Progesterone.

If conservative attempts at therapy are unsuccessful and lactation is persistent, alternatives may be considered. Progesterone administration (megestrol acetate, 2 mg/kg/day for 8 days) actually returns the bitch to a diestrus condition hormonally and usually alleviates signs of clinical pseudopregnancy. However, when progesterone administration is discontinued, there is a repetition of the same hormonal events that initially caused the signs. Thus lactation may recur as the effects of the progesterone dissipate and prolactin is secreted. This form of therapy is not recommended (Concannon and Lein, 1989).

Estrogen or Testosterone.

Estrogen therapy (diethylstilbestrol [DES], 1 mg/day orally for 7 days) may alleviate pseudopregnancy but also may cause signs of proestrus or estrus. Testosterone can be administered at a dose of 1 to 2 mg/kg intramuscularly. The androgen mibolerone (Cheque) has been moderately successful in reducing the physical and psychologic signs of pseudopregnancy. The dose recommended is 0.016 mg/kg orally, once daily, for 5 days (Brown, 1984). However, fewer than 50% of the 63 dogs with physical evidence of pseudopregnancy responded. The response seen in bitches with psychologic problems associated with pseudopregnancy was better.

Prolactin Inhibitors.

Ergot alkaloids (ergolines) and their derivatives have been identified as potent prolactin inhibitors (Krulich et al, 1981; Ferrari et al, 1982). They act via direct dopamine receptor stimulation at the level of the pituitary gland. Bromocriptine, an ergoline compound and dopamine agonist, inhibits pituitary secretion of prolactin. Bromocriptine, administered orally at 0.01 to 0.1 mg/kg/day in divided doses, does inhibit lactation and should be given until lactation ceases (Mialot et al, 1981, 1982; Janssens, 1986). Side effects to bromocriptine are common and include vomiting, anorexia, depression, and behavioral changes (Peterson and Drucker, 1981). Vomiting can be reduced by administering an antiemetic drug at the time bromocriptine is given. This is our drug of choice if aggressive treatment of a bitch is necessary; however, we have never needed to use it.

An equally effective but better-tolerated ergoline compound (cabergoline) was identified and evaluated. Cabergoline, administered at a dose of 5 μg/kg once daily for 5 to 10 days, was effective at sharply dropping prolactin concentrations and suppressing lactation in more than 95% of the bitches treated (Di Salle et al, 1984; Jochle et al, 1987; Arbeiter et al 1988). Side effects were considered mild and included lethargy (25% of dogs), inappetence, and vomiting (<5% of dogs). Success was slightly lower (21 of 26 dogs) in a more recent study (Harvey et al, 1997). Furthermore, the conclusion of the most recent study was that cabergoline is effective in suppressing prolactin release from the pituitary gland, but that this suppression may only be transient.

The drug has also been used to induce abortion in the second half of pregnancy in the bitch (Post et al, 1988). In a comparison between cabergoline and bromocriptine use in women, cabergoline was more effective and better-tolerated when used for hyperprolactinemic amenorrhea (Webster et al, 1994).

Ovariohysterectomy.

Ovariohysterectomy (OVH), also referred to as spaying, is the one therapy that should not be considered or recommended in any pseudopregnant dog. The procedure may exacerbate the syndrome by eliminating progesterone from the system and further stimulate prolactin secretion. On rare occasions, OVH may result in prolonged signs. In fact, because of this concern, some authors recommend avoiding OVH until a period of 4 to 5 months after the previous heat has passed (Harvey, 1998).

Systemic Disease.

Any factor causing significant stress or damage to the uterus or fetus can cause fetal death. Included among these problems is any serious disease within or outside the reproductive tract. For example, a bitch that develops severe cardiac disease during pregnancy is likely to have a compromised uterine blood supply, leading to fetal death. Similar problems can arise with any major organ disease. Hypothyroidism has been included as a potential cause for abortion. The veterinarian must remember that a bitch ill from any significant systemic illness may be euthyroid but have thyroid function test results consistent with hypothyroidism (euthyroid sick syndrome; see Chapter 3). Diabetes mellitus, perhaps the most common endocrine disease in dogs, is definitely associated with an inability to carry a litter to term and abortion. All female dogs with diabetes should undergo OVH.

Uterine Disease.

Another broad subcategory includes the abnormal uterus that is unable to support pregnancy. Among these problems are cystic endometrial hyperplasia, chronic uterine infections, uterine neoplasia, and uterine adhesions.

Hypoluteoidism.

Pregnancy is maintained by progesterone derived from ovarian corpora lutea. Failure to maintain progesterone concentrations above a critical level (1.0 to 2.0 ng/ml) is likely to result in expulsion of the fetus. A luteal phase defect has been associated with pregnancy failure in women, but the diagnosis is considered controversial (Meis et al, 2003). The syndrome has not been well documented in dogs (Olson, 1988), although one case has been described (Purswell, 1991). Progesterone insufficiency is possible, and progesterone concentrations may be low at the time of an abortion. The decreases, however, may be secondary to fetal death rather than representing the primary cause. It has been demonstrated that fetal death will result, within days, in subsequent decreases in serum progesterone concentration (Concannon et al, 1990). Furthermore, fetal distress secondary to virtually any cause may result in decreased serum progesterone concentrations (Johnston et al, 2001). Subnormal progesterone concentrations in a bitch that has already aborted is not proof of hypoluteoidism.

If progesterone is administered to a bitch with impending abortion, delivery may be interrupted even if the cause of the disorder is an infectious disease. Therefore it is advisable to educate owners regarding the potential adverse effects of preventing delivery: continued fetal growth and subsequent dystocia; and potential teratogenic effects, especially masculinization of female fetuses. Maintaining the inciting cause of abortion (e.g., infected fetus) could further harm or threaten the life of other fetuses or the bitch.

The diagnosis of hypoluteoidism is difficult, explaining the controversial nature of the diagnosis. It is imperative that pregnancy be confirmed with ultrasonography and closely monitored. Serum progesterone concentrations should be assessed at least twice weekly. If a known pregnant bitch aborts a litter following documented premature decreases in progesterone concentration in the serum, and no cause for the abortion is identified despite thorough necropsy, culture, and other testing of fetal and placental tissue, the diagnosis of hypoluteoidism can be considered.

It is accepted that serum progesterone concentrations must be in excess of 2 ng/ml for maintenance of pregnancy. However, such concentrations are at the detection limits of ELISA kits, which usually estimate concentrations as less than 1 ng/ml, 1 to 5 ng/ml, and greater than 5 ng/ml. Precise determination of progesterone concentration is critical in the diagnosis. The veterinarian cannot be completely confident using in-hospital assay systems. The bitch described in the Purswell report may not have had hypoluteoidism, because the laboratory progesterone value at the time of diagnosis with the kit was rechecked and documented to be 6.5 ng/ml (Purswell, 1991). One value should be considered inadequate to confirm a diagnosis. Laboratory progesterone concentrations should be used to confirm or deny borderline results. Does the syndrome exist? Possibly.

If treatment is attempted for hypoluteoidism, several strategies can be employed. It is important to know the first day of diestrus, as defined with vaginal cytology (see Chapter 19). Exogenous progesterone should be discontinued after 50 to 53 days of diestrus (whelping typically occurs 55 to 58 days into diestrus). A recent study demonstrated that 3 mg/kg of progesterone in oil, intramuscularly, once daily (Progesterone Injection; Steris Laboratories Inc, Phoenix, AZ) is adequate to maintain serum concentrations above 10 ng/ml. Serum progesterone concentrations decreased below 2 ng/ml 48 to 72 hours after the final injection (Scott-Moncrieff et al, 1990). As little as 2 mg/kg every 48 hours may be sufficient to maintain pregnancy (Eilts, 1992). Alternatively, synthetic progesterone (17α-ethyl-19-nor-testosterone [Steraloids Inc, Denville, NJ]), 1 mg/kg SC daily, has been used successfully in maintaining pregnancy in ovariectomized bitches (Steinetz et al, 1989). The use of Ovaban (Schering, Union City, NJ) for preventing hypoluteoidism has not been described, although undocumented reports of 5 mg/day until day 55 of diestrus have been suggested.

An oral progestogen, allytrenbolone (Regumate, Hoechst RA), has been evaluated for maintaining pregnancy in ovariectomized bitches. Bitches were treated following ovariectomy on day 30 to 32 of pregnancy. Treatment was continued through day 54 of cytologic diestrus. The use of 0.044 mg/kg daily maintained pregnancy in only two of six pregnant bitches. The use of 0.088 mg/kg (0.2 cc/10 pounds) resulted in three of three bitches carrying their litters to term, with parturition beginning on the expected date in each. However, although two bitches had normal parturition, one had dystocia and death of all puppies. None of the bitches receiving the Regumate at either dosage had optimal milk production. Several litters were said to have been nursed by untreated controls, one bitch was able to nurse most of her litter 3 days after whelping, and one was able to nurse her entire litter beginning 3 days after whelping. Prolactin secretion was assumed to be suppressed by the drug in all bitches. If use of the drug is contemplated, clients must be warned that milk supplementation may be needed. In addition, the drug should not be used unless whelping dates have been reliably estimated, with serial progesterone concentrations obtained during proestrus and early estrus or with vaginal smears used for identifying day one of diestrus (Eilts, 1992).

Trauma.

Trauma is an extremely unlikely cause for abortion. However, any significant blow to the abdomen has the potential of causing damage to the uterus or fetus, which could lead to abortion.

Nutrition, Drugs, Vaccines.

These factors are considered uncommon causes for abortion. Each is reviewed in Chapter 20.

Brucella canis Infection.

See Chapter 26.

Canine Herpesvirus Infection.

Canine herpesvirus (CHV) is fairly ubiquitous in dogs, with 80% to 100% of certain populations having been exposed. Dogs in contact with many other dogs, via shows or in kennels with a great deal of turnover, are at greatest risk. Lifelong states of latent infection can occur, and immune responses are characterized as minimal and/or short-lived. Therefore, any serum-neutralizing antibody titer is significant, especially if coupled with clinical signs. Recrudescent canine herpes with virus shedding may be stimulated by the stress of pregnancy and parturition.

CHV infection in neonatal pups is an acute fatal infectious disease characterized by generalized focal necrosis and hemorrhage. The disease in adult dogs is usually subclinical or mild, such as conjunctivitis, serous or mucopurulent ocular and/or nasal discharges, and vaginal/vestibular/vulvar lesions that are vesicular early in the course of the disease and later become circular and pock-like. Genital lesions usually disappear shortly after infection, but they may reappear with the onset of proestrus. Canine herpes virus infection can result in fetal resorption and/or mummification if the bitch is infected early in gestation, abortion if the bitch is infected in mid-gestation, or premature birth if infection occurs in late pregnancy (England, 1998). A bitch may have dead and/or mummified fetuses in the same litter with unaffected live pups. Abortion has occurred between 44 to 51 days of gestation following infection on day 30. It is also possible for an infected bitch to be infertile or to have litters that are small in number. The fetal placenta from a bitch with canine herpesvirus infection is typically underdeveloped and congested. Several grayish white foci ranging in size from miliary to “rice grain” in size can be observed in the placental labyrinth. Sometimes the lesions form zonal structures 2 to 3 mm wide. Typical changes are also seen histologically.

Transmission of herpesvirus can occur venereally, transplacentally, via fetal contact with virus-filled vesicles that rupture during birth, or through respiratory routes of infection. Diagnosis depends on viral isolation. Viral isolation requires fastidious sampling and culture techniques from refrigerated but not frozen tissue. A negative culture for this virus may be due to inadequate methodology. Separation of infected animals from noninfected animals is advisable, especially in the final 3 weeks of gestation and the first 3 weeks of life. Because no vaccine is available for prevention, veterinarians can only recommend careful physical examination and review of the history from dogs to be used in a breeding program (Hashimoto and Hirai, 1986; Evermann, 1989).

Toxoplasmosis.

This is an uncommon cause of canine abortion; dogs are an intermediate host for Toxoplasma infection. Cats are the only definitive host. Routes of infection include congenital exposure, ingestion of oocysts in cat feces, or ingestion of infected meat. Diagnosis should be suspected when paired serum samples obtained 3 weeks apart demonstrate a greater than fourfold increase in titer. Previous exposure can produce increased titers. Prevention is accomplished by preventing exposure to cat litter or raw meat.

Mycoplasma and Ureaplasma Infections.

These microorganisms are among the recognized normal flora in the canine vagina. Mycoplasma and Ureaplasma isolates have been implicated in infertility, early embryonic death/resorption, abortion, stillbirths, and neonatal morbidity and mortality. Dogs may be exposed to large concentrations of these organisms in crowded kennel conditions. Diagnosis is always tentative at best because positive vaginal cultures may simply include normal flora, and identifying the pathologic situation usually depends on demonstrating pure infection with one of these organisms in a bitch with metritis/vaginitis. Mycoplasma- or Ureaplasma-induced abortion is rare. Treatment involves the administration of chloramphenicol or tetracycline for 10 to 14 days. These antibiotics should not be given to neonates or to nursing bitches. The pregnant bitch can be treated with erythromycin, although this antibiotic is not as effective and it may result in gastrointestinal problems (Lein, 1986; Purswell, 1992).