Theriogenology Question of the Month

Chun K. Mak 1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Emi Sasaki 2Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Rudy W. Bauer 2Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Luis H. de Aguiar 1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Viviane C. L. Gomes 1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Jenny L. Sones 1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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Carlos R. F. Pinto 1Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803.

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History

A 2-year-old 14.7-kg (32.3-lb) sexually intact female Australian Shepherd was referred to the Louisiana State University Veterinary Teaching Hospital (LSU VTH) Theriogenology Service for evaluation because of a 1-week history of anorexia and vomiting and a 7-week history of serosanguineous discharge from the vulva since preterm labor and delivery (50 days after mating) of 9 stillborn pups, with 3 pups delivered vaginally and the remaining 6 pups delivered by cesarean section performed by the referring veterinarian. Postmortem examination of the fetuses was not performed, and the reason for the preterm labor was not further investigated. The referring veterinarian had prescribed enrofloxacin, which the bitch had been receiving for approximately 50 days since the cesarean section.

On referral examination, the bitch had a copious amount of mucoid serosanguineous vulvar discharge, had vital signs within reference limits, and was bright, alert, and responsive. No abnormalities were detected on a CBC and coagulation profile, and plasma progesterone concentration measured with an automated analyzera was < 0.1 ng/mL (reference range, < 0.5 ng/mL for bitches at > 1 week postpartum). In addition, results of a rapid slide agglutination test for the presence of antibodies against Brucella canis were negative. Cytologic examination of a vaginal swab sample revealed predominantly noncornified vaginal epithelial cells (parabasal and small intermediate cells) with numerous RBCs; no trophoblast cells were observed. Transabdominal ultrasonography revealed enlargement of the uterus (uterine diameter, 1.62 cm; reference range, 0.6 to 1.4 cm) with no apparent intraluminal fluid or other contents. Vaginoscopic examination revealed no active bleeding or mucosal bruising. Antimicrobial treatment was discontinued owing to signs of gastrointestinal adverse effects (nausea, anorexia, and emesis) presumed to have been associated with the medication, and the bitch was fitted with an Elizabethan collar and sent home with the owner, who had instructions to call or return if the vulvar discharge persisted.

One month later, the bitch was returned to the LSU VTH Theriogenology Service because of frequent serosanguineous vulvar discharge. The owners reported that the bitch otherwise seemed to have been in good health and was eating and drinking normally. Results of a recheck CBC and coagulation profile were again within reference limits. Cytologic examination of a vaginal swab sample revealed numerous RBCs interspersed among noncornified epithelial cells. Results of abdominal radiography indicated that the uterus was diffusely enlarged and had mineralization in the left uterine horn (Figure 1). Transabdominal ultrasonography revealed that the left uterine horn was diffusely thickened (diameter, 1.93 cm), had intraluminal fluid, and had an area of acoustic shadowing indicative of possible mineralization (Figure 2). The right uterine horn was slightly enlarged but had no intraluminal fluid or areas of abnormal echogenicity.

Figure 1—
Figure 1—

Right lateral (A) and ventrodorsal (B) abdominal radiographic images of a 2-year-old 14.7-kg (32.3-lb) sexually intact female Australian Shepherd with an 11-week history of serosanguineous discharge from the vulva since preterm labor and delivery (50 days after mating) of 9 stillborn pups, with 3 pups delivered vaginally and the remaining 6 pups delivered by cesarean section. A tubular soft tissue–opaque structure, consistent with an enlarged left uterine horn, is superimposed with the dorsal aspect of the urinary bladder, extends cranially and toward the left, and appears to have an area of amorphous, faint mineralization (arrowheads).

Citation: Journal of the American Veterinary Medical Association 257, 11; 10.2460/javma.2020.257.11.1129

Figure 2—
Figure 2—

Transabdominal cross-sectional ultrasonographic image of the left uterine horn (arrowheads) in the bitch described in Figure 1, showing diffuse thickening of the left uterine horn (approx 1.93 cm in diameter), intraluminal fluid (asterisk), and a hyperechoic area with shadowing indicative of possible mineralization (arrow). The scale to the right of the image is in centimeters.

Citation: Journal of the American Veterinary Medical Association 257, 11; 10.2460/javma.2020.257.11.1129

Question

What are differential diagnoses for persistent serosanguineous vulvar discharge with focal mineralization of the uterus in postpartum bitches?

Answer

Subinvolution of placental sites (SIPS), mummified or macerated fetal remnants, retained fetal membranes, endometritis, inflammation of the caudal aspect of the reproductive tract, trauma, neoplasia of the genital tract, and coagulopathy are key differential diagnoses for persistent serosanguineous vulvar discharge with focal mineralization of the uterus in postpartum bitches.

Results

The bitch was referred to the LSU VTH Soft Tissue Surgery Service for an exploratory laparotomy to evaluate the uterus. During laparotomy, both uterine horns had circumferential and segmental thickening and segmental hemorrhagic serosal surfaces. In addition, 2 cysts were identified on the serosa of the right uterine horn, and there were multiple, raised, soft nodules evident in the enlarged uterine horns and body. Because of the potential risk of erosion of the uterine wall leading to hemoabdomen and peritonitis, the owner elected ovariohysterectomy.

The resected reproductive tissues were submitted for gross and histologic examination; however, before fixation in neutral-buffered 10% formalin, the left uterine horn was incised. The lumen contained a small volume of serosanguineous fluid, and the endometrium appeared diffusely red-brown and was segmentally covered with friable necrotic tissue (Figure 3). The left uterine horn also contained segmental swellings in the endometrium, and there was a cystic structure in the lumen of the right uterine horn. Histologic examination revealed evidence of hemorrhage, eosinophilic amorphous acellular debris, fibrin, and moderate numbers of neutrophils in the uterine lumen and in the endometrium at the placental attachment sites. The epithelial cells of the endometrium were hyperplastic and formed numerous papillary projections into the uterine lumen (Figure 4). These epithelial cells had abundant eosinophilic, vacuolated cytoplasm, indicative of progesterone stimulation. The endometrium had areas of ulceration with infiltration of moderate numbers of neutrophils and hemosiderin-laden macrophages, and fewer lymphocytes and plasma cells. There were foci of mineralization and acicular clefts, indicative of cholesterol crystals, in some areas of necrosis. Endometrial glands were dilated and occasionally contained basophilic granular secretory material. The underlying myometrium was markedly compressed and infiltrated by similar inflammatory cells seen in the endometrium. In addition, the myometrium contained a few granulomas that consisted of central basophilic amorphous material surrounded by epithelioid macrophages and fewer lymphocytes and plasma cells. Definitive trophoblast cells were not observed in the examined tissue sections; however, rare, pale basophilic accumulations were seen and closely resembled the mucoid material in endometrial glands, which suggested that the accumulations may have been extruded glandular product. The grossly observed cystic structure of the right uterine horn was identified to have been within the myometrium, lined by a single layer of well-differentiated, cuboidal epithelial cells, and surrounded by a relatively prominent smooth muscle wall. This structure was consistent with a mesonephric duct cyst and considered to have been an incidental finding. Both ovaries contained several corpora lutea that histologically did not appear to have been completely regressed. Retained fetal membranes or evidence of neoplasia was not observed in the examined tissue sections. The histologic findings were supportive of the clinical diagnoses of SIPS and moderate to severe chronic endometritis.

Figure 3—
Figure 3—

Photograph of the isolated uterus and ovaries removed from the bitch described in Figure 1 with the left uterine horn incised transversely, showing a small volume of serosanguineous fluid in the lumen (asterisk) and endometrium that is diffusely red-brown and segmentally covered with friable necrotic tissue. LO = Left ovary. LU = Left uterine horn. RO = Right ovary. RU = Right uterine horn.

Citation: Journal of the American Veterinary Medical Association 257, 11; 10.2460/javma.2020.257.11.1129

Figure 4—
Figure 4—

Photomicrograph of a tissue section from the uterus removed from the bitch described in Figure 1. Eosinophilic amorphous acellular debris (black arrowhead) is in the uterine lumen near a placental attachment site. The epithelial cells lining the endometrium have abundant vacuolated cytoplasm and are hyperplastic, forming papillary projections (asterisk) with occasional extracellular amorphous basophilic secretory material (black arrow). The endometrium is infiltrated with moderate numbers of neutrophils, low numbers of macrophages (yellow arrow), and fewer lymphocytes (yellow arrowhead) and plasma cells (red arrow). H&E stain; bar = 50 μm.

Citation: Journal of the American Veterinary Medical Association 257, 11; 10.2460/javma.2020.257.11.1129

Discussion

Subinvolution of placental sites is a disorder that generally occurs in primiparous bitches ≤ 3 years old1,2 and involves a delay in the involution of placental sites in the endometrium. Typically, expulsion of the fetal membranes and passage of lochia occur immediately postpartum, with vulvar discharge that lasts for 1 to 3 weeks. In contrast, SIPS is characterized by fresh blood discharged from the vulva > 6 weeks postpartum in otherwise healthy bitches.3 To our knowledge, there is no information in the literature that shows whether prolonged or premature parturition, as was the case in the bitch of the present report, is a predisposing factor to SIPS, which occurs most commonly after delivery of healthy pups.

The pathogenesis of SIPS is not well understood. On the basis of histologic observations, uterine involution in dogs is typically completed by 12 weeks after parturition.4 It has been suggested that a continuous invasion of trophoblast-like cells into the endometrium and myometrium could be involved in the pathogenesis of SIPS, which would then prevent normal thrombus formation in endometrial blood vessels.1 This could be the reason for the prolonged duration of vulvar hemorrhagic discharge. It is assumed that these trophoblast-like cells are generally present in the endometrium only during the first 2 weeks after parturition; however, the presence of trophoblast-like cells in vaginal swab samples for up to 84 days after parturition could be considered normal.5 In humans, aberrant trophoblast invasion into the myometrium results in abnormal placental attachment, which leads to a condition known as morbidly adhered placenta or placenta accreta spectrum. Its incidence has substantially and consistently increased during the past few decades.6 Placenta accreta spectrum is characterized by severe retention of the placenta after parturition, which may lead to life-threatening hemorrhage after the fetus delivery, and uterine perforation secondary to septic placenta percreta (invasion of chorionic villi into the myometrium and perimetrium) has been reported in a bitch 4 days after parturition.7 However, because no trophoblast cells were observed in the examined tissue sections from the bitch of the present report, the extent of trophoblast invasion could not be evaluated.

A presumptive diagnosis of SIPS is generally made on the basis of clinical history.3 Results of cytologic examination of vaginal swab samples and ultrasonographic examination of the reproductive tract may be helpful; however, SIPS cannot be ruled out by the absence of multinucleated, heavily vacuolated trophoblast-like cells on cytologic examination. The most appropriate confirmative diagnostic procedure is histologic evaluation of uterine tissue obtained with biopsy or ovariohysterectomy.

If an owner plans to keep a bitch with SIPS for future breeding, the animal is usually monitored closely until its vulvar discharge stops. Although spontaneous remission is common, it may take several months; in some instances, affected bitches may show clinical signs until their next estrus.8 Generally, the prognosis is excellent, and future fertility is not affected by SIPS.9 Oral administration of low-dosage megestrol acetate (a progestin) for 2 weeks has been reported to be effective in stopping persistent sanguineous vulvar discharge in 7 bitches with SIPS, with neither adverse effects nor reduced subsequent fertility.8 It has also been suggested that progestogens possibly promote sloughing of residual trophoblast-like cells with endometrial stimulation. Nonetheless, the risk of causing pyometra by treatment with a progestin2 should be acknowledged. Conservative treatment with ergonovine, oxytocin, and prostaglandin F-2α has also been proposed to treat SIPS; however, the efficacy of these treatments remains undetermined. If a bitch with SIPS is not intended for future breeding, then ovariohysterectomy is commonly recommended for treatment. If clinical signs are severe, such as the presence of severe anemia resulting from prolonged blood loss that may become life-threatening, then blood transfusions, ovariohysterectomy, or both may be needed.

In the bitch of the present report, SIPS was diagnosed by excluding other causes of persistent postpartum serosanguineous vulvar discharge. Although definitive trophoblast cells were not identified on cytologic examination of vaginal swab samples or histologic examination of uterine tissue sections, the delay in uterine involution, pattern of segmental lesions in the uterus, and mineralization at the placental sites were strongly suggestive of SIPS. The extent of necrosis and dystrophic mineralization identified may have masked the typical lesion of SIPS (eg, ellipsoidal enlargements at the placental attachment sites).1,10 Similar to other descriptions of SIPS, endometrial epithelial vacuolation was observed in the bitch of the present report. Although it has been proposed that endometrial epithelial vacuolation is caused by progesterone stimulation,10 the bitch in the present report had a very low plasma progesterone concentration. The discrepancy between the low plasma progesterone concentration and the heavily vacuolated cytoplasm of luteal and endometrial epithelial cells remained unexplained. Possible explanations included the potential for progesterone from a prior pregnancy to have had a long-lasting effect on the endometrium. We propose that future clinical investigations of SIPS should include histologic examinations of the uterus and ovaries and measurements of progesterone concentrations in the blood to document whether protracted stimulation of the endometrium with progesterone could be an underlying factor contributing to SIPS.

Outcome

The bitch of the present report recovered from ovariohysterectomy without complication and was bright and alert and had a well-healed incision site on recheck examination. As expected, the vulvar discharge had stopped after surgery.

Footnotes

a.

AIA 360, Tosoh Bioscience Inc, South San Francisco, Calif.

References

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  • 3. Kutzler MA. Subinvolution of placental sites. In: Bonagura JD, Twedt DC, eds. Kirk's current veterinary therapy XV. St Louis: Saunders Elsevier, 2015;957.

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  • 4. Al-Bassam MA, Thomson RG, O'Donnell L. Normal postpartum involution of the uterus in the dog. Can J Comp Med 1981; 45:217232.

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  • 6. Flood KM, Said S, Geary M, et al. Changing trends in peripartum hysterectomy over the last 4 decades. Am J Obstet Gynecol 2009;200:632.e1632.e6.

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  • 7. Rosenberg LM, Marinoff J, Crouch E, et al. Uterine perforation secondary to metritis and placenta percreta in a postpartum bitch. Can Vet J 2020;61:584588.

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  • 8. Voorhorst MJ, van Brederode JC, Albers-Wolthers CHJ, et al. Successful treatment for subinvolution of placental sites in the bitch with low oral doses of progestagen. Reprod Domest Anim 2013;48:840843.

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  • 9. Sontas HB, Stelletta C, Milani C, et al. Full recovery of subinvolution of placental sites in an American Staffordshire Terrier bitch. J Small Anim Pract 2011;52:4245.

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  • 10. Beck AM, McEntee K. Subinvolution of placental sites in a postpartum bitch. A case report. Cornell Vet 1966;56:269277.

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