p 592-604

p 175-179

Canine Contraception

• This device is no longer marketed.
• It was an Elizabethan idea that really needed a proper fit to be effective.

• Zona antibody
• GnRH antibody
• anti LH
• anti estrogen
• anti androgens
• anti riboflavin
• Prolactin inhibitors
• Hydroxysteroid dehydrogenase inhibitors
• Triazole - non hormone prevents implant
• Gossypol
• Targeted toxins

Click Here to see an algorithm on mismate management

or

Click here to open a PowerPoint picture of the mismate algoritmm

p 179-188

• If a dog is presented for mismate management ("abortion shot") several questions should be asked before any therapy is instituted.
• Was the bitch really in heat?
• How long was the bitch gone? In that time could breeding have happened? Did breeding occur?
• Are pups wanted now or in the future? Why are pups wanted?
• Was the bitch really in heat?
• Do a vaginal cytology smear to see if the bitch is really in estrus. If not, then the chance of pregnancy are minimal.

How long was the bitch gone?

• In that time could breeding have happened?
• Since natural breeding takes up to 30 minutes, a bitch that is gone for only 5 minutes has very little chance of being bred.

Did breeding occur?

• Check for sperm cells in the vaginal cytology. The presence of sperm cells definitely indicates that the bitch has been bred, however their absence does not mean that she has not been bred.
• Playing and courtship may be misinterpreted as mating by uniformed clients.

• If pups are not wanted, or wanted for an unfounded reason (to make the bitch a better dog etc. ovariohysterectomy may be best alternative. If possible, have the client pay for a non-estrual surgery now and then return when the bitch is not in heat. It makes it cheaper for the client and an easier surgery for the veterinarian.

• In a study performed to look at pregnancy rates of bitches presented for mismate, 62% of dogs presented after mating were not pregnant (Feldman et al. JAVMA, 1994, 202:1855)
  • This may be because the 'breeding" was misinterpreted by the owner and the bitch was not acutally bred.
• If ovariohysterectomy is not an option, then waiting to determine if the bitch is pregnant is probably the best alternative. Pregnancy examination can be performed by ultrasound as early as 16-18 days after the first day of diestrus.
• If the owner wants immediate action, then some alternatives are available.

Mismate Drugs

Estradiol Cypionate (ECP)

• This drug is probably gone from the market now.
• This is probably the only true mismate drug available.
  
• There are very few academicians who will consider using ECP because of the risks of adverse side effects. When used properly for the correct clients, however it can be relatively safe and efficacious. The best article on this is Bowen, Olson et al. JAVMA, 1985;186:783-788. Click on the blue text if you want to see the article.
• The dose 44 ug/kg IM given once during estrus to be the best dose (0.02 mg/lb)
• It is not effective if used in proestrus or in diestrus, therefore it is essential that the vaginal cytology be examined.
• It can induce pyometra if given during diestrus, so be sure the bitch has not entered diestrus when administered.
• Other side effects
  • The bitch will show continued estrous signs, because of the estrogen. It is important that the bitch not be allowed to breed again.
  • Cystic endometrial hyperplasia can also result after ECP administration.
  • Bone marrow suppression can be dose related or non-dose related. To avoid dose related, do not give a second injection. Non-dose related bone marrow suppression can be totally avoided only by never giving ECP injections.
  • Pyometra
  • No pyometras were seen when the ECP was given during estrus.
• Treatment failure
• The treatment was 100% efficacious when administered during estrus. side effects and no failures when given during estrus.
• Summary: If puppies are wanted it the future and the client is aware that there is a risk and they are willing to take it, then ECP offers an inexpensive, efficacious, relatively safe mismate protocol. However, if the bitch is a valuable breeding bitch, or a surrogate child, then other alternatives may be more attractive to both client and veterinarian.

Prostaglandins (PGF) -Lutalyse

• This is really not a mismate drug, but can be used before pregnancy is recognized, so it is included here.
• If the bitch is pregnant, then prostaglandins can be used.
• There are several prostaglandin products available. Lutalyse most commonly used in the dog. Prostaglandins were originally not considered to be luteolytic until last the last third of diestrus (40 or more days), however it is now known that multiple injections are luteolytic after only the fourth or fifth day of diestrus. (Oettle et al Therio 1988:29;757-763). This may be because the prostaglandin needs to bind to more receptors (if each corpora lutea has 'N' receptors and there are multiple corpora lutea in the bitch, then the bitch needs for example 5N receptors bound with prostaglandin....something that is not attainable with a single dose due to the side effects of prostaglandin) .
• Oettle used a dose of 250 mcg/kg SQ 4 days starting at day 5-8 of diestrus was 80% effective. If the treatment failed, the pregnancy was normal.
• Feldman et al. JAVMA, 1994, 202:1855used a a dose of 0.15 mg/kg, SC, TID for first 1-1½ d, then 0.25 mg/kg TID and continue until loss is complete.
• Monitor the loss by ultrasound or abortion may not be complete.
• Feldman currently recommends a dose of 0.10 mg/kg, SC, TID for first 2 days, then 0.25 mg/kg TID and continue until the pregnancy loss is complete. It is extremely important that the pregnancy be monitored or the treatment may fail because of failure of luteolysis. Progesterone must be <2 ng/ml for 24 hours to result in abortion.
• Side effects include transient diarrhea and vomiting. These usually subside within 30 minutes. (see "pyometra" for side effects)

• Atropine (0.1 mg/kg) reduces side effects, but may also reduce efficacy
• There is also the possibility of circulatory shock, so it is important that a catheter is in place and fluids are ready to treat the shock. This too is transient. Generally, side effects diminish as the treatment protocol continues.
• LSU low dose protocol
  • 0.012 mg/kg QID subcutaneously for 5 days (3 pregnant 30 d and 7 non-pregnant bitches treated)
  • Progesterone concentration declined by day 3 of treatment
  • Day 3 heartbeats still present
  • Some brown discharge - no fetal parts seen
  • No other real side effects
  • Uterus empty at 5 days post treatment

Dexamethasone

• If the bitch is pregnant, then dexamethasone can be used.
• A dose of 5 mg BID, IM, for 10 days at 30 days of gestation aborted 4 bitches 1-3 days after the end of treatment.
• Zone et al. 1995, Therio 43:487
• Zone used 5 bitches at 28 - 51 days of gestation and administered dexamethasone 0.2 mg/kg, PO, TID for 5 d, then progressively decreasing dose from 0.16 to 0.02 mg/kg over 5 days
• In 15 bitches dexamethasone was given at a dose of 0.1 to 0.2 mg/kg, PO, BID for 3 doses, then 0.2 mg/kg on days 2 - 5, then decreasing dose from 0.16 to 0.02 for last 5 doses (total 7.5 d).
• All bitches aborted or resorbed the pregnancy 2-26 days from beginning of treatment.
• We recommend just using the high dose PO BID until signs of pregnancy have disappeared. Just as in using prostaglandin, if a protocol is blindly followed without doing pregnancy examinations, then treatment failures will occur.
• Normal litters have been obtained after this treatment.
• Side effects include a transient polydypsia and polyuria that subsided when the treatments were stopped.
• This is the protocol I generally recommend as it is readily available, cheap and effective.

Prostaglandin (Lutalyse)

• Use the same as 'mismate'.
• Use at greater than 30 days gestation.

• Since prolactin is luteotropic and needed to maintain pregnancy, prolactin antagonists will cause abortion.
• These prolactin antagonists also shorten the interestrus interval.
• Prolactin antagonists prevent mammary development.

Bromocriptine (Parlodel)

• A dose of 30-100 mcg/kg PO BID 5-6 days at 35-40 days of gestation causes abortion in 3-5 days.
• orally at a dose of 62.5 mg/kg twice daily to dogs at 43-45 days post ovulation resulted in only 2/4 bitches aborting.
• Bromocriptine may cause dogs to vomit, so it had not been widely accepted.
• The long term effects on reproduction have not been studied.

• 160 mg orally once daily given to a 32 kg German Shepherd dog resulted in abortion after 7 days with no side effects.
• Even though each dose of cabergoline may be only about $1.80, an initial investment of around $148 needs to be made to purchase the minimum package
• Cabergoline is now available in the United States only in an oral formulation (injectable in Europe)
• Injectable available in Europe
  • 1.65 mg/kg injected subcutaneously for 5-6 days at 25-40 days after the first mating resulted in abortion for all (5/5) those bitches greater than 40 days gestation
  • only 50% (1/4 at 25 days and 4/6 at 30 days) of those less than 40 days

Cabergoline plus cloprostenol ('Estrumate' a synthetic prostaglandin)

• Onclin et al. 1995, Therio, 43:813.
• Cabergoline (1.65 ug/kg/d, sc) plus cloprostenol (2.5 ug/kg/d or 1.0 ug/kg/d) starting day 25 after the LH peak proved 100% effective and had no side effects.
• Cabergoline is now available in the United States as Dostinex.
• The treatment caused a shortened interestrus interval.

• It has a direct smooth muscle action that causes abortion 1-2 days after treatment.
• A dose of 2 mg/kg IV or IP after day 30 of gestation is efficacious.
• Vomiting, diarrhea, and uterine contractions are side effects.
• The LD50 may be close to therapeutic dose.
• Post-treatment fertility is not affected.

• Luteinizing releasing hormone (LHRH) antagonist
• A dose of 2 mg/kg for 7 days given during midgestation is effective.

• Tamoxifan has estrogen activity in dogs.
• It has been administered at a dose of 1.0 mg/kg orally twice a day for 10 days starting either in proestrus, estrus, or days 2, 15, or 30 of diestrus. 
• 100% efficacy for preventing pregnancy when administration began before day 15 of diestrus
• When administered on day 15 of diestrus or later it was not effective 
• Induced a 33 % incidence of pyometra and endometritis.

• Epostane is 3beta-hydroxysteroid dehydrogenase ) delta 5-4 isomerase inhibitor. It inhibits progesterone synthesis.
• A dose of 2.5 - 5.0 mg/kg PO for 7 days starting on the first day of diestrus is effective at terminating pregnancy.

• RU 486 is a progesterone receptor antagonist, so progesterone is prevented from binding to receptors.
• Oral administration of mifepristone at a dose 2.5 mg/kg twice daily for 4.5 days starting at day 32 of gestation resulted in 100% (5/5) of the bitches having a decline in progesterone two days after treatment started and pregnancy loss with no side effects  around three days after treatment initiation.
• Four pregnancies were terminated in bitches that were 35-39 days pregnant using oral drug
• A dose as low as 8.3 mg/kg and up to 20 mg/kg were administered orally for one or two treatments and abortion occurred within 2-11 days.
•  Mifepristone is available as a 200 mg tablet in the United States
  • not labeled to terminate pregnancy in the bitch.
  • can cost as much $50 a dose for a 10 kg dog, 
  • an initial purchase of $1350 is required to purchase the package
• A dose of 2.5 mg/kg PO BID for 4-5 days starting on day 32 of pregnancy produces abortion in 3-6 days. A single SQ dose of 22.7 mg/kg is effective at inducing abortion, however the time to abortion is not reliable.