Endocrinological aspects
Progesterone is essential for the establishment and maintenance of pregnancy in all mammalian species that have been studied.3 In cattle, the corpus luteum (CL) is the primary source of progesterone throughout gestation and luteal regression is necessary for parturition to occur.4 Progesterone is also produced by the binucleate cells in the cotyledon of bovine placental tissue.5,6 After 120 days of gestation the placenta begins to secrete progesterone and between 120–150 days and approximately 240 days the placental source of progesterone alone is sufficient to maintain pregnancy. During the last 4–6 weeks of gestation, placental progesterone gradually declines and the maintenance of pregnancy once again becomes dependent on the CL.7,8 Thus if luteolysis occurred prior to the eighth month of gestation, pregnancy would be maintained for a time but parturition would likely occur several weeks before the normal due date.
As the fetal hypothalamus, pituitary, and adrenal glands mature, increasing amounts of cortisol are produced by the fetus. Rising fetal cortisol in the last 4–6 weeks of gestation appears to gradually reduce uteroplacental synthesis of progesterone.9 This decline in progesterone secretion is due to cortisol induction of enzymes that convert placental progesterone to estrogen. Cortisol induces 17α-hyroxylase and 17,20-lyase activities in the placenta, catalyzing the formation of androgens from progesterone.10 Androgens are rapidly converted to estrogens by the placental P450 aromatase system.
During pregnancy, high concentrations of progesterone maintain uterine quiescence mainly by hyperpolarizing the myometrial cells. At the end of gestation, falling progesterone and increasing estrogen produces depolarization of the myometrial cells and stimulates the formation of myometrial cell gap junctions enhancing the sensitivity of the myometrium to stimulatory agonists.11 Declining progesterone and rising estrogen results in increased expression of oxytocin receptors in the myometrium.12 It appears that increased estrogen concentrations also stimulate the production and release of prostaglandins.13 Recent data from ovine studies suggest that fetal cortisol induces prostaglandin G/H synthetase-2 isozyme in placental cotyledons, thus favoring the prepartum increase in prostaglandin formation.14 Prostaglandin production results in the demise of the CL and a precipitous drop in serum progesterone concentrations. Smooth muscle activation is associated with endometrial synthesis of prostaglandin (PG)F2α which augments the force of contraction. Prostaglandins are also involved in the mechanisms of cervical ripening, which is essential for successful parturition.
Fetal endocrine control of parturition was demonstrated by Liggins in his studies on parturition in sheep. He showed that electrocoagulation of the fetal pituitary prevented normal term parturition and went on to demonstrate that the hypothalamus–pituitary–adrenal (HPA) axis was responsible for initiating parturition as infusion of glucocorticoid or adrenocorticotropin (ACTH) initiated premature parturition.15
The trigger for the spontaneous onset of labor is the greatly increased cortisol production by the adrenal gland of the maturing fetus. The increase in activity of the fetal HPA axis at the end of gestation is likely caused by programmed maturation in the fetal hypothalamus, or elsewhere in the fetal nervous system, rather than a response of the fetal pituitary to a chronic stress such as might be caused by a developing inadequacy of space and nourishment within the uterus. Some other external influence on the maturing hypothalamus, such as a progressive increase in the secretion of the placenta, is another possibility.16
Throughout the last 2–3 weeks of development in utero the fetal adrenal increases in size relative to body weight and the cellular sensitivity to ACTH increases.3 The increase in sensitivity to ACTH is partially the result of increased adrenal cortical mass and partially the result of increased cellular responsiveness to ACTH. The increase in size and sensitivity of the adrenal gland combined with increasing circulation of ACTH account for the increased cortisol secretion that triggers parturition. Recent evidence suggests that at least some of the activity of the fetal HPA axis is due to positive feedback from placental estrogen. Increasing estrogen in fetal plasma greatly increases ACTH concentrations in fetal plasma.17
Since fetal cortisol levels gradually rise in the last month of gestation, particularly in the last week,9 placental maturation may require exposure to elevated cortisol levels for a period of time prior to calving. This hypothesis is supported by a reduction in the incidence of retained placenta when long-acting corticosteroids are used to induce parturition.18,19
Induction of parturition
Indications
The use of induction of parturition in commercial beef herds is usually limited to the treatment of uterine hydrops, cardiac failure, or other health-related matters in which salvage of the fetus, or the life of the cow, is considered. The main factors preventing the use of induction of parturition as a management tool in commercial herds is the lack of known breeding dates with natural mating and elevated rates of placental retention leading to reduced first-service pregnancy rates.
The fetus can gain 0.45–0.68 kg/day in the final weeks in utero in normal gestations.20,21 It appears that when gestations are 1–2 weeks overdue, as is more commonly the case in some of the large European breeds of cattle, fetal weight gains could be as high as 1 kg/day. In such cases, calf birthweight might easily become too large to allow normal parturition. Producers of purebred cattle often employ artificial insemination and thus breeding records are available, gestation lengths can be determined, and overdue gestations could be prevented by induction of parturition. It has been reported that when a short-acting glucocorticoid was used to terminate prolonged gestation in continental breed heifers, there was dystocia due to poor birth canal relaxation and ineffective labor.22 However, too early intervention in the calving process might have been partially to blame for this finding. It has become a common practice by producers to induce parturition after 285 days of gestation rather than to allow gestations to become prolonged. In most cases, the stages of labor and pelvic relaxation are normal. Although no data are available, clinical experience from common usage of the procedure indicates that calf viability and colostral transfer are good. An additional benefit of induction of parturition in these cases might be to allow the female an extra 10–14 days to resume cycling for rebreeding in the subsequent breeding season. However, despite gestations having progressed for a normal duration, placental retention rates appear to be elevated. Thus the subsequent problem of endometritis may cancel any benefits of extra time gained through induction of parturition for the cow to resume cycling since endometritis may delay the first postpartum estrus.
In dairy herds, parturition may be induced 1–2 weeks early to prevent excessive udder edema and distension which may predispose to mastitis and difficulty in milking. Induction of parturition with long-acting corticosteroids has gained widespread acceptance with dairy producers in New Zealand and Australia as an important management tool for initiation and synchronization of lactation with the grazing season.23,24 Calving is concentrated at a time of year when grazing is optimal for milk production. In the limited breeding season that follows it is inevitable that some cows will fail to become pregnant or will become pregnant too late to calve on time the following year. These cows would ordinarily be culled. Induced calving can be applied in association with an extended mating period to reduce herd wastage. Cows that are not pregnant at the end of a defined mating season can be mated and identified by bulls fitted with a chin-ball marking harness. In the following calving season these cows can be induced to calve 1–3 months prematurely. Calves born more than 1 month prematurely will be lost; however, milk yield can be expected to be near normal.
Precautions
At present one of the main obstacles to widespread use of induction of parturition is the need for accurate knowledge of breeding dates to prevent the birth of nonviable calves and an increased incidence of retained placentas. Calves born up to 2 weeks preterm have good vitality and are able to attain good maternal immunity derived from colostrum.25,26 The incidence of placental retention is related to the degree of prematurity of induced parturition. Cows induced 1–2 weeks prematurely usually retain the placenta in over 75% of cases, whereas cows induced within a few days of term, or at term, have a 10–50% placental retention rate. In most reports cows with induced parturition and retained placentas did not have reduced pregnancy rates;27,28 however, first-service pregnancy rates were significantly lower in cows that had retained placentas than cows that did not retain their placentas.29,30
The effect of induction of parturition on milk yield in the following lactation and on the concentration and yield of colostral immunoglobulins most likely depends on how early parturition is induced. In general, when parturition is induced within 2 weeks of normal term, the onset of milk production would be a few days slower than in natural calvings, but overall production levels for the entire lactation period are within expected limits.9,18 When parturition was induced up to 22 days before the normally expected calving date there was a significant decrease in the yield, but not the concentration, of colostral IgG.31 When birth occurred 10–15 days or more before due date, calves had lower levels of colostral immunoglobulin.19,31 This may be due to an impaired ability to absorb immunoglobulin32,33 and reduced intake due to calf weakness.19
When short-acting corticosteroids are used to induce calving close to term, the immunoglobulin concentration of colostrum is not different from that in naturally calving cows; however, the total immunoglobulin content may be lower due to a reduced volume of colostral secretion.31,32 The ability of these calves to absorb immunoglobulin is not reduced as serum γ-globulin concentrations after suckling are similar to those of naturally born calves.22,33
The response and effects of inducing parturition on day 274 of gestation in dairy cows has been investigated in Australia. Cows were injected with dexamethasone trimethylacetate with herdmates as controls. Treated cows calved an average of 2.61 days before their due date. There were no differences in the proportion of cows displaying symptoms of milk fever, mastitis, paralysis, or acute metritis. There were no differences between groups for cow or calf mortality, or for any parameter of milk yield. The incidence of retained fetal membranes was significantly higher in cows with induced parturition but, interestingly, control cows received more assistance at parturition.34
Methods of induction of parturition
Various types and combinations of hormone treatments have been studied for efficacy and safety of induction of parturition, including corticosteroids or prostaglandins in combination with various estrogen preparations27,28,35–40 and oxytocin41 without appreciably reducing the incidence of placental retention. Dimenhydrinate42 and relaxin43 in combination with dexamethasone have been reported to reduce placental retention; however, the number of cows treated with dimenhydrinate was small and relaxin is not commercially available. RU-486, a potent antiprogesterone, used alone or in combination with relaxin and administered to beef cows on day 277 or 278 of gestation, resulted in basal levels of progesterone (P4) by 48 hours after injection and calving at 53–55 hours after treatment. There were no complications at calving and no retained placentas; however, there were only two animals per treatment group and inductions were done very close to normal term, so a great deal more study is needed before this method can be recommended.44
Short-acting corticosteroids
The most commonly used corticosteroids for inducing parturition are dexamethasone (20–30 mg) and flumethasone (8–10 mg) given as a single intramuscular injection. Parturition is induced with 80–90% efficacy when the injection is given within 2 weeks of normal term. The interval from injection to parturition is 24–72 hours, with an average of 48 hours. In cows that have not calved by 72 hours after treatment the induction is considered to have failed. Retreatment in such cases is often successful in inducing parturition. Relaxation of the pelvic ligaments, cervical dilation and filling of the udder occur rapidly, and labor and parturition are normal. Calving difficulty scores that have been recorded for induced parturition have generally not been different from those of natural calvings; however, frequently a higher incidence of minor assistance is given. This is probably because personnel are readily available during induction trials and assistance is more likely to be given even when not absolutely necessary.
Calves born less than 2 weeks prematurely are vigorous and calf mortality is not increased. The actual secretion of milk at the onset may not be plentiful in induced cows; however, colostral immunoglobulin levels and total milk production for the lactation period are very close to normal. Induced calves attain similar blood levels of immunoglobulins as calves born naturally.
Long-acting corticosteroids
Long-acting corticosteroids are not used when calf viability is of primary importance; however, they have gained wide acceptance where seasonal milk production is of primary importance and calving (lactation) is synchronized with the grazing season. Dexamethasone trimethylacetate (25 mg) or triamcinolone acetonide (4–8 mg) may be used and appear to provide similar outcomes.18,34,35 An intramuscular injection is given once 2–4 weeks prior to the due date for calving and parturition occurs over a wide range of 4–26 days. Usually the farther a cow is from her due date, the longer it takes for a response.24 Despite prolonged elevated systemic corticosteroid levels, cow health is generally good; however, preexisting diseases, particularly subclinical infections, may be exacerbated by the treatment and there is a potential increase in cow mortality.
The udders of treated cows are consistently engorged with milk about 1 week after injection, although it may be another week before they actually calve. It has been suggested that these cows should be milked before calving if the udder is obviously full to prevent regression of secretory tissue. Total milk production per lactation can be expected to be reduced by 4–7%.
The incidence of retained placentas with the use of long-acting corticosteroids is quite low (9–22%) compared with short-acting corticosteroids. However, there is a high incidence of calf mortality (7–45%), which appears to be due to premature placental separation, an increased frequency of uterine inertia, and calf prematurity. Calf mortality may be reduced somewhat by careful observations and provision of prompt assistance.
The variability in response to treatment with a long-acting corticosteroid can be reduced by treating with a short-acting corticosteroid or prostaglandin about a week after the long-acting corticosteroid treatment.19 Most cows will calve 2–3 days after the the second injection. The interval from injection to calving tends to be shorter and more predictable after prostaglandin than after a short-acting corticosteroid, and fewer repeat injections are required with prostaglandins. Calf mortality and the incidence of retained placentas are not reduced by giving a second injection.
