Pregnancy Toxemia in Small Ruminants
ACVIM 2008
Melanie J. Boileau, DVM, MS, DACVIM
Stillwater, OK, USA

Introduction

Pregnancy toxemia (PT) is a metabolic disease also called pregnancy ketosis, twin lamb disease, lambing or kidding sickness, paralysis or ketosis and typically affects small ruminants (SR) during the last 4 weeks of gestation, primarily in pregnancies with more than one fetus. This disease is becoming a common cause of dam and fetal loss in the southern United States, especially in Boer show goats. It is initiated by a period of negative energy balance (NEB) where ketone bodies (KB) accumulate to a pathologic level. Factors involved in the NEB dynamic include decreased feed intake, increased energy demands from carrying multiple late-term fetuses, hormonal dysregulation of fat and carbohydrate metabolism, altered glucose utilization by the tissues, or a combination of the above.

Economic Significance

Occasional clinical of PT occur sporadically, unpredictably, and at a low level in most flocks, independently of adequate management and feeding practices. Affected ewes/does generally comprise less than 1% to 2% of the flock, yet death rates often exceed 80% of clinical animals.1 Mortality is especially high (despite intensive treatment) when producers delay treatment until affected SR become recumbent. Sporadic cases often involve SR with concurrent health problems that lead to anorexia and NEB.

Pregnancy toxemia also occurs at the flock level, and is characterized by numerous clinical cases during the last month of gestation. Affected animals often include 5% to 20% of the breeding age females within the flock with mortality rates often exceeding 80%.1 The entire flock may lamb or kid during a brief 30 day period and create a situation in which 80-90% of the animals are at identical stages of gestation and therefore at risk for developing PT.1 When flock involvement occurs, economic losses can be substantial.

Predisposing Factors

There are several predisposing factors that lead to the development of clinical PT in SR. Most of them are related to management practices or production purposes.1 Pregnancy toxemia may occur in association with stressors (feed or weather changes, hauling, predator attack) or with anorexia caused by other concurrent diseases (parasites, foot rot, pneumonia, CAE).2 Quantity and quality of feedstuffs offered and consumed combined with confinement (which may stimulate competition for feed between individual animals) can also contribute to development of PT. Additional related inherent animal risk factors include an increase in late-gestation nutritional demands associated with developing fetuses, increased fecundity (ewes: twins or triplets, does: triplets or quadruplets) especially in older SR (parity > 2), extreme body condition scores (BCS) i.e., thin (BCS: <1/5) or overconditioned (BCS: 5/5),3 concurrent hypocalcemia (20% of PT cases),1,4 metabolic acidosis,5 and reduced rumen capacity due to physical expansion of the gravid uterus which can be further limited with fat deposition in the abdominal cavity. Lastly, research suggests that susceptible animals may be insulin-resistant and therefore unable to regulate glucose homeostasis during late pregnancy; predisposing them to PT. This increased tissue resistance to insulin is most likely an inherited trait, suggesting that PT may be very similar to insulin-dependent diabetes mellitus in humans or type II ketosis in dairy cows.1 Genetic and individual variation could best explain why long-established flocks with inadequate feeding practices experience very few cases of PT. Susceptible insulin-resistant individuals may have been naturally culled from the flock gene pool.1 Nevertheless, offspring from affected SR should not be retained for flock replacements.1

Late-Gestation Facts

Late gestation fetal growth and pregnancy energy requirements are roughly 150% (single fetus) to 200% (twins) and 200-250% (triplets) above maintenance levels.1 Nearly 80% of fetal growth occurs during the last 6 weeks of gestation. Since KB cannot be utilized as an energy source,6 glucose represents the most important metabolite for fetal and placental growth.3 Fetal uptake of glucose appears to function independently of blood glucose regulation of the dam. As maternal hypoglycemia develops, fetal glucose demands remain satisfied, ensuring short-term fetal viability.1 Additionally, plasma concentration of insulin decreases more distinctly in healthy late pregnant ewes carrying twins rather than a single fetus.7

Pathophysiology

In pregnant SR, any lack, even transient, of dietary energy intake implies insufficient substrate available for ruminal production of the glucose precursor propionate, resulting in a period of NEB.2,8 During that time, hypoglycemia develops, the insulin to glucagon ratio decreases, and these as well as other hormones (catecholamines, cortisol) activate hormone-sensitive lipases that promote mobilization and transportation of tissue fat in the form of free fatty acids (FFAs) or non-esterified FFAs (NEFAs) and glycerol, to the liver. In the liver, glycerol may be used to produce glucose or may be recombined with FFAs to make triglycerides (TGs). Mobilized FFAs can be degraded through β oxidation and converted to acetyl-CoA; the latter combines with oxaloacetate to enter the Krebs cycle for production of energy. In anorexic SR, depletion of oxaloacetate is common (converted to glucose) thus the normal Krebs cycle and the use of FFAs is inhibited.2 Consequently, acetyl-CoA is converted to KB: acetoacetic acid (AcAc), acetone, and β-hydroxybutyric acid (BHBA). In ruminants, KB are produced mainly by the rumen epithelium (from acetate and butyrate during the absorption process) and by the liver and can readily be utilized as an energy source by several organs but not the brain.6 Despite its sparing effect on glucose, KB reduce appetite and feed consumption (centrally mediated) and perpetuate the NEB.7 In ewe carrying twins, KB also impair BHBA turnover and disposal thus facilitate development of PT.9 When the liver is overwhelmed with mobilized FFAs, greater amounts of TGs accumulate locally. Most of these TGs get repackaged as very low density lipoproteins (VLDL) (inefficient mechanism in ruminants) before release into the peripheral circulation. Hepatic lipidosis results when the rate of hepatic TG formation exceeds oxidation of FFAs and the formation and release of VLDLs.

Types of Pregnancy Toxemia

There are 4 types of PT: primary, fat ewe/doe, starvation and secondary. Primary PT is very common in most flocks. It results from a combination of a fall in the plane of nutrition during last 2 months of pregnancy or management changes that create a brief period of fasting.1 Fat ewe/doe PT usually occurs secondary to overconditioning of the flock or certain individuals during early pregnancy (show circuit) resulting in fat, overweight late pregnant SR. As previously mentioned, affected animals experience a voluntary fall in food intake in late pregnancy due to the "space-occupying" intra-abdominal fat and developing fetuses.1 Starvation PT is sporadic and occurs in ewes/does that are excessively thin (BCS: <1/5). It appears to be uncommon but usually results from mismanagement, including unavailability of feed resources following periods of drought, flooding or snow cover. Unfortunately, in a few instances, there is simply no feedstuff available. Secondary PT, although referenced infrequently,1 appears to occur on a regular basis. Concomitant diseases should be thoroughly investigated and treated promptly when managing pregnant SR.

Clinical Signs

Initially, affected SR lag behind the rest of the flock, fail to flee from approaching people, dogs or equipment, are mildly to moderately depressed, experience partial anorexia, and are reluctant to move. As the condition progresses, they may stagger about or stand for long periods of time in the same area and typically progress to a recumbent (sternal) position within 3-4 days after clinical signs are first exhibited. Other suggestive indications include teeth grinding, apparent blindness, muscle tremors, tachypnea ± grunting, constipation, decreased ruminal contractions, fruity or sweat smell to the breath, and moderate to severe edema of distal extremities. Eventually, they become significantly depressed to comatose, exhibit head pressing or star-gazing (hypoglycemic encephalopathy),10 are unable to rise, dehydrated, and show complete rumen atony. Death inevitably ensues if left untreated.

In the author's experience, whether or not parturition is induced, treated SR with PT are subjected to a high incidence of dystocia; many either fail to go into active labor (stage II parturition) or develop ringwomb. Furthermore, postpartum SR with prior or unresolved PT generally have poor mammary development and therefore insufficient colostrum and milk to meet passive transfer and nutritional requirements of multiple offspring. Experimental induction of PT in twin-pregnant ewes causes a significant shortening of the gestation period (~7 days), lower lamb birth weight (1.1 kg), and a higher lamb mortality (16.6%, 4/24 fetus).11 Expectations for lamb and kid survival vary greatly depending upon severity and duration of the NEB, BCS and concurrent diseases of the dam, treatment administered, and number of fetuses present. The offspring born from very thin PT dams are frequently stillborn or, if born alive, are very weak. They struggle to maintain normal body temperature and glycemia and typically expire within 24-72 hours after birth. Lastly, 5-15% of severe PT cases develop renal failure due to fatty infiltration of the kidneys which is, more often than not, fatal despite treatment.7

Differentials

Most likely differentials for PT based on history and clinical signs described above include: hypocalcemia, hypomagnesemia, polioencephalomalacia, listeriosis, bacterial or viral encephalitis, meningeal worm (P. tenuis), and severe haemonchosis.

Diagnosis

Diagnosis of PT is based on historical findings, clinical signs, confirmation of pregnancy status as well as the number of live fetuses present via transabdominal ultrasound (3.5 MHz curvilinear probe), and high levels of KB in urine with ketosticks or multisticks > 60 mg/dL) or serum (BHBA > 5-7 mmol/L,7,9 NEFAs > 0.4mEq/L).8 On initial presentation, affected SR are usually hypoglycemic (normal blood glucose (BG); 50-80 mg/dL)2 but can also be normo- or hyperglycemic, the latter presumably stress-induced. Other common abnormalities found on serum chemistry and CBC include pre-renal or renal azotemia with increased BUN and creatinine, hypocalcemia, hypokalemia, low cholesterol (< 70-80 mg/dL)2,8 and marked neutrophilia. Cortisol is usually elevated and insulin levels are low.7 In cases of severe PT, elevated liver enzymes (GGT, AST) and metabolic acidosis (HCO3 < 15 mEq/L, blood pH < 7.0) are commonly present. Some may have decreased bromosulphthalein (BSP) clearance from the liver.11

Treatment

Treatment goals include correction of ketosis, NEB, hypoglycemia, hypoinsulinemia, hydration status, electrolyte imbalances, metabolic acidosis, stimulation of appetite and feed intake, and removal of source of energy demand (fetuses) if necessary. If treated early, affected animals generally respond favorably. Once recumbent, response to therapy tends to be poor.

In cases of Mild Ketosis with Normal Feed Intake or Partial Anorexia

Small ruminants with mild ketosis that are still eating can be treated on the farm. Current recommendations include: offer better quality roughage (ex: alfalfa), increase amount of concentrates (see prevention section) and treat concurrent diseases. Several drenching options are available and can be readily administered by the owner. They include propylene glycol @ 60ml PO q12hr coupled with oral sodium bicarbonate (NaHCO3) @ 15-20gr/50ml water PO q24hrs (the latter promote insulin secretion in case of metabolic acidosis),8 Advanced Agri Solution® (AAS) drench energy malt mix @ 4 oz/quart water PO q24hrs, and calf scour electrolytes alone or a combination of the following: 1 quart water, 1oz propylene glycol, 2oz AAS drench, and ½ package calf scour electrolytes @ 150ml PO q8-12hrs. Provide supplemental Ca2+, Mg2+, P-, and K+ via oral paste or gel as well as vitamins B complex.

In cases of Moderate to Severe Ketosis with Partial or Complete Anorexia

Small ruminants that do not respond or deteriorate despite 24-48 hrs of therapy administered in the field should be referred to a veterinary clinic or teaching hospital. Add transfaunation (2 pints of rumen fluid PO q12-24hrs from canulated bovine) and/or force-feeding alfalfa gruel to the treatment instituted on the farm. In well hydrated animals, administer 100ml boluses of 5% dextrose IV q6-8hrs. In moderately to severely dehydrated SR, IV fluids are indicated and specific type should be selected based on electrolytes, BG and acid-base abnormalities. Fluid replacement alone will lower BG; however, if dextrose is not given, further ketonemia may occur.12 Fluid of choice for PT typically includes ½ strength NaCl and dextrose or Normosol-R with added dextrose (5-10% solution) at maintenance rate (60ml/kg/day) after dehydration is corrected. It is recommended to supplement IV fluids with Ca2+ borogluconate(25-75ml/L) and KCl(10-30mEq/L). To reduce chances of developing cerebral edema, avoid overhydration and limit the rate at which BG level drops.12 Since serum lactate levels can be elevated in dehydrated SR with PT, avoid lactated ringers. Use NaHCO3 only if severe metabolic acidosis is present (blood pH<7.0).12 Administer insulin (Vetsulin®, Pzi Vet®) @ 0.4 IU/kg SC q24hrs for 3 to 4 consecutive days. Clinical trials using insulin in sheep with PT have shown improved clinical scores, improved survival rates, increased insulin:glucagon ratio and no significant decrease in blood glucose.7

Since a breeding date is rarely known, age of the fetuses is difficult to determine. Fetal viability and survival is best if the dam is induced within 5-7 days from gestational term. Depending on response to therapy, owner's preference, and economical constraints, induction of parturition or emergency c-section (left paralumbar fossa) can be performed. To induce parturition in a doe, give 10mg of prostaglandin F2α and 20mg of dexamethasone IM. Expect kidding within 30-36hrs of induction. In a ewe, lambing is expected within 48-72 hours following administration of 20mg of dexamethasone IM.

Monitoring

It is imperative to evaluate BG, ketonuria and glucosuria at least 2-4 times a day, not only within the first 2-3 days of hospitalization but also throughout the entire treatment period; adapt therapy as needed. Once the patient is stable, frequency of monitoring can be decreased to 1-2 time/day. Monitor acid-base status via arterial or venous blood gas, serum creatinine, and electrolytes (especially K+) every 1-3 days. Metabolic acidosis increases ECF K+ levels, and dextrose administration combined with insulin lowers them.12 Assessment of fetal viability with ultrasounds (1-2x/d) helps with the decision to induce parturition (live fetus) or perform a c-section (dam's condition severe; dead fetus).13 The normal fetal heart rate in meat goats ranges from 130-160 bpm.

Postmortem Examination Findings

In fat ewes/does, the uterus contains multiple fetuses. The liver is enlarged, friable, pale yellow and has rounded edges. However, this finding alone is not sufficient for a diagnosis of pregnancy toxemia. Fatty infiltration of the liver is a normal event during late pregnancy (the liver of normal ewes may increase from 3 to 30% in fat content).1 Emaciated or thin ewes/does usually have serous atrophy of kidney and cardiac fat. When starvation is the primary cause of pregnancy disease a large, a single fetus is not uncommon. In both fat and thin ewes/does, stress-related enlargement of the adrenal glands is common.

Prognosis

Based on personal observations and limited information published, the prognosis tends to be poor if SR develop clinical PT early in pregnancy (>3 weeks before due date), have prolonged reduced feed intake and rumen motility, are severely depressed and recumbent, have stillborn fetuses, and have low serum potassium or high BHBA levels.7 The prognosis is fair to good if SR develop clinical PT in late pregnancy (within 7 days of due date), are still ambulatory, are not completely anorexic, and deliver live fetus(es).

Prevention

Economic necessity and overall outcome for both dam and fetuses suggests that practitioner recommendations should focus on prevention (proper nutrition, management) of PT in the flock instead of individual animal treatment.

Identify the Animals at Risk

Ideally, perform transabdominal ultrasound pregnancy exam within 45-90 days after breeding in all females.2 Based on ultrasonographic findings, separate ewes/does with >2 fetuses from the flock and feed accordingly. Monitor ketonuria once a day in all late pregnant ewes/does within 2 weeks of parturition or earlier if showing clinical signs of PT. Pool blood samples and measure BHBA as an indicator of PT at the flock level: < 0.8mmol/L (adequate energy intake), 0.8-1.6 mmol/L (inadequate energy intake), > 1.6 mmol/L (severe undernourishment), > 6.5mmol/L (PT).2 In case of early outbreaks, post-mortem aqueous humor BHBA > 2mmol/L is diagnostic of PT.14

Nutrition, Feeding Guidelines and Body Condition Scores

As a rule, most 100% forage diets fail to meet individual animal late gestation requirements for SR pregnant with multiple fetuses, unless forage quality, availability, and digestibility are exceptional. In most management systems, late gestation occurs during the winter months, when less pasture is available and poorer-quality feedstuffs are offered.2 To minimize the physiologic decline in dry matter intake during late gestation with reduced rumen volume, high quality energy-dense rations should be fed.8 Feed reductions in obese animals should not take place during late pregnancy; this often precipitates clinical cases of pregnancy toxemia.1 Indeed, it is best to decrease body condition during the lactation or maintenance phase of production. The following are feeding guidelines for 150 lbs ewes or does: in early gestation, offer at least 4 lbs of medium-quality hay (8-10% protein). In late gestation, provide 3.5-4 lbs of better-quality hay (>10% protein) and 1-2 lbs/head/day of concentrates (corn, oats, barley, or a combination). During period of stress, particularly cold wet weather, cereal grains may need to be increased at 2-3 lbs/head/day.8,13 Suggested BCS in SR are on a scale of 1 (thin) to 5 (obese). Depending on the production level, recommendations consist of the following: Maintenance: 2-2.5, Breeding: 3, Early gestation: 3, Late gestation: 3-3.5, Lambing/kidding: 3.5, and Weaning: 2-2.5.1

Management

Briefly, avoid sudden changes in types of feedstuffs (feed analysis recommended), provide extra feed during inclement weather, have free choice mineral mixture available at all times, and ensure sufficient trough space (1 foot/head) for each animal. Limit confinement and promote exercise. Diagnose and treat ongoing diseases. Add molasses to drinking water of late pregnant SR. To improve feed efficiency, supplement late pregnant SR with lasalocid (0.5-1 mg/kg/day) or monensin (1mg/kg/day) 2-4 weeks before gestational term.2 However, monensin should be used with caution because toxicity at levels >30 ppm may occur in SR.2,15 To improve detection of BCS and increase lamb birth weight, shear ewes 4 to 8 weeks prior to the expected lambing date.2,16 The cold stress of winter shearing negatively affect insulin secretion resulting in increased BG levels without apparent risks of developing clinical PT.16

References

1.  Rook JS. Vet Clin North Am Food Ani Pract 2000;16(2):293.

2.  Pugh DG. Sheep & Goat Medicine 2002;97.

3.  Schlumbohm C, et al. J Dairy Sc 2004;87:350.

4.  Schlumbohm C, et al. J Dairy Sc 2003;86:1953.

5.  Bigner DR, et al. J Dairy Sc 1996;79:2182.

6.  Heitmann RN, et al. J Nutr 1987;117:1174.

7.  Henze P, et al. J Vet Med A 1998;45:255.

8.  Van Saun RJ. JAVMA 2000;217(10):1536.

9.  Harmeyer J, et al. Res Vet Sci 2006;81:254.

10. Scott PR, et al. Br Vet J 1995;151:39.

11. West HJ. Br J Nutr 1996;75:593.

12. Trachtenbarg DE. Ame Fam Phys 2005;71(9):1705.

13. Navarre C. Large Ani Proceeding of North Am Vet Conference 2007;21:264.

14. Andrews A. In Practice 1997;19:306.

15. Jones A. Can Vet J 2001;42:135.

16. Symonds ME, et al. Br J Nutr 1986;56:635.

Speaker Information
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Melanie Boileau, DVM, MS, DACVIM
Oklahoma State University
Stillwater, OK


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