A Combination of Oral Cabergoline and Double Cloprostenol Injections to Produce Third-Quarter Gestation Termination in the Bitch
To assess the efficacy and safety of a combined cabergoline and cloprostenol protocol to terminate third-quarter pregnancy, 22 pregnant bitches that ranged from 35 to 45 days after mating were randomly assigned to a treatment group (n=13) or to an untreated control group (n=9). The animals were monitored for 12 days, and pregnancy termination was confirmed by ultrasound examination. Twelve of the 13 treated bitches aborted within 9 days of the initiation of treatment (mean 4.6 days). Only mild side effects were observed. The control animals had normal gestational courses, as did the bitch that did not respond to the therapy. This combination of drugs appeared to be a practical, safe, and efficient abortifacient when used in third-quarter pregnancies.
Introduction
Nonsurgical termination of unwanted pregnancy is one of the major reproductive difficulties in canine practice. While ovariohysterectomy is the solution in many cases, nonsurgical termination can be difficult because of the unavailability of some abortifacients in certain countries and the side effects associated with some of the more commonly used drugs. Such side effects may require the dogs to be hospitalized for several days, with the resultant significant expense.1
Prostaglandin F2α (PGF) analogs and dopaminergic agonists, as well as their combinations, have been used successfully for pregnancy termination in the dog.2–11 A synergistic effect may explain how dopaminergic agonists and PGF decrease serum progesterone, the essential hormone for pregnancy maintenance.9 Prostaglandin F2α analogs have a direct luteolytic action, while dopaminergic agonists act indirectly on the corpus luteum by withdrawing the main luteotropic hormone (i.e., prolactin) during the second half of the luteal phase.2,12–14 Cabergoline and cloprostenol are among the most potent representatives of the dopaminergic agonists and PGFs, respectively.12,14,15 As a result, the dosages required of these drugs can be reduced significantly in relation to other compounds in the same pharmacological groups, thus diminishing their side effects.
As a general rule, the action of combined abortifacient drugs is facilitated (i.e., is more rapid) by advanced gestational age. Protocols initiated later in gestation usually require a shorter treatment period, although they may result in abortion of recognizable fetuses, which some clients may find objectionable.5,15 In clinical practice, rapidity of effect should be weighed against the abortion of developed fetuses. Third-quarter pregnancy termination (i.e., days 35 to 45) appears to be a good compromise that produces relatively rapid pregnancy termination in a fashion that is acceptable to the owner.
Another practical aspect to consider when selecting a pharmacological protocol for pregnancy termination is the number of parenteral applications required. Numerous injections may be objectionable or may cause compliance problems, resulting in failure. The purpose of this study was to assess the efficacy and safety of a combined protocol of cabergoline per os [PO] and two subcutaneous [SC] injections of cloprostenol to terminate pregnancy at 35 to 45 days in bitches.
Materials and Methods
Study Animals
Twenty-two, healthy, mixed-breed and pure-bred bitches that had been referred for pregnancy termination were included in this trial. The dogs ranged in age from 1 to 10 years and in weight from 10 to 45 kg. Pregnancy was confirmed in all the animals using transabdominal ultrasonography.16 The bitches remained in their normal surroundings at home during the study, except at the times of injections and clinical examinations. Written, informed consent was obtained from all owners.
Pharmacological Protocol
Between days 35 and 45 from the first mating, the bitches were allocated randomly to either a treatment or control group.17 Dogs in the treatment group (n=13) received cabergolinea (5 μg/kg PO q 24 hours) for 7 days in food, and cloprostenolb (1 μg/kg SC after tenfold dilution in physiological saline) on days 1 and 3, given at least 8 hours after food. If pregnancy was not terminated by day 8, the same dose of cabergoline was continued until day 12. Dogs in the second group were not treated in any way and were used as controls (n=9).
Clinical Follow-up
All the dogs were clinically monitored for 12 days after initiation of the trial. Clinical examinations included evaluation of behavioral changes, body temperature, vulvar discharge, evidence of abortion, and appearance of local or systemic side effects. Clinical suspicion of pregnancy termination was considered when vaginal discharge or prepartum behavior developed, body temperature decreased by >1°C (33.8°F), or fetuses were expelled. Owners were encouraged to observe their dogs as often as possible and to record when and if abortion occurred during the study period.
Ultrasonographic Monitoring
Within 8 hours of the owner suspecting that pregnancy termination had occurred, bitches were monitored ultrasonographically to confirm that termination had taken place.c,16 Success was defined as uterine vacuity.5,9,17 If no clinical signs of termination were visible externally, ultrasound examination was repeated on day 8. If no evidence of termination was found, ultrasonography was repeated again on day 12.
Statistical Analysis
The frequency of pregnancy termination in bitches was analyzed by PROC FREC (i.e., chi-square).d Days to pregnancy termination were characterized by PROC MEANS (i.e., descriptive statistics), and results were expressed as least square means ± standard error of the mean (LSM ± SEM).d A statistically significant P value was set at <0.05.
Results
Significant differences were found between the two groups of dogs. In 12 of the 13 treated bitches, pregnancy termination was confirmed ultrasonographically within 4.6±0.7 days (range 2 to 9 days) after initiation of treatment. For 11 dogs, the entire abortion probably occurred in <8 hours, except for one animal (case no. 5) in which abortion occurred on 2 days, 48 hours apart. This animal was excluded from the descriptive statistics, because treatment response was different from the rest of the group. Seven of the aborting bitches exhibited preparturient-like behavior (e.g., anxiety and nesting) and had a decrease in body temperature before termination. In eight of these 12 dogs, neither the abortion nor the expulsed fetuses were observed by the owners. The nonresponsive bitch (case no. 11) and all the control animals developed no clinical signs compatible with pregnancy termination, and ultrasound examinations on days 8 and 12 revealed normal gestations [see Table].
Side effects were mild, occurred in only three of the treated bitches, and included vomiting, nausea, retching, and panting. Signs were observed 10 to 15 minutes after the cloprostenol injections and lasted for approximately 15 to 20 minutes. Abortion was followed by 5 to 8 days of mucoid sanguineous vulvar discharge in all the dogs. Slight mammary enlargement (n=6) and milk secretion (n=4) were also noted in some aborting bitches.
Discussion
In designing the present protocol, the availability of the drugs, the practicality of administration, efficacy, and safety were all considered. Both cabergoline and cloprostenol are available either in the veterinary and/or human pharmaceutical market in many countries. This combined protocol was easily administered in an outpatient setting. In the present trial, nine (69%) of 13 treated bitches required a total of three visits (i.e., first pregnancy diagnosis and initial medication, PGF administration, and abortion confirmation) to the clinic. For the other three responding animals, only one additional visit was necessary.
Although in combined protocols, gestational age is known to affect the number of days treatment is required, in most clinical settings the duration of pregnancy is estimated from the date of mating.5,15 In the present trial, the date of mating was used rather than an actual endocrine-proven gestational age. In cases where the owners do not know the breeding date, gestation duration may be calculated by an ultrasound examination.16
In a previous study, a similar protocol was used, but cloprostenol was given on days 1 and 5 starting 25 days after mating.9 In that study, resorption of fetuses was achieved in four of five treated bitches at 5 to 12 days after the initiation of the treatment.9 In the present trial, a higher success rate (92.3% versus 80%) and a more rapid effect were obtained. These differences may simply be explained by the later onset of the pharmacological treatments in the present trial. Considering that resorption is usually better accepted than abortion by clients, owners should be fully informed beforehand about the abortion process and advised about the number of potential clinic visits required. The actual abortion period was probably short, as most of the owners did not observe the abortion or the expulsed fetuses. It is also possible the bitches ingested the expelled material.
In the present trial, the proportion of failures was low, but the exact cause of these failures remains difficult to explain. Prolongation of dopaminergic agonist and use of PGF protocols until the desired effect is achieved have been previously recommended and may have altered the outcome of this study.5
Although rare, split abortions (as occurred in case no. 5) have been previously reported using this combination of drugs.5 Measuring daily progesterone serum concentrations in the future may reveal the reason for prolongation of the process in some cases. Demonstration of a split abortion emphasized that treatment and evaluation must continue until abortion is deemed complete by ultrasonographic evaluation. Educating the owners about the clinical signs to look for and the ultrasound evaluations is crucial for rapid success of confirmation of pregnancy termination and avoidance of unnecessary prolongation of treatment.
Similar to earlier studies, no side effects or only minor side effects were associated with the low dose of PGF used in this study. The fact that the potent PGF cloprostenol was administered at least 8 hours after feeding may have lessened the severity of the side effects.5,9 The mammary enlargement and lactation that was induced in some of the aborting animals may have occurred from a decline in progesterone-related negative feedback following pharmacological luteolysis, which subsequently resulted in an elevation of serum prolactin.18
Conclusion
Pregnancies were terminated in 12 of 13 bitches treated with a combination of oral cabergoline and two cloprostenol injections, 35 to 45 days after mating. This combination appeared to be a practical, safe, and efficient abortifacient protocol and was suitable for use in an outpatient setting. Future evaluations of this combined protocol in a larger number of dogs are warranted.
Galastop; Ceva-Santé Animate, Libourne, France
Estrumate; Schering Plough, Buenos Aries, Argentina
Toshiba Core Visión Pro; Shimoishigami, Otawara-Shi, Tochigi-Ken, Japan
Statistical Analysis System (SAS); SAS Institute, Cary, NC 27513
Acknowledgments
The authors thank Ceva-Santé Animate in Libourne, France, for supplying the Galastop, and Schering Plough in Buenos Aries, Argentina, for supplying the Estrumate for the study.
Contributor Notes
