenses in the uterus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1611
4. Role of pathogens versus immune defense in reproductive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1612
4.1. Escherichia coli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613
4.2. Arcanobacterium pyogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613
5. Emerging understanding of infection and inammation in the reproductive tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613
6. Treatment of reproductive tract disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1614
7. Prevention of reproductive tract disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1615
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1616
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1616
* Corresponding author. Tel.: 1 519 824 4120 ext. 54594.
E-mail address: sleblanc@uoguelph.ca (S.J. LeBlanc).
Available online at www.sciencedirect.com
Theriogenology 76 (2011) 16101618
www.theriojournal.com
0093-691X/$ see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.theriogenology.2011.07.017
1. Introduction
Essentially all peripartum dairy cattle have bacterial
contamination of the uterus for 2 to 3 wk after calving;
a substantial minority have at least one form of pathol-
ogy of the reproductive tract, ranging from overt sys-
temic disease to subtle (but important) chronic inam-
mation. This high risk of disease is attributable, in part,
to reduced immune function from approximately 2 wk
before to 3 wk after calving. The severity of concurrent
insulin resistance, reduced feed intake, negative en-
ergy balance, and weight loss contribute to the de-
gree and duration of reduced immune defense. Innate
immunity from neutrophils is a primary means of
immune response in the uterus, and neutrophil mi-
gration and phagocytic and oxidative activity are
associated with the risk of retained placenta (RP) [1],
metritis, and endometritis [2]. Although metabolic
(e.g., ketosis and fatty liver) and uterine diseases are
excessively common, the determinants of disease
risk between herds or even within a herd, in which
cows apparently have similar nutritional and man-
agement experiences, are unclear. This paper briey
reviews recent data and concepts on the development
and mitigation of infection and inammation in the
reproductive tract of dairy cows during the rst 2 mo
after calving.
2. Origins of reproductive tract disease
There is abundant evidence that the vast majority of
cows have bacterial contamination of the uterus for 2 to 3
wk after calving [3], including bacteria associated with
uterine disease. Nevertheless, the lactational incidence of
metritis is typically between 10 and 20%, of clinical en-
dometritis or PVD approximately 15%, and of subclinical
or cytological endometritis a further 15%. In a recent large
eld study [4], among almost 1600 cows from three
farms, 37% had at least one of metritis, PVD, or cytolog-
ical endometritis. Although these incidence risks are un-
desirably high, they represent less than half the proportion
of cows that have bacterial contamination of the uterus
soon after calving. What then determines whether an in-
fected cow will develop systemic or more subtle disease,
or progress through normal involution and not experience
conditions that may impair fertility? Attention has focused
on the role of the immune system in clearing uterine
contamination. It is clear that many or most dairy cows
experience several weeks of substantial reduction of
immune function around calving, typically reaching
a nadir approximately 1 wk postpartum [3,5], al-
though recent data have suggested that phagocytic
overall power (the product of neutrophil activity,
function, and circulating numbers) may not be as
impaired as commonly thought [6]. The precise
causes of impaired immune function in transition
cows are unclear, although the peripartum drop in
caloric, vitamin and mineral intake, negative energy
balance and mobilization of body fat and protein,
dramatic changes in progesterone and estrogen con-
centrations in late gestation, and the massive tran-
sient increase in cortisol concentrations at calving,
appear to contribute [7,8]. The hormonal and nutrient
repartition effects of lactation appear to exert an
immunosuppressive effect beyond those associated
with parturition [9]. Cows in greater negative energy
balance have more pronounced impairment of at least
some immune functions [2]. Cows with RP, metritis,
or endometritis have earlier and more profound im-
pairments of innate immunity, starting several weeks
before disease occurs [2,1012].
3. Immune defenses in the uterus
The mechanisms of impairment of immune defense
in the mammary gland in the transition period have
been described [13] and may be a useful reference for
the uterus, which also depends heavily on innate im-
munity, largely from neutrophils. Less is known about
the determinants of uterine health or how resistance to
uterine disease may be enhanced through animal man-
agement. Uterine immunity in dairy cows has recently
been reviewed [14,15] and readers are directed to these
papers for details. Cows with severe metritis eat less (2
to 6 kg of dry matter per day) than healthy cows in the
2 to 3 wk preceding clinical signs of metritis [16].
Lower feed intake is associated with increased circu-
lating concentrations of NEFA, which contribute to the
risk of fatty liver, which in turn is associated with
impaired neutrophil function [17]. Additionally, NEFA
have been shown to inhibit neutrophil function in vitro
[18]. Due to both high metabolic demands and patho-
gen challenges, cattle also routinely experience sub-
stantial oxidative stress in early lactation [19], which
also contributes to a pro-inammatory state that may
not be effective for immune defense [20].
Sheldon et al [15] have demonstrated that toll-like
receptor 4 (TLR4) which binds endotoxin (lipopolysa-
charide; LPS), is a key player in the inammatory
cascade in the bovine uterus. They have also shown that
both prostaglandin type switching (F series, luteolytic)
to E series (luteotrophic) in response to LPS and the
presence of TLR4 complexes in ovarian follicles may help
1611 S.J. LeBlanc et al. / Theriogenology 76 (2011) 16101618
to explain links between uterine infection and inamma-
tion and impaired ovulation, steroidogenesis, and luteal
regression (see [15] for details of their framework of
infection and inammation). There is evidence in other
species that fatty acids may bind to TLR4 and induce a
pro-inammatory cascade [20], which may be an impor-
tant link between lipid metabolism and innate immune
function.
Retained placenta is a disease of immune function,
with changes in neutrophil function and IL8 concentra-
tions 2 wk before calving [21]. Recruitment and func-
tion of an adequate ux of neutrophils to the uterus is
also important in the days after calving for clearance of
bacteria and lochia and prevention of subsequent endo-
metritis [22]. However, there is evidence that substan-
tially higher, apparently excessive, inammatory status
in the rst [23] and perhaps second [24] week postpar-
tum is associated with endometritis. Specically, there
was substantially greater expression of genes for the
pro-inammatory cytokines IL1A and IL1B, their re-
ceptor IL1R2, and TLR4, as well as a higher ratio of
IL1 to the anti-inammatory IL10 in Week 1 postpar-
tum among four cows with cytological endometritis at
Week 5 postpartum and that failed to become pregnant
during that lactation, relative to four cows without endo-
metritis that were pregnant at rst AI [23]. Additionally,
increased expression of pro-inammatory cytokines IL6,
IL8, and interferon (IFN), nuclear factor B (NFKB1)
which is a transcription factor for the pro-inammatory
cytokines above, and IL12A within 2 wk postpartum ap-
pears to be associated with greater uterine inammation at
that time [24] and possibly later.
Measurable changes were noted in phagocytosis,
TNF, and IL6 prepartum in cows with postpartum
endometritis [25], weeks before disease became mani-
fest, coincident with the onset of insulin resistance and
lipolysis, at least in cows at higher risk of disease.
Cows in greater negative energy balance, and in par-
ticular those that go on to develop metritis or endome-
tritis, have more pronounced impairment of at least
some immune functions [2]. Cows in a greater degree
of negative energy balance prepartum, as evidenced by
higher NEFA concentrations, were 80% more likely to
have RP, and that those with lower circulating vitamin
E were at greater risk of RP [26]. This supports the
notion that severe negative energy balance may con-
tribute to impairment of immune function. This concept
is further supported by recent evidence that worse post-
partum negative energy balance is associated with more
severe or prolonged uterine inammation and impaired
tissue repair capacity, based on their respective changes
in gene expression [27]. Among other genes, those for
IL1 receptor and IL8 and its receptor (IL8R), which
are associated with uterine inammation, were substan-
tially more expressed in cows with severe NEB.
Hammon et al [2] reported that cows with metritis or
cytological endometritis had worse neutrophil myelo-
peroxidase activity, a measure of killing capacity after
phagocytosis, than did unaffected cows, and that these
changes preceded disease by several weeks. They also
reported associations between increasing NEFA con-
centration, especially in the last week before calving,
and reduced neutrophil myeloperoxidase activity. Ad-
ditionally, there was an association between less feed
intake in the 3 wk before calving and reduced neutro-
phil killing capacity from 1 wk before to 3 wk after
calving. Similarly, Galvo et al [28] found associations
of increased concentrations of BHBA and NEFA near
calving with the risk of metritis and cytological endo-
metritis. Cows that later developed metritis or endome-
tritis had less neutrophil glycogen concentrations than
healthy cows [28]. Huzzey et al [16] did not evaluate
measures of immune function, but similarly showed
that cows that developed metritis had reduced feed
intake compared to unaffected cows starting 2 wk be-
fore calving. Taken together, these studies support the
evidence from mechanistic studies [27] of important
interactions between energy and lipid metabolism and
immune function in peripartum dairy cows, and point to
the importance for reproductive performance of unre-
stricted access to feed, though not excessive caloric
consumption, in the 3 wk before calving [29]. The data
on the association of prepartum feed restriction with
uterine health are contradictory [16,29] and based on
relatively small numbers of cows per study.
4. Role of pathogens versus immune defense in
reproductive disease
Metritis and endometritis are commonly associated
with mixed bacterial infection of the uterus, often in-
cluding anaerobes, notably Fusobacterium and Pre-
votella species. Current evidence shows that E. coli is
particularly prevalent in the rst week postpartum and
is associated with metritis and with increased risk of
infection with A. pyogenes in Weeks 2 and 3 [30,31].
Infection with A. pyogenes that persists beyond 3 wk
postpartum has been associated with endometritis. Con-
versely, uterine inammation may be present in cows
with no bacteria isolated concurrent with the diagnosis
of inammation [15,22]. Until recently, these patho-
gens have been assumed to be generic or not specif-
1612 S.J. LeBlanc et al. / Theriogenology 76 (2011) 16101618
ically adapted to or associated with metritis or endo-
metritis. Recent studies have explored the potential for
specic virulence factors or strains of bacteria to be
associated with uterine disease.
4.1. Escherichia coli
Silva et al [32] examined 72 E. coli isolates from 12
healthy cows and 18 with metritis and found no asso-
ciations of phylogenetic group or specic virulence
factors with disease, although strain associations with
herd were noted. Sheldon et al [33] used 114 E. coli
isolates from 64 cows from one herd sampled between
Weeks 1 and 4 after calving; there was an association of
phylogenetic group B2 with metritis. Escherichia coli
from cows with metritis were more adherent and inva-
sive to endometrial epithelial and stromal cells, despite
a lack of 16 genes typically associated with these fac-
tors in other pathogenic E. coli. These strains, coined
endometrial pathogenic E. coli or EnPEC, or their
LPS, could reproduce inammation through TLR-4 in a
mouse model. In cell culture, LPS from EnPEC induced
a greater inammatory response than LPS from strains
not associated with metritis. These results pointed for
the rst time to possible variables in the type of E. coli
that may contribute to the risk of metritis. Soon after,
Bicalho et al [34] reported on the same question with a
large sample of 611 E. coli isolates from 374 cows in
four herds collected in the rst week after calving that
considered 32 potential virulence genes. They found six
genes, mH, astA, cdt, kpsMII, ibeA, and hlyA, most
associated with adhesion or invasion, associated with
both metritis and clinical endometritis. The mH ad-
herence gene was present in 87% of uterine E. coli and
in 29% of cows and was strongly associated with in-
creased risk of disease. In fact, metritis was six times
more likely in cows with E. coli with mH relative to
culture-negative cows, and the risk of metritis was
highest when this gene was present with one of the
other ve virulence genes identied. The presence of E.
coli with mH, cdt, or astA genes at Week 1 postpar-
tum was associated with 3 to 5 times greater odds of
purulent vaginal discharge at 4 wk postpartum.
4.2. Arcanobacterium pyogenes
Arcanobacterium pyogenes is consistently, though
not always, associated with purulent vaginal discharge
[31,35]. The susceptibility of A. pyogenes to antimicro-
bial drugs is variable [3638], but the clinical relevance
of this is unclear. The presence of the adherence gene
mA has been associated with A. pyogenes from cows
with metritis [37]. Arcanobacterium pyogenes secrete
the exotoxin pyolysin [39]. Based on in vitro and in
vivo inoculation with killed bacteria or bacteria-free
ltrate, it appears that a heat-labile component rather
than A. pyogenes itself may be responsible for inducing
uterine inammation, but that intact endometrium in
healthy animals may be protective [40]. Therefore, al-
though A. pyogenes are commonly found in cows with
metritis, and especially with endometritis, it is not clear
that there are specic strains or virulence factors of A.
pyogenes associated with uterine disease [32].
5. Emerging understanding of infection and
inammation in the reproductive tract
It is clear that PVD is associated with substantial
reductions in subsequent reproductive performance
[4,4143]. It was assumed that this discharge found in
the cranial vagina, or less commonly, observed exter-
nally on the vulva or tail, resulted from endometritis.
There are data that demonstrate the association between
the nature of vaginal content and the density of putative
bacterial pathogens in the uterus [3]. However, we
recently reported [44] only fair agreement between
PVD and endometritis dened by uterine cytology.
This leads to the question of the source of the pus in the
vagina, if it is not always from the uterus. There are
emerging data to indicate that cervicitis exists as a
distinct condition, though sometimes concurrent with
endometritis, which is associated with both separate
and additive impaired reproductive performance [45
47].
Metritis and endometritis are associated with uterine
infection with E. coli in the rst week after calving, and
PVD is associated with A. pyogenes infection that per-
sists beyond 2 to 3 wk postpartum [30,31,35,48]. Con-
versely, there are conicting data [22, Osawa and
LeBlanc, unpublished data] regarding the association of
bacterial infection with cytological endometritis. Pre-
ventive antibiotic treatment at calving reduced the prev-
alence of PVD, but not of cytological endometritis, at 5
wk postpartum [4]. In the same study, the prevalence of
PVD was three-fold greater (15 vs 5%) in cows with
RP, dystocia or twins, but the prevalence of cytological
endometritis was the same (13%) in both groups. The
relationship between bacteria in the uterus and endo-
metrial inammation has been described [22,49] but is
not well understood, and it has been suggested that
endometrial inammation may persist after bacterial
pathogens are no longer detected [15].
Endometrial inammation appears to be an inevita-
ble and necessary part of involution, but down-regula-
1613 S.J. LeBlanc et al. / Theriogenology 76 (2011) 16101618
tion of the immune response within a few weeks after
calving appears to be important, and apparently exces-
sive inammation even in the rst week postpartum is
associated with persistent and deleterious inammation
1 mo later [23]. It is not clear if excessive or persistent
inammation is provoked by the type (species, strain or
virulence factors) or quantity of bacterial infection, by
genetic or metabolic inuences on immune function
and regulation, or both. Although the risk factors and
pathophysiology of PVD and cytological endometritis
are at least partly shared, uterine and cervical tissue
trauma and bacterial infection appear to have a greater
role in PVD, whereas regulation of the immune re-
sponse appears to have a greater role in cytological
endometritis. These hypotheses require further investi-
gation, both mechanistically and under eld conditions.
Endometritis diagnosed based on uterine cytology is
common and consistently associated with substantial im-
pairment of reproductive performance. There is good
agreement that 5 to 8 % neutrophils of the total leuko-
cytes and endometrial cells in an endometrial smear at 4 to
5 wk postpartum identies cows with an undesirable level
of inammation (Table 1 and Fig. 1). However, it may be
that not all uterine inammation after 3 to 5 wk postpar-
tum, coincident with the expected completion of gross
uterine involution [50], is undesirable. Interestingly, in an
observational study of 201 cows in one herd in which
cytobrush cytology was conducted 4 h after the rst AI
(median 78 d postpartum), cows with no neutrophils
had signicantly less probability of pregnancy to that AI
(39%) than cows with 1 to 15% neutrophils (58%); how-
ever, cows with 15% neutrophils were not statistically
different (30%) from those with 0% neutrophils [51].
These data suggest that perhaps in cows, as in mares,
insemination provokes an inammatory reaction that may
be physiologic rather than pathologic [52].
6. Treatment of reproductive tract disease
Treatment of reproductive tract disease has been
reviewed [50]. There is consistent evidence that cows
Table 1
Summary of studies of the prevalence of endometritis diagnosed by cytology in postpartum dairy cows.
Reference No. cows DIM* Diagnostic
method
Prevalence Impact
Median DTP
Unaffected Endometritis
Kasimanickam et al
2004 [57]
228 in 2 herds 20 to 33 Cytobrush 18%
neutrophils
35% (excluding cows with
PVD the day before)
112 141
Gilbert et al 2005
[58]
141 in 5 herds 40 to 60 Flush 5%
neutrophils
53% (no vaginal
examination)
118 206
Barlund et al 2008
[59]
221 in 8 herds 28 to 41 Cytobrush 8%
neutrophils
12% (not excluding cows
with PVD)
121 145
Galvo et al 2009
[54]
202 (subset of a clinical
trial) in 1 herd
48 to 54 Flush 5%
neutrophils
29% (not excluding cows
with PVD)
112 126
Galvo et al 2009
[55]
406 in 1 herd 32 to 38 Flush 7%
neutrophils
38% (not excluding cows
with PVD)
121 151
Dubuc et al 2010
[44]
2072 in 6 herds 32 to 38 Cytobrush 6%
neutrophils
20% (13% cytological
only and 7% both
cytological and PVD)
132 148 (cytological
only) 195 (both
cytological and
PVD)
* DIM, days in milk.
All differences in DTP P 0.05 in survival analysis.
DTP, days from calving to pregnancy, accounting for censored animals (those that did not become pregnant).
PVD, purulent vaginal discharge.
Fig. 1. Distribution of cytobrush endometrial cytology in cows from
six herds examined at Week 5 (n 2072) and at Week 8 (n 2022)
postpartum. Data are from Dubuc et al 2011 [4].
1614 S.J. LeBlanc et al. / Theriogenology 76 (2011) 16101618
with PVD have improved reproductive performance
when treated with a single intrauterine (IU) infusion of
cephapirin approximately 1 mo before rst insemina-
tion, relative to receiving no treatment [41,43,53]. In-
trauterine infusion of ceftiofur at approximately 6 wk
postpartum, between two injections of prostaglandin
(PG) F
2
2 wk apart, reduced the prevalence of uterine
bacterial infection with E. coli from 10 to 2% and
with A. pyogenes from 6 to 1% among cows with
PVD, but did not improve the probability of preg-
nancy or the rate of pregnancy in the rst 310 d
postpartum [54]. In the same study, it is notable that
only 41% of cows with PVD had any bacteria cul-
tured from the uterus at the time of diagnosis. These
data support the assertion that the association be-
tween cytological endometritis and uterine bacterial
infection is weak or non existent [47].
Numerous less recent studies reported that one or
two injections of PGF
2
improved reproductive perfor-
mance or produced clinical outcomes similar to IU
antibiotics. However, in studies of cows with risk fac-
tors for, or with endometritis, PGF
2
consistently did
not improve reproductive performance; however, many
of these studies lacked valid case denitions, statistical
power, or both [49]. We recently conducted an exten-
sive clinical trial with more than 2000 cows, including
over 600 with PVD, cytological endometritis or both, in
which cows were randomly assigned to receive PGF
2
at Weeks 5 and 7 postpartum, or remain as untreated
controls [4]. Overall, or among cows with reproductive
tract disease, there was no difference in time to preg-
nancy between PGF
2
-treated and control cows, which
is similar to the ndings of Galvo et al [55] for cyto-
logical endometritis.
Taken together, it appears that IU cephapirin is ben-
ecial in cases of PVD, which may be associated with
cervicitis or endometritis, but that PGF
2
, as commonly
employed, is not. Nevertheless, there is one study [56]
that reported a benet to reproductive performance of
either PGF
2
or IU cephapirin relative to no treat-
ment, and further investigation of rapid cow-side
diagnostic tests and treatment for cytological endo-
metritis are needed. Development of such treatments
will require a better understanding of the factors that
initiate and sustain endometrial inammation, but
investigation of anti-inammatory approaches to
treatment are of interest.
7. Prevention of reproductive tract disease
Presently, there are few management practices or
interventions that can be supported specically to pre-
vent metritis or endometritis. Based on current under-
standing of these diseases, the general objective is to
support and maintain innate immune function. It is
thought that enhancing immunity reduces the risk that
the inevitable inammation and bacterial contamina-
tion after calving progress to metritis, endometritis, or
cervicitis. Excessive negative energy balance and cir-
culating NEFA concentrations, and excessive insulin
resistance contribute to a state of metabolic- or meta-
inammation that may impair neutrophil function [20].
There is a great deal still to be learned about the
determinants of immune function in dairy cattle in the
transition period, and in particular, about specic
means to prevent uterine disease. Nevertheless, Table 2
proposes management practices generally recom-
Table 2
Summary of management practices and monitoring targets to reduce the risks of metritis, purulent vaginal discharge and cytological
endometritis in dairy cows.
Recommendation Reference(s)
Prevent consumption of dietary energy above requirement in the far-off dry period (Weeks 8 to 3 before calving) [60,61]
Provide for unrestricted feed bunk access (i.e., all cattle able to eat at the time of fresh feed delivery) i.e., 75 cm of
linear bunk space per cow, or no more than 4 cows per 5 headlocks
[62,63]
Provide space to allow for lying approximately 12 h/d or 1 free stall/cow or 10 m
2
of bedded pack/cow [63,64]
Minimize pen moves and social group changes [63]
Build dry cow and early lactation pens for approximately 140% of the expected average number of calvings per
month
[63]
Provide heat abatement (fans and sprinklers) when the temperature-humidity index exceeds 72 [65]
Manage nutrition so that cows calve at a body condition score of 3.0 or 3.25 (on the 5-point scale), and maintain a
minimum body condition of 2.5
[66]
Monitoring methods and targets (serum or plasma tests)
NEFA 0.5 mMol/L in the week before expected calving [67]
BHBA 1.1 mMol/L in Week 1 and 1.4 in Week 2 after calving [67,68]
Haptoglobin 0.8 g/L in Week 1 after calving [67]
1615 S.J. LeBlanc et al. / Theriogenology 76 (2011) 16101618
mended for peripartum dairy cows that are likely to
contribute to reducing the incidence of reproductive
disease in the early postpartum period.
A recent large clinical trial was conducted to explore
the hypothesis that reduction of the load of potential
bacterial pathogens in the uterus immediately after
calving could reduce the risk of uterine disease. More
than 1000 cows at high risk of uterine disease, i.e.,
having had RP, dystocia or twins, were randomly as-
signed to receive a single injection of a long-acting
antibiotic containing ceftiofur crystalline free acid that
was expected to be effective against E. coli, A. pyo-
genes, and relevant anaerobic bacteria, or to remain as
untreated controls [4]. There were conditional and
modest reductions in the incidence of metritis, and a
signicant overall reduction in the prevalence of PVD
at 5 wk postpartum from 28 to 20%. Further studies are
needed to better identify selection criteria for metaphy-
lactic treatment of cows for uterine disease and to
identify treatments that result in greater reductions in
the incidence of metritis or endometritis. Although pre-
ventive treatment with antibiotics is not recommended,
these results nevertheless support the notion that the
degree or nature of bacterial contamination soon after
calving is one component of both metritis and purulent
vaginal discharge 1 mo later. Conversely, on balance it
appears that innate immune function may be an even
more important determinant of reproductive tract health
[15].
8. Conclusion
Infection and inammation of the uterus and cervix
affect approximately one out of every three dairy cows,
with substantial impacts on the probability and timing
of pregnancy. Although there are well-validated diag-
nostic tools and criteria for both PVD and cytological
endometritis, and an efcacious treatment for PVD,
much remains to be learned about what initiates and
sustains harmful inammation of the reproductive tract.
Such information is necessary to develop effective
treatments for the various forms of disease and, more
importantly, to develop means, from genetic to phar-
macologic to nutritional and management, to prevent
uterine diseases. In particular, vaccination against spe-
cic uterine pathogens and interventions to modulate
innate immune response appear to be important ave-
nues for investigation. Presently, commonly recom-
mended best management practices for cows in the
transition period are likely to be helpful to mitigate the
risk of reproductive disease.
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