Dietmar Holm and Martin van der Leek
Department of Production Animal Studies,
Faculty of Veterinary Science, University of Pretoria
From Southern Cape Proceedings 2018
Milk fever or parturient paresis
Milk fever is a production disease of dairy cows (usually high producing, older cows) that occurs around parturition and the beginning of lactation and that is associated with clinical hypocalcaemia. The name “milk fever” is a classic historical misnomer because in fact most cows with hypocalcaemia have a lower than normal temperature due to reduced muscle tone and reduced circulation. The condition is characterized by an imbalance of blood mineral levels especially low serum calcium; general muscular weakness; depression of consciousness; circulatory collapse and eventually coma and death. Milk fever has quite an interesting history:
– The condition was first described in 1793 by Eberhardt
– During the 19th century several descriptions were made of the epidemiology that is still relevant today.
– Treatments advocated during the 19th century included drenching with various organic and inorganic compounds including boiling ale.
– Bleeding of susceptible cows before calving was used for prevention, about 5 litres of blood had to be removed.
– In 1897 Schmidt described a method to treat milk fever that reduced mortality from 40-60% to 10-24%. The method used was insufflation of the udder with potassium iodide and air. It was believed that the condition was caused by a neurological toxin similar to botulism that originated in the udder.
– In the 20th century it was discovered that the condition was caused by lowered serum Ca levels, and around the mid 1920’s treatment with Ca borogluconate was first started. It was then believed that dietary intake could not sustain Calcium loss through milk production.
– Early in the 20th century the role of parathyroid hormone in Calcium metabolism was described, but in the middle of the 20th century prevention was mainly achieved by administering synthetic vitamin D. This at first caused problems with metastatic soft tissue calcification and when the product was improved still only had adequate effect if treatment was administered 3 to 6 days before calving. Since it is not always possible to predict the exact onset of calving, the treatment was later combined with 5mg flumethasone in order to induce parturition. This practice continued into the 1970’s.
– During the 1970’s and 1980’s changes were being made to dry cow rations to reduce Ca intake in order to “prime” Ca metabolism as was then understood. This is still a viable option today (see later)
– During the 1990’s and 2000’s Goff and others developed the DCAB theory to prevent milk fever, and this is now widely used in combination with Calcium drenches post partum.
– Despite the above improvement of our knowledge of hypocalcaemia and milk fever it remains one of the most important and most challenging production diseases in a dairy.
Milk fever as a production disease
In most cases, hypocalcaemia is caused by a basic metabolism output problem. A fall in serum Ca levels is seen in all adult cows at the onset of lactation. This is assumed to be due to the sudden outflow of Calcium due to the onset of lactation in combination with a failure to rapidly mobilize calcium reserves from bone, and/or to rapidly absorb calcium from the gastro intestinal tract.
Phosphate, magnesium and to a lesser extent potassium may also play subsidiary roles. Milk fever is caused by an imbalance in Ca throughput/output (Normal serum Ca levels are 2.0 2.9 mmol/l).
In hypocalcaemia in cattle, paralysis occurs as a result of inadequate calcium availability at the neuromuscular junction, where it is required for the release of the neurotransmitter acetylcholine. Impulse conduction through peripheral nerves (above the level of the neuromuscular junction) and through muscle fibres (below the level of the neuromuscular junction) is also modulated by calcium through its membrane stabilizing effect and hypocalcaemia will also have an effect at these locations.
Calcium input is determined by intestinal uptake and skeletal mobilisation. Calcium output is determined by levels in colostrum and milk, foetal tissue and calcium loss in faeces and urine.
Pathophysiology of Milk Fever
The diagramme below is a simplified representation of the mechanisms involved in maintaining blood Ca levels. Make sure that you revise and understand these mechanisms and interactions: a sound knowledge of this is needed to understand and interpret this disease at farm level.
The amount of Calcium (Ca++) freely available in the blood is very small relative to the amount required for milk production (see figure). Most of the body’s Ca++ is stored in bone, and there has to be an active metabolism of Ca++ to ensure rapid availability of stored Ca++ at the onset of lactation. Osteoblasts are active bone cells that deposit Ca++ in bone while osteoclasts are similar cells that break down stored Calcium structures in bone and deposit Ca++ in the blood. Ca++ metabolism is regulated mostly by two prominent hormones: parathyroid hormone (PTH) and calcitonin. PTH responds to low blood Ca++ levels and is responsible to increase levels back to normal, while calcitonin is secreted in response to high blood Ca++ levels having the opposite effect to PTH. Vitamin D3 also plays a role by increasing intestinal uptake of Ca++, and the manufacturing of this vitamin from cholecalciferol in the kidney is stimulated by PTH and inhibited by calcitonin. Apart from its effect on Vitamin D3, calcitonin also has a direct inhibitory effect on intestinal Ca++ uptake, a stimulatory effect on urinary loss of Ca++, an inhibitory effect on osteoclasts and a stimulatory effect on osteoblasts. PTH on the other hand stimulates osteoclastic activity and stimulates kidney reabsorption of Ca++ in exchange for phosphorus. It is important to note that the loss of Ca++ in milk is not hormonally regulated, leading to ongoing loss despite critical deficiencies.
High levels of dietary Calcium in the period preceding calving leads to the release of calcitonin, inhibiting the number and activity of osteoclasts in bone. When Ca++ levels suddenly drop at the beginning of lactation, PTH is secreted in response to this, but there seems to be a refractory period of 48-72 hours during which adequate osteoclastic activity does not take place despite adequate PTH levels, due to the earlier calcitonin supression. This is exactly the time when most cows develop milk fever.Apart from this, it is now known that a metabolic alkalosis causes a change in the morphology of PTH receptors in bone and kidney cells, leading to secreted PTH to be ineffective when its effect is desirable. Diets that cause a metabolic acidosis (low blood pH) on the other hand activate PTH receptors making osteoclastic activity much more effective after PTH stimulation. For this reason anionic salts are added to dry cow rations to induce a mild metabolic acidosis, in order to prime PTH receptors leading to a much smoother change-over from an anabolic to a catabolic Calcium state.
Magnesium is an important co-factor in the production, secretion and action of PTH and Vitamin D3, and a deficiency of dietary Magnesium may also predispose cows to milk fever. Magnesium acts on the production and secretion of PTH, but the main effect of Magnesium on Calcium metabolism is a binding site on the adenyl cyclase complex attached to the PTH receptor, which is responsible for cyclic AMP (second messanger) release into the cell. With inadequate Magnesium this binding site is not saturated, and PTH can not function optimally even at a low pH.
Diagramme illustrating the metabolic pathways of Calcium homeostasis
Predisposing factors of milk fever
When the pH of the intracellular fluid compartment is high (relative metabolic alkalosis), bone and perhaps also renal tissue are refractory to the effects of PTH. Likewise the stimulatory effects of PTH are enhanced during metabolic acidosis. Diets high in strong cations during the transitional phase, especially Na and K, tend to induce a metabolic alkalosis and milk fever will follow. Diets high in strong anions, primarily chloride (Cl) and sulphur (S) will induce a relative metabolic acidosis and will prevent milk fever.
Other factors that will tend to cause a metabolic alkalosis in the peri-partum period is the secretion of colostrum that is relatively acidic, the presence of rumen hypomotility and where a high protein diet is fed (rumen alkalosis).
Diagrammes illustrating the effects of pH and Magnesium on the PTH receptor
(Adapted from Goff J P 2008 The monitoring, prevention, and treatment of milk fever and subclinical hypocalcemia in dairy cows The Veterinary Journal 176:50-57)
Will retard Ca absorption as Ca salts become more insoluble and are trapped in the rumen.
Rumen intestinal stasis and reduced food intake
Even brief periods of poor appetite or ruminal stasis may trigger hypocalcaemia as continuous function of the alimentary tract is vital to maintain the flow of nutrients for lactation. Dairy cows, being bred for milk production, continue to lactate even though this means that they deplete their bodies of vital reserves. Thus milk fever can be induced by just a brief and temporary interruption in gastro-intestinal function.
A decreased appetite at partus, high oestrogen levels at partus, sudden dietary changes and a relatively alkalotic state may all participate in causing a state of ruminal and intestinal stasis. Fat cows will tend to have a lower intake in the immediate post partum period and seem to be more prone to milk fever than lean cows. Stressful situations will also lead to a decreased feed intake.
Calcium intake during the dry period
Feeding more than 100g of Calcium daily during the last few weeks of the dry period is associated with an increased incidence of milk fever. If calcium intake is excessive the cow’s daily requirement for calcium can be met almost entirely by passive absorption of dietary calcium. Active transport of dietary calcium from intestine to blood and bone calcium resorption mechanisms are then depressed and become quiescent. Because the production of PTH and 1,25 (OH)2 D seems to be adequate in most cows with milk fever it is thought that target tissues in these cows that received too much Ca through the diet have defective hormone receptors that either do not recognize the hormone or there may be fewer receptors present in the target tissues.
A hypomagnesaemia will negatively influence the production and / or secretion of both PTH and 1,25(OH)2D. Magnesium is also a co-factor in the action of PTH and 1,25(OH)2D3 on the bone and small intestine (see above). Both the above factors may lead to an increased incidence of milk fever if there is a deficiency of magnesium in the diet. Furthermore Mg plays a role in the release of Ca from the endoplasmic reticulum in muscle cells, and a reduced Mg level can therefore exacerbate the symptoms.
The ability of the cow to increase intestinal calcium resorption decreases with age. This is the result of both decreased production of 1,25 (OH)2 D and decreased response to this hormone (the number of hormone receptors in target tissues declines with age). Older cows also have fewer osteoclasts to respond to PTH stimulation.
As mentioned before
Level of production
Milk fever is more common in high producers.
Feeding system prepartum
Cation levels in pastures is often impossible to control, and generally high, and certain practices like using slurry for fertilisation/irrigation of dry cow pastures can lead to very high levels of particularly K+ with a resultant increase in milk fever incidence.
Total Mixed Ration (TMR) system where cows are housed throughout the dry period makes management of the intake of cation levels easier. However many dairies still put their dry cows to pasture in order to save costs. The steam-up period is the critical period where things can go wrong.
As mentioned before, stress plays an important role in the manifestation of various production diseases, and it is important for producers to ensure husbandry practices that will lead to minimal stress of the animals. Maintaining adequate dry matter intake is often a problem in stressed cows. However, stressful procedures of short duration are less likely to have adverse effects than ongoing stress. The latter leads to the constant release of cortisol, which in turn inhibits osteoclastic activity in bone and therefore leads to an increased risk of developing milk fever.
Clinical findings of milk fever
Clinical milk fever has three recognisable stages: the first stage when the cow is still standing and showing mild signs only is usually not recognised. The diagramme below gives a summary of the most common clinical signs associated with the second stage of milk fever. A thorough knowledge and interpretation of these signs is essential for a practicing veterinarian because this condition is a clinical emergency, and an accurate clinical diagnosis has to be made without laboratory confirmation. The third stage is when the cow becomes comatose and laterally recumbent. The entire condition from the start of clinical signs to coma usually takes only about 8 hours. Most cows die within 24 to 48 hours if no treatment is given.
Subclinical hypocalcaemia – the number 1 metabolic disease of dairy cows
A lot of the economic value in prevention of hypocalcaemia at parturition lies in the prevention of subclinical hypocalcaemia and not so much in the prevention of clinical milk fever. It has, for instance, been demonstrated that diets that were designed to prevent peri-partum hypocalcaemia, increased milk production by 350 – 480kg/cow in the lactation. One can also expect a significant improvement in the conception rate and other reproductive parameters, a reduced incidence of retained placenta and a reduction in the number of cases with udder oedema. It may thus prove to be a good idea to institute steps to prevent milk fever, even in herds where the incidence of the condition is less than 5%.
Occasionally hypocalcaemia with typical “milk fever” signs occurs in cattle (dairy or beef) at other times than the typical post-parturient presentation. This may be seen as individual cases or even as outbreaks, and the following factors, or combinations of these, may play a role:
- Conditions that lead to a reduction in dry matter intake that lasts for 12-16 hours: Oestrus, bad weather, other disease conditions such as mastitis/metritis/LDA/rumen acidosis etc.
- Dietary factors such as reduced Calcium or Magnesium in the feed, vitamin D deficiency or plants containing Oxalate that binds available Calcium. The feeding of chicken manure is a risk factor.
- Conditions leading to a metabolic alkalosis such as LDA, dietary intake of rations high in Potassium or protein.
- Kidney failure leads to ongoing loss of Calcium and reduced intestinal uptake despite deficiency (vit D deficiency). This presents as an unresponsive hypocalcaemia.
- Conditions that lead to endotoxaemia cause Ca to be moved into the intracellular compartment, also leading to an unresponsive hypocalcaemia.
Herd surveillance for animals at risk in herds using anionic salts as preventative measure
When strategies to prevent milk fever are in place, an ongoing surveillance plan should be implemented to monitor the success of the prevention strategies, and to attempt to identify individual animals at risk, in order to make sure that extra measures are taken in these animals to prevent the disease.
Firstly one could use Epidemiological knowledge and identify multiparous, high producing cows and cows that have suffered with milk fever in previous lactations as animals at riks.
Secondly, and currently the most common method used, is to test urine pH in dry cows to indirectly supply evidence of osteoclastic activity. Urine pH should ideally be in the range 6 to 6.8. It is however common to find individual cows with higher urine pH, and these cows are at risk of developing milk fever.
A minimum of 3 days on the anionic salt ration is recommended before urine pH is monitored. The veterinarian must therefore verify the duration on the ration before including cows in a surveillance sample.