termination of pregnancy in bitches - Jivaonline.net

GENERAL ARTICLETERMINATION OF PREGNANCY IN BITCHESAbhilash.R.S, Anil kumar.K, Biju.S and Ajith.K.S,Livestock Research Station, Thiruvazhamkunnu, PalakkadJ. Ind. Vet. Assoc., Kerala. 10 (1)INTRODUCTIONTermination of pregnancy is one of the mostcommon requests from dog owners. The usualreasons include too young age, too old age,disproportionate size of mating partners or unwantedor accidental mating. Over the last 20 years manynew drugs have been used for termination ofpregnancy in canines. There are different treatmentprotocols such as oestrogen therapy, PGF2 and itsanalogues, dopamine agonists, combination ofprostaglandins and dopamine agonists, anti progestintherapy etc. Although most of these drugs havealready been used for years in other species, only feware widely marketed or approved for use in dogs. Theaim of the present article is to briefly review the stepsto be taken before proceeding with termination ofpregnancy, the drugs available for the termination ofpregnancy in bitches, their pharmacologicalproperties and availability.INITIAL EXAMINATIONA thorough history is valuable prior toattempt termination of pregnancy in bitch. Confirmwhether the animal has actually mated or not. Avaginal smear is the best diagnostic tool forevaluating mating and to find the stage of the cycle.The presence of sperm or sperm head confirmsmating whereas absence of sperm does not indicatethat a fertile breeding did not occur. Pregnancyshould be confirmed by ultrasound scanning aroundday 30 of the last breeding before starting thetreatment. The points to ponder in planning to abort abitch include its pregnancy confirmation and the60safety, reliability and the ease of administration ofthe drug used.The first stage of pregnancy begins atfertilization and ends a few days after implantation.During this time pregnancy cannot be confirmed andinduction of abortion is difficult because of therefractory nature of corpus luteum to exogenousmedications. Termination of pregnancy at this stagecan be attempted with medications like estrogens,prostaglandins and anti progestins. During thesecond stage, pregnancy can be confirmed andabortion can be induced if necessary. Abortion can beinduced with prostaglandins, antiprolactin agents(dopamine agonists such as bromocriptine orcabergoline), combination of prostaglandins anddopamine agonists or with inhibitors of progesteronesecretions (epostane) or antiprogestins (mifepristoneor aglepristone). Third stage is one that begins withthe calcification of fetal structures and abortion isalways associated with expulsion of foetus. In thisstage abortion might induce premature parturitionwith delivery of live pups. Hence the best time forinitiation of abortion protocols in bitches is betweendays 30 and 35 from the date of last breedingINDUCTION OF ABORTION PRIOR TOIMPLANTATIONFertilization of eggs and the initial 6-10 daysof embryonic development take place in theoviducts. Large doses of estrogens can prolongretention time of embryo within the oviduct thatleads to the degeneration and death of embryo. Themechanism of action of oestrogen is in two ways,firstly it tightens uterotubal junction and thus

GENERAL ARTICLEprolong oviductal retention of embryos and secondlyoestrogen has direct degenerative effects on ova andmay alter the endometrium.1. OESTROGENSOestrogens are widely used to preventunwanted pregnancies. They act by altering thetransport time of zygotes and thus interfering withimplantation. In some bitches estrogens given duringoestrus results in early luteolysis and this effect maybe mediated either directly upon luteal progesteroneproduction or by inhibition of LH release which isluteotrophic.a. Diethyl Stilbesterol (DES)Injection of DES at a dose rate of 2mg/kgbody weight, up to 25mg once or twice within 5 daysof mating is found to be highly effective interminating pregnancy. However injectable DES isnot available for veterinary practice. Oral DES hasbeen recommended at a dosage of 1 to 2 mg/day for 7days after mating, but oral therapy has not been foundto be completely reliable.b. Oestradiol cypionateIt was an oestrogen compound commonlyused by veterinarians for the management ofunwanted mating. The treatment protocol involved isadministration of 0.25 to 1 mg total dose within 3days of mating. A dose rate of 0.04 mg /kg is 100percent successful in preventing pregnancy inbitches. The total dose should not exceed 1mg.Despite the potentially favourable action ontermination of pregnancy, it has major side effectssuch as permanent bone marrow suppression ordestruction resulting in severe anaemia, leukopenia,thrombocytopenia and death.c. Conjugated oestrogenConjugated oestrogens can be used for thetreatment of misalliance in dogs within 5 daysfollowing breeding. They are mainly isolated frommare's urine and hence it can be called as conjugatedequine oestrogen. Most commonly used for thetreatment of osteoporosis, atrophic vaginitis,atrophic urethritis etc as a complication ofmenopause in woman. Commonly availablepreparation is PREMARIN 0.625mg and 1.25mgtablets. Dosage 1.875mg daily for 3 daysHowever estrogens can result in thedevelopment of pyometra by causing cervicalrelaxation thus allowing the vaginal bacteria to enterthe uterus. Estrogens may also produce dose relatedbone marrow suppression. Diethyl stilbesterol,oestradiol benzoate and estradiol cypionate havebeen widely used to prevent implantation.But oestrogen preparations are notrecommended in veterinary practice because of theirharmful side effects. Oestrogen is thought topredispose pyometra in bitches by sensitizingprogesterone receptors and enhancing binding ofprogesterone to the endometrium. It has been alsoreported that excess serum estrogens can lead tooestrogen- induced bone marrow destruction.2. PROSTAGLANDINS ANDITS ANALOGUESPregnancy in the bitch depends onprogesterone secretion from corpora lutea. Manystudies indicate that bitches that have corpora luteaare relatively resistant to the luteolytic effects ofprostaglandins during the first 14 to 28 days ofpregnancy. PGF2 (Natural Prostaglandins ieDinoprost) is luteolytic and uterotonic, inducingintense uterine contractions due to the smoothmuscle contraction effects and may lead to adversereactions. Synthetic analogs (cloprostenol sodium)characterized by more specific activity on the corpusluteum and less on smooth muscle stimulationproperties have fewer side effects.A. Natural Prostaglandin: - Prostaglandins arefound to be highly effective for termination ofpregnancy in bitches after 30 days of gestation. Itsuse prior to 30 day is not recommended. Mostpreferred treatment protocol is 0.1 mg/kg s/c every 8hours for 2 days and then 0.2 mg/kg given s/c every 8hours until abortion complete, the average wasJIVA Vol. 10 Issue 1 April 201261

GENERAL ARTICLEJ. Ind. Vet. Assoc., Kerala. 10 (1)approximately 5-7 days (Feldman et.al, 1993 andRenukaradhya et.al, 2008). This protocol resulted inthe least side effects. After administration of drug,the dog should be observed for 30 minutes for anyside effects. The dog should be fed 1-2 hours afterprostaglandin injection so as to avoid vomiting. It hasbeen observed that plasma progesterone less than 2.0ng / ml result in pregnancy termination and pretreatment concentration of plasma progesterone ismore than 6ng/ml (Feldman et.al, 1993). Most of theanimals treated will exhibit some of the followingside effects like panting, respiratory distress, excesssalivation, vomiting, defecation, stranguria andurination. Normally these side effects start within 30seconds to 3 minutes and usually persist for 5-20minutes. Side effects are usually severe during thefirst few injections and side effects will bediminishing after each subsequent injection.Preparation - LUTALYSE 5ml &10ml vials areavailable. Concentration 5mg/mlb. Prostaglandin analogs:- It has greater luteolyticeffectiveness at relatively low doses and decreasesthe occurrence of myometrial contractions andseverity of side effects compared to naturalprostaglandins. It has much greater affinity for theprostaglandin receptors and has a longer half life thannatural prostaglandin. It can be given at the dose rateof 2.5µg/Kg body weight subcutaneously every 48hours for 3 to 4 times (Reddy et.al, 2010). In order toreduce the side effects atropine sulphate can be givenat the rate of 0.04 mg/kg body weight subcutaneously10-15 minutes prior to the administration of drug.Preparation Inj.Clostenol 2ml, Inj.Pragma2ml,Inj.Cyclix 2ml, Inj. Estropur 2ml Concentration-250µg/ml3. DOPAMINE AGONISTSDopaminergic agonists are ergotinederivativealkaloid compounds that exert an antiprolactinergiceffect. The ability of dopamineagonists to inhibit prolactin secretion makes themoptimal for milk suppression, either during overtpseudopregnancy episodes or in the post-partumperiod. It is well known that prolactin is a requiredluteotropic hormone during the second half of canineluteal phase. Therefore, anti-prolactins can also beused to suppress luteal function in progesteronedependent conditions such as pyometra, unwantedpregnancy and mammary tumors. Two of the mostwidely used dopamine agonists in dogs arebromocriptine and cabergoline, which have a directaction on D2-dopamine receptors of the lactotrophiccells of the anterior pituitary gland.a. Bromocriptine: - It has been reported to be aneffective abortifacient after 35 days of gestation butnot prior to day 30. Two different treatment protocolshave been adopted. In one protocol 0.1mg/kg bodyweight daily or BID for 6 consecutive daysbeginning on day 30 of gestation. In the secondprotocol, 0.03 mg/kg twice daily for 4 daysbeginning after day 30 of gestation. Bromocriptinecommonly causes inappetence, anorexia, vomitingand depression. Also the drug is not 100% effectivein terminating pregnancy. Emesis is presumably dueto interaction with dopaminergic elements in theemesis centre of the brain and the ability of the drugto cross the blood brain barrier. The emetic effectmay reduce the absorption of the total doseadministered, and thus compromise efficacy.Because of above reasons the drug has not been usedextensively. Preparation ENCRIPT 2.5 mg tab,PROCTINAL 1.25 & 2.5 mg tabs.b. Cabergoline: - It is a long acting dopaminereceptor agonist and prolactin inhibitor. It is highlyeffective orally and parenterally. A dose of 5µg/kgonce daily cause a sharp decline in serum prolactinconcentration and result in abortion without muchside effects (Reddy et.al, 2010).. The side effects ofcabergoline are milder (compared to those ofbromocriptine) presumably due to the fact that itappears to be a more specific D-2 dopamine receptoragonist and is less able to cross the blood-brainbarrier and have CNS effects.Preparation CABGOLIN Tab 0.25 & 0.5mg, CAMFORTE Tab 0.5 & 1mg62

GENERAL ARTICLE4. COMBINATION OF PROSTAGLANDINAND DOPAMINE AGONISTSimultaneous administration of prostaglandinand dopamine agonist is found to be highly effective.Therapy begins 28 days after first breeding.Cloprostenol is administered subcutaneously onalternative days at a dose rate of 1 µg/kg and the drughas to be administered three times. Oral cabergolinehas to be given at a dose rate of 5µg/kg body weightfor 9 days. This regimen reduces the adverse effectsof prostaglandin therapy alone and increases theefficacy of prolactin antagonists. When the bitcheswere treated for approximately 9 days, 100 percentshowed resorption and there was generally no sideeffects except sanguinous vaginal discharge (Onclinet.al, 1995).5. ANTI PROGESTERONE THERAPYAnti-progestins are synthetic steroids thatbind with great affinity to progesterone receptors,preventing progesterone from exerting its biologicaleffects. After administration of the drug peripheralprogesterone concentration remains unaltered but itsaction is blocked. In dogs, the anti-progestinsmifepristone and aglepristone have been used forexperimental and clinical purposes, includingpregnancy termination and management ofpyometra.a. Mifepristone: -Mifepristone is a progesterone andglucocorticoid antagonist. It is more potent as ananti-progestin than as an anti-corticoid. In pregnantwomen, mifepristone is able to interrupt earlypregnancy in 80 percent of cases without any majorside effects. To improve its efficacy, mifepristone iscurrently used in combination with low doses ofprostaglandin analogs such as misoprostol. Theefficacy of combined treatment (mifepristone plusmisoprostol) is 96 percent in humans. The drug act asa progesterone receptor antagonist at the level of theuterus independent of any additional effects on lutealfunction. Premature cessation of luteal function mayhave occurred secondary to the termination ofpregnancy or may represent a luteolytic effect oftreatment independent of pregnancy status.Mifepristone has been demonstrated to induce directluteolysis and has an anticorticoid activity.This drug is orally active and has beenshown to be safe and effective in terminatingpregnancy after 30 days of gestation. The treatmentprotocol involved oral administration of drug at therate of 2.5 mg/kg twice daily for 4-5 days or untilabortion or resorption occurred (Concanoon et.al,1990). It is a competitive antagonist of progesteroneon the receptor level thus having most clinical effectsin the presence of progesterone. Preparation Tab.MTPILL 200mg, MEFIPIL 200mg, UNWANTED200mgB. Aglepristone: - This is a relatively newantiprogesterone drug developed for animal use.Aglepristone can be used any time up to day 45 forsafe effective termination of pregnancy (Fieni et. al,2001). Aglepristone does not modify plasmaconcentrations of progesterone, prostaglandins,oxytocin or cortisol within 24 hours after itsadministration but induces an increase inconcentrations of prolactin within 12 hours in bitchestreated in mid pregnancy (Galac, et. al, 2000). Thiscan explain the mammary gland congestion typicallyobserved after mid pregnancy termination.Shortening of the inter-oestrous interval andprolactin release seems to prove a direct or indirectaction of aglepristone on hypothalamic-pituitaryaxis. As an abortifacient, aglepristone acts like aprogesterone antagonist, at the uterus level and doesnot have direct and immediate luteolysis properties.Termination of pregnancy occurs in the presence ofhigh plasma progesterone concentrations (Baanet.al, 2005)..The early administration of aglepristone at 0to 25 days after mating always resulted in preventionof pregnancy. The later administration ofaglepristone at day 26 to 45 after mating inducedresorbtion or abortion within seven days in 96percent of cases. There were no untoward sideeffects. The drug can be administered at a dosage ofJIVA Vol. 10 Issue 1 April 201263

GENERAL ARTICLEJ. Ind. Vet. Assoc., Kerala. 10 (1)10mg/kg body weight (0.33ml/kg/day)subcutaneously twice at 24 hour interval. Efficacy oftreatment for termination of pregnancy is reported tobe 95 percent. No side effects were observed exceptmammary development and lactation. PreparationALIZIN 10 ml vial 30 mg/ml.6. OGESTERONE SYNTHESIS INHIBITORSProgesterone production can be blocked bythe hydroxyl steroid dehydrogenase isomeraseenzyme inhibitors, which prevent the conversion ofprognenelone to progesterone. Prognenelone isbiologically inactive, and therefore progesteronesupport for the pregnancy is lost, resulting inresorption or abortion (Simpson, 1998). Epostane isone such enzyme inhibitor that has no intrinsicoestrogenic, androgenic or progestogenic activity.When administered subcutaneously at the onset ofmetoestrus (dioestrus), epostane will prevent orterminate pregnancy. It can be given at a dose rate of5mg/kg body weight orally for 7 days (Keister et. al,1989).7. TAMOXIFEN CITRATEIt acts as an antiestrogen in premenopausalwomen but has estrogenic activity in dogs. It mayinterfere with zygote transport and/or implantation.Relatively high doses of drug are given twice dailyduring proestrus, oestrus, and early metoestrus. Thedrug was effective in preventing or terminatingpregnancy if administration began during proestrusor estrus or on day 2 of estrus. Efficacy was muchpoor in if the treatment commenced on day 15onwards. It can be given at a dose rate of 1mg/kgorally twice a day for 10 days. A high incidence ofpathological changes in the bitch's reproductive tractis induced by tamoxifen, including ovarian cysts andendometritis, and the compound is of little value forpotential breeding animals (Bowen et.al, 1988).Preparation TAMOFEN Tab 10 mg, TAMOXIFENTab 10, 20 and 40 mg.8. EMBRYOTOXIC AGENTSSeveral novel embryotoxic agents such asphenyltriazole isoindole and isoquinolinecompounds have been evaluated in the bitch. Theyare most effective when given around the time ofimplantation and often only a single administration isrequired. A single sub cutaneous or intra muscularinjection of 2-(3-ethoxy-phenyl)-5, 6-dihydro-striazole[5,1-a]isoquinoline(DL 204-IT) dissolved orsuspended in an oily vehicle is sufficient. Theoptimal time of treatment was found to be day 20 ofgestation, at which time the smallest effective dosewas 6.25 ng/kg (Galliani et. al, 1982). Howevermany of these agents have toxic side effectsincluding vomiting, diarrhoea, weight loss, pyrexia,lethargy and immunosuppression.9. DEXAMETHAZONEDexamethasone administered beginning atmid-gestation can terminate pregnancy in dogs,presumably by activating endogenous mechanismssimilar to those involved in parturition. It can resultin the production of oestrogen and prostaglandin bythe fetoplacental unit. Single dose of glucocorticoidsare not efficacious in the bitch. It can be given at adose rate of 200µg/kg body weight for 7 days andthen at a tapering dose of 10-20 µg/kg for next 3 days(Wanke et. al, 2002). Advantages of such a therapyfor pregnancy termination include the fact that itinvolves only oral administration of a relativelyinexpensive drug; however repeated administrationand high doses make the method impractical.Preparation: - DEXONA Tab 0.5mg, WYMESONETab 0.5 mgCONCLUSIONBefore deciding treatment for misalliance,vaginal cytology should be performed to make surethat mating had taken place. Aglepristone,oestrogens and tamoxifen citrate are the drugs whichcan be preferred for the treatment of misalliance in64

GENERAL ARTICLEdogs. Among these aglepristone is the best drug ofchoice. Due to adverse side effects diethylstilbesterol and tamoxifen citrate are not preferred.During mid gestation from 28-30 days onwardssynthetic prostaglandins, anti prolactins andantiprogesterone therapy are found to be effective. Acombination of prostaglandin and antiprolactin(cabergoline) is found to be highly effective interminating pregnancy. This treatment has theadvantages of being free of side effects, it inducesabortions by resorption, and it works as early as day25. The embryo toxic agents such as phenyltriazoleisoindole and isoquinoline compounds are drugswhich can be tried for pregnancy termination but thetoxic side effects limits its use in dogs.REFERENCEBaan, M, Taverne, M.A.M, Kooistra,H.S, J. deGier, Dieleman, S.J and Okkens, A.C (2005)“Induction of parturition in the bitch with theprogesterone-receptor blocker aglépristone”Theriogenology Volume 63, Issue 7 , Pages1958-1972, 15 April 2005Bowen RA, Olson PN, Young S, Withrow SJ. 1988“Efficacy and toxicity of tamoxifen citrate forprevention and termination of pregnancy inbitches” Am. J. Vet. Res. Jan; 49 (1):27-31.Concannon PW, Yeager A, Frank D, Iyampillai A.1990 “Termination of pregnancy and inductionof premature luteolysis by the antiprogestagen,mifepristone, in dogs” J. Reprod. Fertil. Jan;88(1):99-104.Feldman EC, Davidson AP, Nelson RW, Nyland TG,Munro C 1993 Prostaglandin induction ofabortion in pregnant bitches after misalliance J.Am. Vet. Med. Assoc. Jun 1;202(11):1855-8.Fieni,F, J.F. Bruyas, I. Battut and D. Tainturier 2001“Clinical Use of Anti-Progestins in the Bitch”International Veterinary Information Service,Ithaca NY (www.ivis.org), A1219.0201Galac,S, H.S. Kooistra,J. Butinar, M.M. Bevers, S.J.Dieleman, G. Voorhout, A.C. Okkens 2000Termination of mid-gestation pregnancy inbitches with aglepristone, a progesteronereceptor antagonist. Theriogenology, Volume53, Issue 4 , Pages 941-950.Galliani, G, Lernerm, L.J, Caramel, C., Maraschin.R, Nani, S., Nava, A, Nava, A. 1982 “Pregnancytermination in dogs with novel non-hormonalcompounds. Studies of 2-(3-ethoxy-phenyl)-5,6-dihydro-s-triazole [5,1-a] isoquinoline (DL204-IT)” Arzneimittelforschung. 32 (2): 123-7.Gilian, M. Simpson. 1998 Basava Manual of SmallAnimal Reproduction and Neonatology.Published by British Small Animal VeterinaryAssociation, United Kingdom pp 121-124Keister DM, Gutheil RF, Kaiser LD, D'Ver AS 1989Efficacy of oral epostane administration toterminate pregnancy in mated laboratory bitchesJ. Reprod. Fertil. Suppl. 39:241-9.Onchn, K., L. D. M. Silva and J. P. Verstegen 1995Termination of unwanted Pregnancy in dogswith the dopamine agonist, cabergoline, incombination with a synthetic analog ofpcxzalpha, either cloprostenol or alphaprostol.Theriogenology 43:813-622.Reddy,R.C.K., Sadasiva Rao,K, Solomon Raju, K.G,K.B.Raghavender and A. Gopal Reddy 2010Ind. J. Anim. Reprod. 31(2) 19-22Renukaradhya, G.J, Krishnaswamy, A. andHonnappa,T.G (2008) Studies on thetermination of pregnancy in bitches usingnatural prostaglandins. National Symposium onRecent trends and Future Strategies forimproved Reproduction of Livestock,Companion and wild animals pp - 186Wanke, M.M, S. Romagnoli, J. Verstegen and P. W.Concannon 2002 Pharmacological Approachesto Pregnancy Termination in Dogs and CatsIncluding the Use of Prostaglandins, DopamineAgonists, and Dexamethasone InternationalVeterinary Information Service (www.ivis.org),Ithaca, New York, USAJIVA Vol. 10 Issue 1 April 201265