Laboratory Animal Science Vol 49, No 4 Copyright 1999 August 1999 by the American Association for Laboratory Animal Science

Pregnancy Toxemia in the European Ferret (Mustela putorius furo)

Margaret A. Batchelder,1* Judith A. Bell,2 Susan E. Erdman,1 Robert P. Marini,1 James C. Murphy,1 and James G. Fox1† Background and Objective: toxemia may lead to appreciable mortality among jills and their off- spring. The objective of this report was to increase awareness of the disease, its likely cause, and practical prevention and treatment measures. Methods: Ten cases of pregnancy toxemia were evaluated. Jills were in late gestation (mean, 38 days; range, 34 to 42 days) and had large litters (mean, 11.5 kits; range, 7 to 15 kits). Results: The most common clinical signs of disease were lethargy, inappetence, dehydration, and excess shedding. Hematologic and clinical biochemical abnormalities included anemia (4 of 8 jills tested), hypopro- teinemia (5 of 7), azotemia (7 of 7), hypocalcemia (5 of 6), hyperbilirubinemia (3 of 3), and high liver enzyme activities (6 of 6). Two jills were found dead; two jills were euthanized, six received supportive treatment, and cesarean section was performed on five. The three jills that survived tended to have less pronounced azotemia, , and liver enzyme activity increases and were not anemic. Hepatic lipidosis was observed grossly in all jills that died and was confirmed by histologic examination in four jills. Conclusions: Pregnancy toxemia in ferrets resembles metabolic diseases in several other animal species and requires aggressive treatment, including supportive care, nutritional supplementation, and cesarean section. Maintaining adequate nutrition and avoiding stress late in gestation may prevent the disease.

Pregnancy toxemia is a metabolic disease of ferrets that is Materials and Methods associated with substantial mortality among affected jills and Animals: The signalment, clinical history, physical exami- their offspring. Although it is a recognized clinical syndrome, it nation, treatment, clinical pathologic, necropsy, and histo- has been only briefly described in literature (1–4). The disease pathologic findings were reviewed for 10 cases of pregnancy is characterized by abnormal fat and carbohydrate toxemia that developed in European ferrets (Mustela putorius due to energy imbalance and is potentially fatal for the jill and furo) housed at a facility that has animal care and use pro- kits. It develops sporadically during late gestation, with in- grams accredited by AAALAC, International (cases 1 to 5) or creased prevalence in primiparous jills, those with a high fetal at a commercial ferret breeding facility (cases 6 to 10). Fer- load, or in association with environmental or dietary stresses. rets at the research facility had been obtained from the The primary etiologic factor in the disease is development same commercial breeding facility for use in studies ap- of a relative energy deficiency, either from excess demand or proved by the Institutional Animal Care and Use Committee. from inadequate dietary intake. The pathophysiology re- In addition, samples were obtained from six anes- sembles that of several periparturient diseases in rumi- thetized, apparently healthy primaparous jills from the nants, camelids, rodents, and mink (5–16) as well as feline same source as jills 6 to 10 within several hours of parturi- idiopathic hepatic lipidosis (IHL) (17, 18) and human acute tion to provide nontoxemic postpartum hematologic and se- fatty liver of pregnancy (AFLP) (19). In contrast, pregnancy rum biochemical values. These jills lacked maternal instinct toxemias in humans (preeclampsia-eclampsia), some nonhu- and had savaged or abandoned their litters, a relatively com- man primates, nonobese guinea pigs, and hamsters appear mon occurrence among primaparous jills (2 to 6% in this fa- to have a different etiopathogenesis (20–28). cility). The jills were otherwise completely normal and had We describe the syndrome of pregnancy toxemia in ferrets, no signs of toxemia or other disease. review 10 clinical cases, and discuss etiologic, diagnostic, Jills at the research facility were housed under conven- and treatment considerations. We also compare the etio- tional conditions in stainless steel cages (24 x 24 x 24 in.) pathogenesis with that of feline IHL, pregnancy toxemia in with drop pans and wire grid floors lined daily with paper- humans and other animal species, and human AFLP. board (Techboard; Sheperd Specialty Papers, Inc., Kalamazoo, Mich.), and were provided stainless steel nest Division of Comparative Medicine, Massachusetts Institute of Technology, boxes with torn paperboard bedding. Food (Purina Cat Cambridge, Massachusetts1; and Unit 98, 301 College Avenue, West, Guelph, Ontario Canada2 Chow; Ralston Purina Co., St. Louis, Mo., or Laboratory *Present address: Institute for Animal Studies, Albert Einstein College High Density Ferret Diet; PMI Feeds, Inc., St. Louis, Mo., of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. except as otherwise noted under treatment) and water were †Address correspondence to: Dr. James G. Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, Bldg. 16-825, 77 Massa- provided ad libitum. The ferrets were maintained in a con- chusetts Avenue, Cambridge, MA 02139-4307. trolled environment with a room temperature of 18 to 23ЊC,

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humidity of 40 to 65%, photoperiod of 14 h light/10 h dark, to diet to achieve 30% total fat and 40% crude protein; and ventilation with 100% fresh air supply and 12 complete Nutrical; Ensure, Ross Products Division, Abbott Laborato- air changes/h. Jills were screened during quarantine by use ries, Columbus, Ohio; Liquical, Advanced Nutritional Tech- of fecal flotation analysis and rectal specimen culture for nologies, Inc., Dublin, Calif.; commercial human baby food; common enteric pathogens and were free of Salmonella and and/or “eggnog,” a homogenate of 8 oz. milk, 2 oz. cream, and Campylobacter spp. 1 egg yolk), sulfamethoxazole and trimethoprim (Sulfatrim Jills at the commercial breeding facility (including control suspension, 0.5 ml orally once daily; Barre-National, Inc., jills) were individually housed under conventional condi- Baltimore, Md.), and flunixin meglumine (1.1 mg/kg i.v. once tions in galvanized metal cages (1 x 1-in. wire mesh, 18 x 24 daily for 2 days). Pregnancy toxemia was not recognized in x 12 in. high) with plastic nest boxes filled with shredded jill 8 prior to cesarean surgery, and it did not receive any aspen bedding. Food (Marshall Premium Ferret Diet; other treatment. Marshall Farms, North Rose, N.Y., except as otherwise noted Jill 5 had nine kits (six stillborn) on day 42 of gestation. under treatment) and water (automatic watering system) Jills 6 to 10 underwent cesarean section on days 36 to 42 of were provided ad libitum. The photoperiod was 16 h light/8 h gestation while under anesthesia using halothane (jills 6, 7, darkness, and room temperature was maintained between 7 and 9) or a mixture of 12.5 mg of ketamine and 2.5 mg of to 15.5ЊC during the study period. Microbiological status xylazine per jill i.m., followed by 1.1 mg of yohimbine/kg i.v. was undefined, but coccidia were often present in juveniles after surgery (jills 8 and 10). in the facility. Jills were treated topically for ear mites with ivermectin (100 ␮g/kg) 3 weeks prior to their due date. Results Diagnostic methods: Diagnostic methods included one Signalment, history, physical examination, and out- or more of the following (Tables 1 and 2): signalment, his- come: The signalment, history, physical examination find- tory, and physical examination; hematology (packed cell vol- ings, and outcome for each case are summarized in Table 1. ume [PCV] and white blood cell [WBC] count performed Cases 1 to 5 were adult multiparous jills (>12 months of in-house at each institution); biochemical analysis age), and cases 6 to 10 were 6- to 7-month-old primiparous (Corning Clinical Laboratories, Cambridge, Mass.; Maryland jills. All cases were observed during the last 8 days of gesta- Medical MetPath, Baltimore, Md.); urinalysis (Multistix 10 tion. The litter size was recorded in eight cases; the average SG; Miles, Inc., Elkhart, Ind.); and abdominal radiography. recorded litter size was 11.5 (range, 7 to 15). For the three Blood samples for jills 3 to 5 were taken the day clinical ferrets that survived toxemia, the average litter size was 9.3 signs of disease were noticed, before treatment was initi- (range, 7 to 12); the average litter size for five toxemic jills ated. Blood samples for jills 6, 7, 9, and 10 were taken after that died or were euthanized was 12.8 (range, 7 to 15). The anesthesia for cesarean section, but before fluid therapy. The six control postpartum jills had an average litter size of 10. sample from jill 8 was taken the day after surgery, just prior Among the eight jills alive at presentation, the reported to death. Gross and/or histologic examination was performed clinical signs of disease included lethargy (7 of 8), decreased in jills that died. Gross liver appearance was noted during appetite (6 of 8), clinical dehydration (6 of 8), excess shed- surgery in jills 7 and 9. ding (4 of 8), melena (2 of 8), slight icterus (2 of 8), diarrhea Treatment: Jills 1 and 2 were found dead. Jill 3 was (1 of 8), and dyspnea (1 of 8). Rectal temperature recorded in treated subcutaneously with lactated Ringer’s solution jills 3 and 5 was slightly low (37.2ЊC and 36.8ЊC; normal, (LRS), intravenously (i.v.) with gentamicin sulfate (2.2 mg/ 37.8 to 40.0ЊC [29]). Jill 5 was thin; jill 4 had a recorded kg, once; Steris Laboratories, Inc., Phoenix, Ariz.) and heart rate of 200 beats/min (normal 200 to 400 beats/min [29]). flunixin meglumine (Banamine, 1.1 mg/kg i.v., once; Five jills (cases 5, 7 to 10) produced live offspring. Jill 5 Schering-Plough Animal Health, Kenilworth, N.J.) before gave birth to three live and six stillborn kits on day 42 of euthanasia due to poor prognosis. Jill 4 was not treated prior gestation, although abdominal radiography on day 34 of ges- to euthanasia. Jill 5 was treated subcutaneously with LRS, tation had not definitively demonstrated fetal ossification. and by hand feeding with moistened Laboratory High Den- The live kits were removed to a foster jill but did not survive. sity Ferret Diet and dietary supplements (Nutrical; Evsco Jills 7 to 10 underwent cesarean section, and each had some Pharmaceuticals, IGI Inc., Buena, N.J. and canned Science live kits that were removed to foster jills. Some surviving Diet Feline Growth; Hill’s Division of Colgate-Palmolive Co., kits were returned to jills 7 and 9, 24 to 48 h after recovery Topeka, Kans.), calcium gluconate (Lyphomed, 52 mg/kg in from surgery. The number of kits surviving to weaning was subcutaneous fluids once daily; Fujisawa USA Inc., not recorded, but at least some were reared successfully. Deerfield, Ill.), and vitamin B complex (0.5 ml intramuscu- Hematologic and clinical biochemical results: He- larly [i.m.] once daily; Phoenix Pharmaceuticals, Inc., St. Jo- matologic and clinical biochemical findings are summarized seph, Mo.). in Table 2. On the basis of the hematologic and biochemical Jills 6, 7, 9, and 10 were treated according to the standard values derived from the postpartum control jills (mean Ϯ 2 treatment protocol for jills with pregnancy toxemia at the SD), half (4 of 8) of the toxemic jills tested were anemic; two commercial breeding facility. This included subcutaneous or had hemolysis despite careful blood sample collection. Hypo- i.v. fluid administration at the time of cesarean surgery proteinemia (5 of 7), azotemia (7 of 7), hypocalcemia (5 of 6, (LRS supplemented with 5% dextrose); hand feeding with even after adjustment for low albumin concentration), and moistened Marshall Premium Ferret Diet, nutritional high liver enzyme activities (6 of 6) also were detected. Some supplements (one or more of the following: animal fat added jills had hyponatremia (2 of 4), hypochloremia (3 of 4), hy-

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Table 1. Signalment, history, physical examination findings, and outcome for 10 jills with pregnancy toxemia Source and identification no. of jills Research facility Commercial breeding facility 12345678910 Signalment Age (mo, approx.) >12 12 >12 12 12 6–7 6–7 6–7 6–7 6–7 Primagravida – – – – – + + + + + Gestation (d) late 34 40 37 34 40 40 42 40 36 Number in litter 15 7 9 13 7 14 12 15 Kit survivala ––––– – + + History Inappetance + + + + + + Lethargy + + + + + + + Diarrhea + Melena + + Physical Lethargy + + + + + + examination Dehydration + + + + + + Dyspnea + Icterus Slight Slight Excess shedding ++–++ Gross findings Yellow/fatty liver + + + + + +b ++b + Outcome Died Died Euthanized Euthanized Survived Died Survived Died Survived Died + = yes or present; – = no or absent; blank, not evaluated/not reported. aOne or more kits survived until weaning. bObserved during surgery. perkalemia (1 of 3), or acidosis (2 of 4). Blood glucose concen- areas of necrosis were seen in the placental tissue of jills 1 tration was normal (5 of 7), low (1 of 7), or high (1 of 7). Val- and 3, but were interpreted to have developed just prior to or ues for the toxemic jills sometimes were outside the normal after death and were not considered pathologically relevant. range for nonparturient adult jills (29), but within the range derived from the six postpartum control jills. In three of six Discussion cases, the phosphorus values were below those of postpar- The term “pregnancy toxemia” may designate different tum jills, but within the lower nonparturient normal range disease syndromes depending on the species under consider- (mean Ϯ 2 SD, 3.5 to 9.5 mg/dl [29]). Eleven days after par- ation. There appear to be two general types of pregnancy turition (18 days after initiation of treatment), serum bio- toxemias, principally metabolic or principally vascular in chemical values in jill 5 were near or within the normal origin. Pregnancy toxemia in the ferret is of the metabolic nonparturient ranges (29) (data not shown). type. The pathogenesis is similar to that of several Urinalysis: Ketonuria and bilirubinuria were detected in periparturient metabolic diseases in other species (6) as well jill 5 on the day of presentation; urinalysis results for glu- as feline IHL (17, 18). These diseases are characterized by cose were negative, and quantities were insufficient to per- abnormal energy metabolism, which leads to variable de- form additional analyses (data not shown). Four days later, grees of hyperlipidemia, , ketosis, and hepatic prior to parturition but after initial treatment, bilirubinuria lipidosis. Ovine pregnancy toxemia develops in late gesta- persisted but ketonuria was not detectable. At that time, tion in ewes with a large fetal load and/or a decreasing plane protein (100 mg/dl), urobilinogen (0.2 mg/dl), and a trace of of nutrition (5, 8, 11, 13, 14). Ketosis has also been reported blood were detected. Urine specific gravity was 1.033, the pH in obese pregnant cattle (12), a pregnant alpaca and a preg- was 6.8, and glucose was not detected. nant llama (7), obese pregnant guinea pigs (9), and starved Gross and microscopic findings: Of the four jills un- pregnant rats (30). Lactational stress may lead to ketosis in dergoing full necropsy (cases 1 to 4), one (case 1) had cattle (8, 10, 14). Nursing sickness in mink also is metabolic hepatomegaly and three (cases 1, 3, and 4) had a yellow or in origin, although ketosis and hepatic lipidosis have not pale liver coloration (Figure 1). All four had histologic le- been reported (15, 16). Feline IHL typically develops in sions of hepatic lipidosis (Figure 2), confirmed in case 4 by obese cats with prolonged anorexia (17, 18); a similar syn- oil red O-staining of frozen tissue. Of the five jills undergo- drome has been reported in stressed nonpregnant obese ing cesarean section (cases 5 to 10), three (cases 7, 9, and 10) guinea pigs (9). were observed during surgery to have yellow coloration of One common basis for these metabolic syndromes appears the liver, supporting the clinical diagnosis of pregnancy tox- to be a decrease in energy intake relative to demand, leading emia with hepatic lipidosis. Jills 6, 8, and 10 had hepatic to excess fatty acid mobilization, particularly in obese ani- lipidosis grossly at necropsy. The liver of the six postpartum mals. Hepatic pathways for oxidative fatty acid metabolism control jills, which were euthanized after sample collection, and very low-density lipoprotein (VLDL) formation may be- were grossly normal. come overwhelmed, leading to fat accumulation within Additional necropsy findings in jill 3 included focal gastric hepatocytes. In addition, hypoglycemia leads to a shortage of ulcer associated with gastrointestinal tract hemorrhage and glucose-derived oxaloacetate, interrupting the tricarboxylic chronic lymphocytic gastritis. Organisms consistent with acid cycle and leading to increased ketone formation. This Helicobacter mustelae were found during phase-contrast mi- energy imbalance may be compounded by protein deficiency, croscopy of stomach tissue. Jill 4 had hemorrhage in the which reduces the supply of protein cofactors for mitochon- stomach (black, watery fluid that tested positive for occult drial transport of fatty acids and formation of VLDL. The blood); microscopic gastric lesions were not evident. Focal net result is a shift in the physiologic balance away from

374 Pregnancy Toxemia in Ferrets

Table 2. Hematologic and serum biochemical findings for 10 jills with pregnancy toxemia Control jills (n = 6)a Animal no. and outcomeb Variable Units mean (SD) 3 4 5 6 7 8 9 10 Hematologic PCV % 40.0 (3.0) 25.0 31.2 42.8 42.0 40.0 30.0c,d 37.0 25.0c WBCe x 1,000/␮l 7.2 (2.3) 3.6 15.8 4.3 Biochemical TP g/dl 6.0 (0.4) 3.7 4.4 4.0 5.4 4.8 4.2 5.2 Albumin g/dl 3.1 (0.1) 1.9 1.8 2.0 2.2 2.3 2.7 BUN mg/dl 32 (8) 90 110 75 198 114 121 122 mg/dl 1.1 (0.4) 1.0 1.3 0.7 0.7 0.6 2.7 0.5 LD IU/L 600 (159) 2,640 3,800 2,835 342 6,263 396 AST IU/L 98 (51) 2,350 1,525 328 2,405 363 ALT IU/L 130 (123) 2,430 2,300 1,745 256 1,368 517 SAP IU/L 40 (8) 83 50 51 42 109 33 mg/dl 0.5 (0.7)f 0.5f 1.2f 0.6f -Direct mg/dl 0.0 (0.0) 0.1 0.9 0.4 -Indirect mg/dl 0.5 (0.7)f 0.4f 0.3 0.2 Ca mg/dl 10.0 (0.8) 6.2 6.0 5.5 6.6 10.1 6.9 -Adjustedg mg/dl 7.8 7.7 7.0 7.9 11.3 7.7 P mg/dl 9.3 (1.6) 6.9 8.0 6.0 5.8 6.9 6.0 Na mEq/dl 147 (5) 142 147 131 126 K mEq/dl 5.0 (0.6) 4.9 7.0 4.4 Cl mEq/dl 113 (3) 104 116 98 94

CO2 mEq/dl 23 (3) 21 10 21 13 Glucose mg/dl 180 (50) 137 68 296 142 204 266 117 Outcome Euthanized Euthanized Survived Died Survived Died Survived Died Blank, not evaluated. Values in bold are outside the normal range (mean Ϯ 2 SD) for postpartum control jills. a n = 5 for bilirubin, Na, K, Cl, CO2. bJills 1 and 2 were found dead. Their data are not included. cHemolysis dLipemia eNot measured in control group; normal for nonparturient jills (29). fOne control jill had a value of 1.7; the remaining jills had values below 0.3. gCalcium value adjusted for low albumin concentration = measured calcium + (3.5 - measured albumin). TP = total protein; LD = ; AST = aspartate ; ALT = ; SAP = serum . fatty acid metabolism or export in favor of pathologic ketosis cause (19, 20, 23, 33, 46–49). Nutritional imbalance does not and hepatic lipidosis (8, 10–14, 17, 18, 30–32). appear to be the initiating factor, although at least some hu- In humans, pregnancy toxemia refers to the syndrome of man cases have been associated with a hereditary defect in preeclampsia-eclampsia (20–23, 27, 33). Although it also de- fatty acid metabolism (19, 50). The pathophysiology of AFLP velops during late gestation and is more common with first closely resembles the ruminant and ferret periparturient and with twinning, it has a different clinical syndromes (48, 50). These findings, along with recent studies presentation and pathogenesis than does metabolic preg- that have speculated on a metabolic component to preec- nancy toxemia. The initiating event is unknown, but lampsia (51), may ultimately document that there is more uteroplacental ischemia appears to be an important compo- overlap of the pathophysiologic mechanisms of these syn- nent, possibly mediated by abnormal endothelial cell func- dromes than is currently appreciated from their different tion (28) or an abnormal maternal immune response (34). clinical presentations. Preeclampsia is characterized by hypertension, , and In ferrets, pregnancy toxemia is associated with age, diet, proteinuria with variable degrees of hematologic abnormali- and litter size. It is seen most commonly in young, primipa- ties, such as disseminated intravascular coagulation and rous jills carrying large litters. In addition to meeting the systemic thrombosis. The more severe eclampsia is associ- energy demands of pregnancy, these jills are still growing to ated with seizures, coma, or even death. Nonobese guinea their adult body weight. Pregnancy toxemia can also develop pigs (24), hamsters (25), and Patas monkeys (26) have been in older ferrets under conditions that initiate an imbalance reported to develop pregnancy toxemias that resemble hu- in energy metabolism, such as a change to a lower-energy man preeclampsia. Attempts have been made to produce an diet late in pregnancy, temporary lack of access to water, or experimental animal model of preeclampsia by reduction of the stress of illness or shipping (1, 2). In the experience of uterine blood flow in rats, dogs, rabbits, and nonhuman pri- one of the authors (JAB), pregnancy toxemia is seen in at mates (35–40), by inhibition of nitric oxide synthesis (41), or least 75% of jills carrying 8 or more kits that are deprived of by infusions of endotoxin (42) or endothelin-1 (43). food for 24 h during the last week of gestation. Over 50% of Two syndromes characterized by liver dysfunction may jills carrying more than 15 kits develop toxemia even if not develop as complications or perhaps variant manifestations deprived of food, but these may respond to supplemental of preeclampsia. One is characterized by hemolysis, high feeding alone. Most jills carrying 18 to 20 kits develop tox- liver enzyme activities, and low platelet count (HELLP), and emia even when consuming an excellent diet. This may be may represent liver injury associated with endothelial dys- due in part to limitations of the abdominal capacity, which function and damage and/or intravascular coagulation (20, on gross inspection appears insufficient for the kits and the 23, 44, 45). A second syndrome, acute fatty liver of preg- volume of food necessary to meet energy demands (2). nancy (AFLP), develops only rarely and is of undetermined The onset of toxemia is acute and usually occurs within

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A

B

Figure 1. Gross necropsy findings in a ferret with pregnancy tox- emia. Enlarged, pale liver (which was yellow in color) and dis- tended gravid uterus. the last week of gestation. Clinical signs of disease often in- clude lethargy, dehydration, inappetence, weight loss, and diarrhea and/or melena, and affected jills often shed excess amounts of hair (1, 2). Palpation may confirm presence of a heavy fetal load, or the abdomen may feel doughy. Other findings, such as dyspnea, icterus, or hyperemic mucous membranes, may be seen in some cases. Sudden death may occur. Radiography or ultrasonography (52) may aid in de- termining fetal development and viability. Hematologic and clinical biochemical analyses and uri- nalysis may be of use in determining the diagnosis and the prognosis. Anemia is a common but nonspecific finding. Gas- tric hemorrhage and/or ulcers were seen in two of our cases Figure 2. Photomicrograph of sections of the liver from a normal and have been reported elsewhere (1, 2). These lesions may ferret (A) and from a ferret with pregnancy toxemia showing he- be associated with H. mustelae infection (53–55) and may patic lipidosis (B). Large and small hepatocyte vacuoles are filled have contributed to the metabolic stress precipitating preg- with lipid. H&E stain; magnification x100. nancy toxemia. Conversely, gastrointestinal tract ulceration may develop terminally (1). The pathogen- or hemorrhage can result from metabolic disturbances such esis of hypoproteinemia, which may be present even in dehy- as azotemia or decreased hepatic production of coagulation drated animals, has not been confirmed but is possibly factors. The observed azotemia is most likely secondary to attributable to decreased protein intake, decreased hepatic dehydration but, if severe, may indicate renal failure. High protein synthesis, proteinuria, and/or continued demand of hepatic enzyme activities and bilirubinemia or bilirubinuria the growing fetuses. Most jills tested had low blood calcium correlate with the development of hepatic lipidosis and asso- values, even after correction for low albumin concentration, ciated hepatic insufficiency. Blood glucose concentration although clinical signs specific to hypocalcemia were not ap- tends to be low early in the disease (usually <50 g/dl), but parent. Hypocalcemia has been reported previously in ani-

376 Pregnancy Toxemia in Ferrets

mals with similar metabolic syndromes (7, 11, 12, 56, 57), presence of gastric ulceration or hemorrhage in two jills in but its relevance remains undetermined. Periparturient hy- this series would suggest that it be seriously considered. pocalcemia (“milk fever”) is a recognized syndrome in cattle In most instances, cesarean section is indicated as soon as and sheep (5, 58) but appears to be more directly related to the jill is stabilized to reduce the excess metabolic demands calcium supply (diet) and demand (lactation). Other causes of pregnancy. Viable kits are unlikely prior to day 40 of ges- for hypocalcemia include renal failure, pancreatitis, and en- tation, but postponing surgery to try to save the kits may docrine disorders. Some cases had additional abnormal labo- lead to death of the jill. Inhalant anesthesia is recommended ratory findings, such as hyperkalemia and hematuria; the (1, 2). Although splenic sequestration of red blood cells has cause and relevance of these findings await further investi- been documented in normal ferrets under isoflurane anes- gation. If present, ketonuria may aid in diagnosis. It has thesia (60), in the experience of one of the authors (JAB), been reported anecdotally, particularly in severe cases (2, this effect appears to have far less importance for survival 59), and was documented in one case of this study. than does inability to metabolize injectable anesthetics (1). The three jills that survived tended to have less pro- Both jills of this study anesthetized with injectable agents died. nounced azotemia, hypoproteinemia, and increased liver en- The survival of the jill depends on her condition prior to zyme activities and were not anemic at the time of diagnosis surgery and on intensive postoperative supportive care (1, (mean PCV of the survivors was 39.9%, compared with 2). Jills with advanced pregnancy toxemia, characterized by mean PCV of 30.6% for the five jills that died after presenta- marked lethargy, dehydration, weight loss, and/or gas- tion, P < 0.05). Initial PCV may therefore prove to be a prog- trointestinal tract hemorrhage, have a poor prognosis de- nostic indicator for toxemic jills. It should be noted, however, spite any method of treatment. Those that recover usually that PCV results from blood samples taken after initiation do so completely and do not have apparent predisposition to of anesthesia must be interpreted with caution due to poten- recurrence. Agalactia is common, particularly after cesarean tial effects of anesthetic agents on red cell distribution (60). section, and often necessitates cross-fostering of any surviv- Our sample sizes were not adequate to evaluate any rela- ing kits. Kits may be hand-fed with puppy or kitten milk re- tionship between anesthetic agent, duration of anesthesia, placer six times daily until the jill recovers from surgery; and PCV in this study. however, if the jill does not lactate, prolonged hand-rearing The diagnosis of pregnancy toxemia is most often made on of newborn kits is labor intensive and unrewarding (1, 61, 62). the basis of signalment, history, and clinical findings. Labo- Prevention of pregnancy toxemia is far preferable to treat- ratory findings, observation of abnormal liver color and con- ment. Its development can be minimized by careful atten- sistency during cesarean section, and/or response to tion to husbandry, avoidance of diet changes or stress, treatment may support the diagnosis; definitive diagnosis maintenance of a high plane of nutrition (Ն20% fat and relies on the histopathologic finding of hepatic lipidosis. (1, Ն35% crude protein [1]), and close monitoring of appetite 2, 4, 59). Components of the differential diagnosis, such as and body condition during the last half of gestation. Provi- septicemia, dystocia, metritis, pyometra, renal failure, or un- sion of water in a water bottle and an open dish, as well as related gastrointestinal tract hemorrhage, must be consid- multiple food bowls to minimize losses due to spillage or con- ered, as well as any concurrent systemic disease that may tamination, are highly recommended. contribute to the development of toxemia. In conclusion, pregnancy toxemia is a clinically relevant Medical treatment must be prompt and aggressive, and disease of ferrets that results from metabolic stress and en- should be geared toward increasing energy intake and cor- ergy imbalance and carries a poor prognosis. The principal recting associated clinical abnormalities such as dehydra- characteristics are acute onset during late pregnancy and tion and imbalances (1, 2). Although specific development of hepatic lipidosis. It is similar to a number of treatment differences were not evident between jills 7 and 9 periparturient metabolic diseases in other species and to fe- (which survived) and jills 6 and 10 (which did not survive), line IHL, but is different from human pregnancy toxemia all successfully treated cases had therapeutic interventions (preeclampsia). Preventative measures, prompt detection that included parenteral administration of fluids with elec- and treatment, cesarean section, and fostering of any live trolytes and glucose, and intensive supplementation with a kits are keys to minimizing jill and kit mortalities. high-energy diet, including frequent hand- or force-feeding if necessary. High protein intake also is recommended, despite azotemia (usually secondary to dehydration) and liver dys- References function. Studies in cats with experimentally induced IHL 1. Fox, J. G., R. C. Pearson, and J. A. Bell. 1998. Diseases of have indicated that, unless hepatic encephalopathy is sus- the genitourinary system, p. 247–272. In J. G. Fox (ed.), Biol- pected, protein-based caloric intake decreases the severity of ogy and diseases of the ferret, 2nd ed. Williams & Wilkins Co., Baltimore. hepatic lipid accumulation and results in more rapid clinical 2. Bell, J. A. 1997. Periparturient and neonatal diseases, p. 53–62. improvement (17, 18). The beneficial effects of dietary pro- In E. V. Hillyer and K. E. Quesenbury (ed.), Ferrets, rabbits and tein most likely reflect an increased hepatic supply of carnitine, rodents: clinical medicine and surgery. W. B. Saunders Co., necessary for transport of fatty acids into mitochondria for oxi- Philadelphia. dation, and precursors necessary for the synthesis and re- 3. Ryland, L. M., S. L. Bernard, and J. R. Gorham. 1983. A clinical guide to the pet ferret. Compend. Contin. Educ. Pract. lease of lipoproteins. Medical treatment for gastric Vet. 5:25–32. ulceration has been recommended for cats with IHL (18). 4. Ryland, L. M., and J. R. Gorham. 1978. The ferret and its Even though this has not been evaluated in toxemic jills, the diseases. J. Am. Vet. Med. Assoc. 173:1154–1158.

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5. Jensen, R. 1982. Diseases of ewes, p. 19–30. In R. Jensen 29. Fox, J. G. 1998. Normal clinical and biologic parameters, and B. L. Swift (ed.), Diseases of sheep, 2nd ed. Lea & Febiger, p. 183–210. In J. G. Fox (ed.), Biology and diseases of the ferret, Philadelphia. 2nd ed. Williams & Wilkins Co., Baltimore. 6. Assali, N. S., L. D. Longo, and L. W. Holm. 1960. Toxemia- 30. Scow, R. O., S. S. Chernick, and M. S. Brinley. 1964. Hyper- like syndromes in animals. Obstet. Gynecol. Surv. 15:151–181. lipemia and ketosis in the pregnant rat. Am. J. Physiol. 206: 7. Anderson, D. E., P. D. Constable, K. E. Yvorchuk, et al. 796–804. 1994. Hyperlipemia and ketonuria in an alpaca and a llama. 31. Grimbert, S., B. Fromenty, C. Fisch, et al. 1993. Decreased J. Vet. Intern. Med. 8:207–211. mitochondrial oxidation of fatty acids in pregnant mice: possible 8. Bergman, E. N. 1993. Disorders of carbohydrate and fat me- relevance to development of acute fatty liver of pregnancy. tabolism, p. 492–502. In M. J. Swenson and W. O. Reece (ed.), Hepatology 17:628–637. Dukes’ physiology of domestic animals, 11th ed. Comstock Pub- 32. Grimbert, S., C. Fisch, D. Deschamps, et al. 1995. Effects of lishing Associates, Ithaca, N.Y. female sex hormones on mitochondria: possible role in acute fatty 9. Ganaway, J. R., and A. M. Allen. 1971. Obesity predisposes liver of pregnancy. Am. J. Physiol. 268:G107–G115. to pregnancy toxemia (ketosis) of guinea pigs. Lab. Anim. Sci. 33. Crawford, J. M. 1994. The liver and the biliary tract, 21:40–44. p. 831–896. In R. Cotran, V. Kumar, and S. L. Robbins (ed.), 10. Grummer, R. R. 1993. Etiology of lipid-related metabolic dis- Robbins pathological basis of disease, 5th ed. W. B. Saunders orders in periparturient dairy cows. J. Dairy Sci. 76: Co., Philadelphia. 3882–3896. 34. Orvieto, R., A. Achiron, Z. Ben-Rafael, et al. 1993. The pos- 11. Marteniuk, J. V., and T. H. Herdt. 1988. Pregnancy tox- sible role of intravenous immunoglobulin in preventing pre-ec- emia and ketosis of ewes and does. Vet. Clin. North Am. Food lampsia. Med. Hypotheses 41:160–164. Anim. Pract. 4:307–315. 35. Schafer, W., J. Tielsch, F. W. Casper, et al. 1993. Urinary excre- 12. Tyler, J. W., P. M. Dowling, J. S. Spano, et al. 1994. Severe tion of 6-keto-PGF1 alpha TxB2 and PGE2 in a rat animal model for prepartum ketosis in an obese beef cow. J. Am. Vet. Med. Assoc. preeclampsia-like syndrome. Prostaglandins 46:167–175. 204:1665–1667. 36. Golden, J. G., H. C. Hughes, and C. M. Lang. 1980. Experi- 13. West, H. J. 1996. Maternal undernutrition during late preg- mental toxemia in the pregnant guinea pig (Cavia porcellus). nancy in sheep. Its relationship to maternal condition, gesta- Lab. Anim. Sci. 30:174–179. tion length, hepatic physiology, and glucose metabolism. Br. 37. Cavanagh, D., P. S. Rao, C. C. Tsai, et al. 1977. Experimental J. Nutr. 75:593–605. toxemia in the pregnant primate. Am. J. Obstet. Gynecol. 128: 14. Bruss, M. L. 1993. Metabolic fatty liver of ruminants. Adv. 75–83. Vet. Sci. Comp. Med. 37:417–449. 38. Abitbol, M. M., C. L. Pirani, W. B. Ober, et al. 1976. Produc- 15. Clausen, T. N., C. R. Olesen, O. Hansen, et al. 1992. Nursing tion of experimental toxemia in the pregnant dog. Obstet. Gynecol. sickness in lactating mink (Mustela vison) I. Epidemiological and 48:537–548. pathological observations. Can. J. Vet. Res. 56:89–94. 39. Abitbol, M. M., G. R. Gallo, C. L. Pirani, et al. 1976. Produc- 16. Wamberg, S., T. N. Clausen, C. R. Olesen, et al. 1992. Nurs- tion of experimental toxemia in the pregnant rabbit. Am. J. ing sickness in lactating mink (Mustela vison) II. Pathophysi- Obstet. Gynecol. 124:460–470. ology and changes in body fluid composition. Can. J. Vet. Res. 40. Combs, C. A., M. A. Katz, J. L. Kitzmiller, et al. 1993. Experi- 56:95–101. mental preeclampsia produced by chronic constriction of the lower 17. Johnson, S. E. 1995. Diseases of the liver, p. 1313–1357. In S. J. aorta: validation with longitudinal blood pressure measurements Ettinger and E. C. Feldman (ed.), Textbook of veterinary inter- in conscious rhesus monkeys. Am. J. Obstet. Gynecol. 169: nal medicine, vol. 2, 4th ed. W. B. Saunders Co., Philadelphia. 215–223. 18. Dimski, D. S., and J. Taboada. 1995. Feline idiopathic he- 41. Yallampalli, C., and R. E. Garfield. 1993. Inhibition of nitric patic lipidosis. Vet. Clin. North Am. Small Anim. Pract. 25: oxide synthesis in rats during pregnancy produces signs similar 357–373. to those of preeclampsia. Am. J. Obstet. Gynecol. 169:1316–1320. 19. Treem, W. R., M. E. Shoup, D. E. Hale, et al. 1996. Acute 42. Faas, M. M., G. A. Schuiling, J. F. W. Baller, et al. 1994. A fatty liver of pregnancy, hemolysis, elevated liver enzymes, new animal model for human preeclampsia: ultra-low-dose en- and low platelets syndrome, and long chain 3-hydroxyacyl- dotoxin infusion in pregnant rats. Am. J. Obstet. Gynecol. coenzyme A dehydrogenase deficiency. Am. J. Gastroenterol. 171:158–164. 91:2293–2300. 43. Halim, A., N. Kanayama, E. E. Maradny, et al. 1995. Eclamp- 20. Riely, C. A. 1994. Hepatic disease in pregnancy. Am. J. Med. sia-like seizures and electroencephalographic changes in preg- 96:18S–22S. nant rabbits with endothelin-1 injections. Gynecol. Obstet. In- 21. Kaplan, P. W., and J. T. Repke. 1994. Eclampsia. Neurol. vest. 39:1–7. Clin. 12:565–582. 44. Barton, J. R., and B. M. Sibai. 1992. Care of the pregnancy 22. Barron, W. M. 1992. The syndrome of preeclampsia. complicated by HELLP syndrome. Gastroenterol. Clin. North Am. Gastroenterol. Clin. North Am. 21:851–872. 21:937–950. 23. Anday, E. K., and A. Cohen. 1990. Liver disease associated 45. Reubinoff, B. E., and J. G. Schenker. 1991. HELLP syn- with pregnancy. Ann. Clin. Lab. Sci. 20:233–238. drome—a syndrome of hemolysis, elevated liver enzymes and 24. Seidl, D. C., H. C. Hughes, R. Bertolet, et al. 1979. True low platelet count—complicating preeclampsia-eclampsia. Int. pregnancy toxemia (preeclampsia) in the guinea pig (Cavia J. Gynecol. Obstet. 36:95–102. porcellus). Lab. Anim. Sci. 29:472–478. 46. Mabie, W. C. 1992. Acute fatty liver of pregnancy. Gastroenterol. 25. Richter, A. G., N. C. Lausen, and A. L. Lage. 1984. Preg- Clin. North Am. 21:951–960. nancy toxemia (eclampsia) in Syrian golden hamsters. J. Am. 47. Kaplan, M. M. 1985. Acute fatty liver of pregnancy. N. Engl. J. Vet. Med. Assoc. 185:1357–1358. Med. 313:367–370. 26. Palmer, A. E., W. T. London, D. L. Sly, et al. 1979. Sponta- 48. Dani, R., G. S. Mendes, J. d. L. Medeiros, et al. 1996. Study neous preeclamptic toxemia of pregnancy in the patas mon- of the liver changes occurring in preeclampsia and their possible key (Erythrocebus patas). Lab. Anim. Sci. 29:102–106. pathogenetic connection with acute fatty liver of pregnancy. Am. 27. Crum, C. P. 1994. Female genital tract, p. 1033–1088. In R. J. Gastroenterol. 91:292–294. Cotran, V. Kumar, and S. L. Robbins (ed.), Robbins pathologi- 49. Simpson, K. R., K. S. Moore, and M. H. LaMartina. 1993. cal basis of disease, 5th ed. W. B. Saunders Co., Philadelphia. Acute fatty liver of pregnancy. J. Obstet. Gynecol. Neonatal Nurs- 28. Friedman, S. A., S. L. Lubarsky, R. A. Ahokas, et al. 1995. ing 22:213–219. Preeclampsia and related disorders. Clinical aspects and rel- 50. Treem, W. R., P. Rinaldo, D. E. Hale, et al. 1994. Acute fatty evance of endothelin and nitric oxide. Clin. Perinatol. 22: liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A de- 343–355. hydrogenase deficiency. Hepatology 19:339–345.

378 Pregnancy Toxemia in Ferrets

51. Sattar, N., A. Gaw, C. J. Packard, et al. 1996. Potential patho- 57. Katz, M. L., and E. N. Bergman. 1966. Acid-base and elec- genic roles of aberrant lipoprotein and fatty acid metabolism in trolyte equilibrium in ovine pregnancy ketosis. Am. J. Vet. Res. pre-eclampsia. Br. J. Obstet. Gynaecol. 103:614–620. 27:1285–1292. 52. Peter, A. T., J. A. Bell, D. D. Manning, et al. 1990. Real- 58. Park, C. S., and N. L. Jacobson. 1993. The mammary gland time ultrasonographic determination of pregnancy and ges- and lactation, p. 711–727. In M. J. Swenson and W. O. Reece tational age in ferrets. Lab. Anim. Sci. 40:91–92. (ed.), Dukes’ physiology of domestic animals, 11th ed. 53. Fox, J. G., B. M. Edrise, E. B. Cabot, et al. 1986. Comstock Publishing Associates, Ithaca, N.Y. Campylobacter-like organisms isolated from gastric mucosa 59. Finkler, M. R. 1987. Personal communication. of ferrets. Am. J. Vet. Res. 47:236–239. 60. Marini, R. P., R. J. Callahan, L. R. Jackson, et al. 1997. Dis- 54. Fox, J. G., G. Otto, N. S. Taylor, et al. 1991. Helicobacter tribution of technetium 99m-labeled red blood cells during mustelae-induced gastritis and elevated gastric pH in the fer- isoflurane anesthesia in ferrets. Am. J. Vet. Res. 58:781–785. ret (Mustela putorius furo). Infect. Immun. 59:1875–1880. 61. Fox, J. G., and J. A. Bell. 1998. Growth, reproduction, and 55. Fox, J. G., and A. Lee. 1997. The role of Helicobacter species breeding, p. 211–227. In J. G. Fox (ed.), Biology and diseases in newly recognized gastrointestinal tract diseases of animals. of the ferret, 2nd ed. Williams & Wilkins Co., Baltimore. Lab. Anim. Sci. 47:222–255. 62. Manning, D. D., and J. A. Bell. 1990. Derivation of gnotobi- 56. Curtis, C. R., H. N. Erb, C. J. Sniffen, et al. 1983. Associa- otic ferrets: perinatal diet and hand-rearing requirements. tion of parturient hypocalcemia with eight periparturient dis- Lab. Anim. Sci. 40:51–55. orders in Holstein cows. J. Am. Vet. Med. Assoc. 183:559–561.

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