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New Approaches to Treating Old Problems:

Retained Placenta, Cystic Ovaries and Endometritis


Jeffrey Wichtel, BVSc PhD Dipl. ACT
Department of Health Management
Atlantic Veterinary College
University of Prince Edward Island
550 University Avenue
Charlottetown
Prince Edward Island, CANADA C1A 4P3
jwichtel@upei.ca

Retained Placenta

Many veterinarians believe that hormonal treatment of retained placenta (RP) is effective.
Oxytocin, prostaglandins and estradiol are often recommended for treatment of RP, in the
hope that the myometrial contractility induced by these drugs might accelerate separation
of the caruncle and cotyledon and lead to faster involution. However, postpartum
hormonal treatments are unlikely to be effective in reducing the time from calving to
placental release, or in reducing the incidence of illness in affected cows.

Retained placenta is common, affecting around 15% of lactations in Canadian herds


(LeBlanc et al. 2002). Its etiology is complex and there have been many risk factors
identified. In most cases of RP there is a disruption in normal placental maturation during
late pregnancy, leading to a failure of placental release at the time of calving (Laven
1996). During pregnancy, placental attachment to the caruncle is firm, i.e., a collagenous
attachment. The process of separation involves remodeling of collagen induced by the
changing melee of hormones (Gustafsson et al. 2004). This process begins much earlier
than one would expect, at least 3 weeks pre-partum. When this process fails, for whatever
reason, we cannot successfully re-create it through administration of exogenous
hormones (Peters 1996). Dexamethasone- or prostaglandin-induced calving, even if
initiated just a few days before term, appears to be sufficient to disrupt this normal
process of maturation, leading to a rate of RP that can approach 50%. The anatomic
nature of the problem is well illustrated because the only successful, if impractical,
treatment proven so far is injection of collagenase through the umbilical vein or uterine
artery (Eiler 1997; Guérin et al. 2004). In cases of placental retention, placental
attachments must undergo slow autolysis before separation can occur. Because of this
firm attachment, removing the cotyledons manually before autolysis is complete will
result in endometrial damage leading to a longer period from calving to conception
(Peters 1996).

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The hypothesis that hormonal treatments can assist placental separation through increased
myometrial contractility should be critically examined. The postpartum uterus,
immediately after calving, is already under the influence of very high levels of
endogenous prostaglandin and oxytocin; contractility is already close to maximal when
the placenta is retained (see Bajcsy 2005a for a review). Exogenous estradiol and
oxytocin at supra-physiologic doses (as commonly used by veterinarians) will alter
motility but tend to cause uterine spasm, not the coordinated caudally-directed peristaltic
contractions typical of natural postpartum uterine contractions (Burton 1990). Such
spasmodic contraction may be harmful, impeding uterine drainage and, it has been
suggested, driving infected lochia in a retrograde direction, predisposing to salpingitis
(Peters 1996). On the other hand, prostaglandin-induced myometrial contraction in
postpartum cows is minor or non-existent (Bajcsy 2005a) and unlikely to be of any use in
this respect: the half-life in blood of a label dose of cloprostenol is 3-4 hours, and that of
prostaglandin F2α a mere 2-3 minutes. It has been suggested that estrogens are further
contraindicated in cases of postpartum metritis because they increase perfusion of the
endometrium leading to more severe bacteremia and an increase in the absorption of
endotoxins from the infected uterus (Peters 1996).

Oxytocin is a natural choice for enhancing uterine contractility and in theory, if


administered repeatedly in physiologic amounts, could lead to improved uterine motility
in the days following retention. The physiologic dose of oxytocin appears to be between
20 iu, increasing to about 40 iu at 3-4 days postpartum as the uterus becomes more
refractory to its effect. Doses of oxytocin greater than this tend to cause uterine spasm, as
explained above. The duration of enhanced motility noted after treatment at these doses is
short – just a few hours (Bajcsy et al. 2005b). If such a treatment protocol were used for
RP, treatment would need to be repeated very often. So far this protocol has not been
tested on field cases of RP, so efficacy remains to be demonstrated. In summary, there
seems to be little indication for routine hormonal treatment of RP at this time, given our
present understanding of the pathophysiology of RP and the hormonal arsenal available
to us at this time.

Our preferred protocol for treatment of RP includes manual extraction only after
separation has occurred (usually > day 6 postpartum). It is our belief that removing the
exposed portion of the placenta by cutting it at the level of the vulva does not
significantly delay separation, and considerably improves the attitude of the milking
personnel. We ask herdsmen to monitor for systemic signs of illness each milking, using
rectal temperature and observing demeanor, feed intake and milk yield, and to treat with
systemic antibiotics (procaine penicillin, ceftiofur sodium) and non-steroidal anti-
inflammatory drugs if indicated. Blanket preventative therapy is not recommended
(Drillich et al 2006). Where clinical postpartum metritis occurs, there is evidence that
intrauterine treatment with oxytetracycline is beneficial (Goshen 2007). We suggest 4-6g,
once daily for up to 3 days. It should be noted that milk needs to be withheld for 48-96
hours following such therapy, and some formulations of oxytetracycline can be irritating.
In general, however, intrauterine treatment with antibiotics and disinfectants (including
intrauterine tablets) is discouraged because it only serves to impede natural uterine

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defense mechanisms and slow down the autolytic process that must occur for separation
to be achieved (Peters 1996).

Cystic Ovarian Disease

It is a widely held belief that cystic structures on ovaries are a cause of infertility. The
corollary of this theory is that normal cyclicity will not return until the cyst is “removed”,
usually though some form of luteotrophic treatment. However, treatment of cystic
ovarian disease (COD) with GnRH is not highly effective, and this been confirmed by
Canadian research (Jou, P et al 1999). Empirically, in cows affected by COD, return to
estrus does not appear to be well correlated to the anatomic disappearance of a cystic
structure on the ovary. We have all experienced the cow that appears to be cycling
normally with a large cystic structure present. Further, our manual diagnosis is prone to
error – we know that palpation for classification of luteal structures is not very accurate
among experienced veterinarians and our accuracy in the diagnosis of cystic structures is
no doubt little better, even with the availability of ultrasound. In many cases apparent
response to treatment can be attributed to misdiagnosis, mistaking a normal corpus
luteum with a cystic centre for a pathologic structure.

Our understanding of the role of COD in infertility has subtly changed over the last
decade. We now have strong evidence that an ovarian cyst is one of many symptoms, not
a cause, of ovarian-pituitary-hypothalamic dysfunction. We know that cysts are more
prevalent in high-producing cows at the time of negative energy balance; low or
intermediate peripheral steroid hormone concentrations and other perturbations of the
ovarian-pituitary-hypothalamic feedback mechanisms may be involved. The primary
defect appears to be a reduced sensitivity of the hypothalamus to the positive feedback
effects of follicular estradiol, leading to ovulation failure (Wiltbank et al. 2002). This
dysfunction can result in several possible outcomes: anovulatory anestrus, ovulation
failure leading to COD, and formation of short-lived corpora lutea. Rather than looking
for therapies that resolve the cystic structure directly (so far shown to be a futile task to
date), the cyst should be essentially ignored and efforts instead directed towards treating
the underlying anovulatory anestrus. We need to induce cyclicity in these cows in the
same way we would treat any other anovulatory cow.

The vast majority of cows with COD are usually presented to the veterinarian at herd
check as cows with no detected estrus. Despite textbook suggestions to the contrary,
nymphomania is rare. When a cyst is identified by manual per rectum palpation or
ultrasound, its presence should be recorded, albeit with the understanding that diagnosis
is not highly specific. No specific treatment is recommended for the cystic structure.
Instead, the cow is included with other anovulatory anestrus cows, and treated in the
same way. Treatment for anovulation in our herds includes Ovsynch (GnRH – PGF –
GnRH) with or without the use of intravaginal progesterone for the first 7 days, and
attention to the underlying cause of anovulation.

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Adequate progestin stimulation is an important prerequisite for inducing a fertile
ovulation in postpartum cows, and for strong signs of behavioural estrus. For this reason,
protocols that include progesterone (e.g. Ovsynch with CIDR or PRID) are generally
more effective for treating anestrus than those that do not (Pursley et al. 2001; Wiltbank
et al. 2002; Rhodes et al. 2003). Treatment with progesterone improves the response rate
in cows that fail to respond to the first GnRH injection in the Ovsynch protocol:
ovulation in response to GnRH is dependant on cows having a follicle with an antral
diameter of more than 10mm (Xu et al. 1995). In a given group of anovulatory cows, a
proportion of the cows may not have a follicle of sufficient size to respond. Cows in deep
anestrus may respond with ovulation and a short luteal phase but may revert to
anovulation thereafter (McDougall et al. 1995). Further, Ovsynch protocols that include a
progestin (such as a CIDR or PRID) appear to be more effective in causing cow to exhibit
strong behavioural estrus, making it more likely that the cows will be detected and
inseminated at the correct time following the therapy (Rhodes et al. 2003).

In summary, non-specific treatment of cows with COD along with other cows with
anovulatory anestrus has proven both effective and efficient in our hands. This is a subtle
but important shift in our understanding and management of COD. Further, it highlights
the central and unifying role of pituitary-hypothalamic dysfunction in the declining
fertility noted in our high producing cows, through its effect on the incidence of delayed
involution, irregular estrus cycles, weak signs of estrus, COD, chronic endometritis (see
below) and prolonged days open. The increased prevalence of pituitary-hypothalamic
dysfunction and subfertility in high producing dairy cows was the subject of the first two
papers in this series. In conjunction with treatment of COD, we need to identify and
correct individual and herd risk factors for anestrus (poor nutritional management, severe
energy deficit, social stresses, and concurrent disease), especially in herds where the rate
of anovulatory anestrus is greater than 5% at 50-60 days in milk.

Endometritis

Another area of controversy involves intrauterine therapy of cows with purulent uterine
discharge (clinical endometritis). Historically, there has been little useful controlled
research on endometritis, making it difficult to formulate good evidence-based
approaches to treatment. Fortunately, there have been a number of well-controlled studies
during the last 5 years that provide useful information regarding the definition, diagnosis
and management of endometritis in dairy cattle. Several of these studies have been
conducted in Canada.

First of all, it is helpful to define endometritis, because not all veterinarians agree on the
definition. Several researchers have recently come together to produce a consensus
document that defines several reproductive disorders, including clinical endometritis.
They define it as follows: the presence of purulent (>50% pus) uterine discharge
detectable in the vagina 21 days or more after parturition, or mucuopurulent
(approximately 50% pus, 50% mucus) discharge detectable in the vagina after 26 days

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post partum (Sheldon et al 2006). Based on these criteria, it should be noted that many
cases of endometritis will remain undiagnosed if vaginoscopy is not routinely used
(LeBlanc et al. 2002; Runciman et al. 2008) . At this stage most uterine infections are
predominantly aerobic and in most cases caused almost exclusively by A. pyogenes.

Secondly, we should comment on the importance of endometritis. The prevalence of


clinical endometritis was 16.9% in a recent Canadian study (LeBlanc et al. 2002). In that
study, accounting for parity, herd, and ovarian status, cows with clinical endometritis
between 20 and 33 days in milk had a hazard ratio of 0.73 for pregnancy (that is, it took
27% longer to become pregnant), and were 1.7 times more likely to be culled for
reproductive failure than cows without endometritis. A similar risk for culling following
diagnosis of endometritis was identified in a large Australian study sponsored by Intervet
(www.intervet.com.au/binaries/82_105112.pdf ). So endometritis is an important disease
that deserves our attention.

The results of Canadian research show that treatment of endometritis, as define above,
using either prostaglandin F2α or intrauterine antibiotics before day 27 post-partum
resulted in no significant improvement in calving-to-conception interval (LeBlanc et al.
2007). The prevalence of endometritis, diagnosed by vaginoscopy and manual palpation,
was very high during the first 33 days postpartum, but most of these early cases self-
cured. This is in agreement with other studies, reviewed by Sheldon (2004). After day 26,
where a corpus luteum was present, the response (decreased days from calving to
conception) to PGF2α and to intrauterine cephapirin benzathine (Metricure® Intervet) was
the same; where a corpus luteum absent, response to Metricure® was superior to PGF2α in
reducing days open. Based on this study, it appears that therapy of endometritis is not
economically justified before day 27 postpartum. In the absence of a corpus luteum,
intrauterine antibiotic was the preferred therapy. In the presence of a corpus luteum,
PGF2α may be as efficaceuos as intrauterine anitbiotics.

In another Canadian study involving 228 cows in a commercial setting, the effect of sub-
clinical endometritis on reproductive performance over 8 months was assessed. Sub-
clinical endometritis was defined as the presence of >18% neutrophils in endometrial
cytology, or fluid present in uterus on ultrasound examination (Kasimanickam et al.
2005). In that study, a single treatment with cephapirin or cloprostenol at 20–33 days in
milk significantly improved the reproductive performance of cows with sub-clinical
endometritis when compared to untreated controls.

In the studies descibed above, the effect of combining injectable PGF2α and intrauterine
cephapirin in treating cycling cows with endometritis was not specifically tested,
however, this is my preferred therapy. In cows with chronic endometrtitis beyond their
voluntary waiting period, I will tend to breed cows at the prostaglandin-induced heat, and
then perfom a post-insemination treatment with cephapirin benzathine 24 hours after
insemination.

(Citations available on request)

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