updated 4/19/99

PREGNANCY AND PARTURITION

I. Development of the Fetus

A. The fetus is the result of differentiation of the inner cell mass of the embryo into ectoderm, mesoderm and endoderm.

Endoderm -- becomes the lining of the gut, glands and bladder

Mesoderm -- becomes connective tissue, vascular system, bones, muscle and the adrenal cortex.

Ectoderm -- becomes the nervous system and the covering of the body.

Organogenesis

The organs of the fetus grow at differential rates resulting in a constant changing of shape.

1. The liver and heart are highly functional in the early embryo and greatly enlarged. The lungs, however, develop functionally just before delivery. In the fetus, the placenta functions as a lung and oxygen-rich blood travels from the umbilical vein through the ductus venous, the caudal vena cava, and through an opening between right and left atrum (foramen ovale) directly into the left atrium. A ductus arteriosus shunts right ventricular blood away from the lungs and directly into the aorta.
   
   
2. The brain and nervous system develop early and the brain (especially its hypothalamus and pituitary) plays a major role in controlling the functional development of other systems of the body. Interference with hypothalamic function at the stage when a particular process is under development can cause permanent defects (birth defects).

B. Growth is orderly and fetal age can be easily determined from crown rump length or length of the long bones or from the time specific structures develop.

C. Factors affecting prenatal development.

1. Heredity.
   
   
2. Maternal size and age influence account for 50-75% of the variation in birth weight. For example, the Shire horse x Shetland pony cross produces a foal nearly the size of a pony when the dam is a pony.
   
   
3. Restricted feed intake in the last 1/3 of gestation results in reduced birth weight, most weight increase occurs in the last trimester.
   
   
4. Large litter cause reduced birth weight and there are preferred locations in the uterus in litter bearing species.
   
   
5. Ambient temperature. Ewes subjected to high temperature produce lighter lambs and have less mammary development.

II. Establishment of Pregnancy:

A. After fertilization embryos spend a short period of time trapped on the ampulla side of the ampullary-isthmic junction of the oviduct. They then pass rapidly through the isthmus to the uterus. In horses the ampullary-isthmic junction allows egg passage only after a fertile mating. It has been suggested that a humoral agent is produced by the embryo which promotes opening or transfer across the ampullary-isthmic junction. Embryos fail to develop beyond the early blastocyst if confined to the oviduct.

Hormonal events associated with the first 14 days of the estrous cycle and pregnancy are essentially identical; however, by day 16 the female must decide if she is pregnant and intends to maintain corpora lutea or to cause their regression and thereby start a new estrous cycle.

Since uterine PGF2a causes corpus luteum (CL) regression and terminates progesterone production in farm animals its secretion, transport or effectiveness at the ovary must be prevented for maintenance of corpora lutea. The way this is accomplished differs for each species.

B. Swine -- Pregnancy is established when the embryo starting at day 12 produces estrogen which acts on the uterus preventing the release of the luteolytic factor (PGF2a) into the uterine vein. The corpora lutea are saved from regression. LH from the sow's pituitary gland is required to maintain the CL throughout pregnancy. The placenta of the sow converts all its produced progesterone to estrogen. Therefore, functional ovaries are the only source of progesterone and needed to prevent uterine contraction throughout pregnancy.

C. Sheep -- The ovine blastocyst prevents CL regression by production of a protein from its trophoblast cells called "ovine interferon tau (oIFN-t). The oIFN-t acts on the endometrium of the uterus to prevent the syntheses of PGF2a. Thus by preventing synthesis of the CL luteolytic agent, PGF2a, the CL is protected and maintained.

D. Cattle -- The bovine blastocyst prevents CL regression by a mechanism similar to that described for sheep except the protein produced by the blastocyst is called bovine interferon tau (bIFN-t) . One half of this protein appears to be similar to oIFN-t of the sheep.

F. Human -- In humans and other primates maintenance of the corpus luteum, progesterone production and pregnancy are dependent on a placental hormone called Human Chorionic Gonadotropin. This hormone, abbreviated hCG, has LH like activity. It is the LH activity that protects the corpus luteum from regression and stimulates its production of progesterone, The hCG is produced initially by the trophectoderm of the blastocyst embryo (8-10 days after conception). As soon as the placenta forms, cells of its chorion layer derived from trophectoderm cells produce and continue to produce hCG. The presence of hCG in maternal blood provides the basis for rapid and accurate immunological assay and pregnancy diagnosis.

III.Maintenance of Gestation:

The maintenance of pregnancy in mammals is dependent on prevention of uterine contraction except in the elephant and perhaps the mare at the end of pregnancy. A "progesterone block" of myometrial activity prevents uterine contraction. The source of progesterone and control of its production differ between species and stages of pregnancy. Species or stages in which the ovary is required generally require a functional pituitary gland except for rodents where the corpora lutea are maintained by a placental gonadotropin.

A. Species with Progesterone from the CL

1. Swine -- progesterone from the CL and CL maintenance are essential for prevention of uterine contraction and maintenance of pregnancy in this species throughout the 114 day gestation. Production of progesterone by the CL is dependent on continued secretion of LH from the anterior pituitary gland. During the first 1/4 of gestation each uterine horn must contain at least 2 piglets, total of 4, to produce sufficient signal to tell the sow she is pregnant and to prevent regression of the CL by PGF2a.
   
   
2. Cattle -- One blastocyst is usually sufficient to signal maintenance of pregnancy although early conception rates are higher when 2 blastocysts are transferred into the uterus. Later they compete and 1 usually dies. The CL and ovarian progesterone are essential for pregnancy maintenance through 215 days of the 280 day bovine gestation. After day 215 the maternal adrenals produce enough progesterone to maintain pregnancy to term. Maintenance of the CL is likely dependent on pituitary LH.
   
   
3. Horses -- The original corpus luteum is maintained through day 140. However, mare will remain pregnant when the ovaries are removed after day 70. About day 35, cells of fetal trophoblast origin from the chorioallantoic girdle invade the endometrial cups of the uterus and by day 40 produce equine chorionic gonadotropin (eCG). The gonadotropic hormone stimulates follicular growth on the ovaries, occasional ovulation and considerable luteinization occurs by day 50 to form numerous accessory corpora lutea. The eCG levels remain high and accessory corpora lutea greatly elevate plasma progesterone through day 140. The accessory and original CL regress and pregnancy is maintained by low levels of progestin or some as yet unexplained mechanism.
   
   Equine blastocyst do not undergo elongation immediately after hatching from the zona as in other species. Rather they remain spherical until day 50 due to a large prominent fluid filled yolk sac. Blastocyst elongation and true implantation occur after day 50. Abortion often occurs at this time of transition from yolk sac attachment to true placentation. Progesterone from the original and eCG induced accessory corpora lutea is essential around this time to prevent abortion.
   
   

B. Species with Pregnancy Maintained by the Placenta

1. Sheep -- The CL and anterior pituitary LH needed to cause CL secretion of progesterone are essential for the first 55 days of ovine pregnancy. Thereafter the placenta produces sufficient progesterone for maintenance of pregnancy until the end of the 146 day gestation when the placenta converts its produced progesterone to estrogen.
   
   
2. Human -- After 2 months of pregnancy the human placenta produces sufficient progesterone to maintain the pregnancy and corpus luteum and its maintenance by hCG are no longer required. There is also evidence that the hormone relaxin is produced during human pregnancy. It also causes some suppression of uterine contraction.

IV.Length of Gestation

A. Length of gestation is calculated as the interval from the last fertile mating to parturition. It is quite precise in swine (114 ± 2 days), especially within breeds, variable in cattle (280 ± 5 days) and sheep (148 ± 5 days) and highly variable in horses (338 ± 15 days) and humans (252-274 days).

B. The length of gestation is influenced by:

1. Heredity -- genotypes of the offspring. In horses, mares have a gestation of 5 days longer when bred to a stallion than when bred to a Jack. Interestingly, the eCG levels in the mare are 10 times higher and found for over a month longer in mares carrying a foal from a stallion than from a Jack. Pony mares have a gestation of approximately 330 days while large saddle mares average 338 days.
   
   
2. Fetal sex -- Male calves and foals are carried 1 to 2 days longer than female.
   
   
3. Twinning -- Twin calves are carried 3 to 6 days less than singles yet litter size in swine has very effect on gestation length until the litter is reduced to one pig, then there is a tendency for prolonged gestation.
   
   
4. Life of the fetus -- late fetal death or abnormalities of the pituitary or adrenal glands will extend gestation in swine, sheep and cattle.

V. Parturition

Parturition is not a decisive single-step terminal event. Preparation for parturition involves coordinated changes in both mother and fetus. The mother must develop the ability to produce and eject milk in order to feed the newborn. In some species, she must develop nest building or protective senses as well. Her uterus must be removed from progesterone influence and stimulated to undergo contraction. These and other events must be, and are, synchronized. Meanwhile, the fetus must develop the ability to respire air, to circulate blood to and from the lungs, to metabolize milk products, to regulate its own body temperature, immune protection from its new environment, and other essential functions. These events are coordinated by the fetus and they in turn are synchronized with the maternal changes.

A. Mechanisms initiating parturition -- for delivery to occur, the uterus must undergo massive contraction and the birth canal (cervix, and pelvis in some species) must be opened. For this to happen, a progesterone block of uterine contraction must be removed. In species such as swine where progesterone is from the corpus luteum, regression of the corpus luteum must occur. In species such as sheep where progesterone is from the placenta, this production must cease.

1. Sheep: Parturition is prevented by removal of the fetal pituitary or adrenal glands and prematurely induced along with lung maturation and other necessary life systems by Adrenal Corticotrophic Hormone (ACTH) or the hormone of the fetal adrenal cortex, cortisol. Thus, the message initiating parturition starts with the fetal brain, its control of ACTH release from the pituitary, and increased cortisol production by the fetal adrenal. The cortisol stimulates placental enzymes which cause placental progesterone to be made into estrogen. The placental estrogen acts on a uterus which is no longer under progesterone influence causing the myometrium to contract. This stimulates the uterus to release prostaglandin F2a which in turn, and in the absence of progesterone, stimulates release of oxytocin and prolactin from the pituitary gland. Prostaglandin F2a and oxytocin cause a cascading effect on the uterus; that is, the more it is stimulated to contract, the more prostaglandin is released and the more prostaglandin released, the more the uterus contracts until delivery occurs. Relaxin release to soften the cervix appears to be stimulated by the elevated estrogen in maternal blood.
   
   
2. Swine: Parturition is prevented by removal of the pituitary glands of the fetuses, fetal decapitation or late fetal death of an entire litter. After day 100, parturition can be prematurely induced by ACTH, glucocorticoids (cortisol is a glucocorticoid) or prostaglandin F2a. Parturition does not occur if prostaglandin synthesis is inhibited. The initiation of parturition is controlled by the fetus as in sheep but different mechanism exists for terminating production of progesterone because it is produced by the corpora lutea in this species. As in sheep, the message initiating parturition starts with the fetal brain and after day 100, the following events: ACTH release, elevation of adrenal cortisol, stimulation of some as yet unknown intermediate which causes the uterus to produce and release prostaglandin F2a. The prostaglandin F2a stimulates release of prolactin and oxytocin cause a cascading of uterine contraction until delivery is complete. Delivery requires about 15 minutes per pig and stillbirths occur if delivery is prolonged. Prostaglandin F2a causes the corpora lutea to release relaxin. Relaxin is capable of softening and relaxing the cervix as well as pelvic ligaments to expand the birth canal. This is essential for rapid and live birth.
   
   
3. Cattle. The mechanisms controlling parturition are similar to those in swine.
   
   
4. Horses. Hormonal events change very rapidly preceding parturition in the mare perhaps because the contractile property of the myometrium is not under heavy progesterone suppression. There is a rapid and high elevation of prostaglandin F2a and oxytocin at the time of labor and delivery is rapidly completed without much prior warning. It is likely that the fetus controls the initiation of parturition in this species but the mare can suppress this stimulation for days if disturbed and nearly all mares choose to foal at night when they are not disturbed. As in sheep, swine and cattle, both glucocorticoids and prostaglandin F2a can be used to induce preterm delivery.
   
   
5. Primates: In the human, the control of corpus luteum function is not dependent on the uterus and in fact the ovary and maternal pituitary gland are not necessary for completion or termination of pregnancy. Although exogenous corticosteroids do not induce labor in the human, the fact that fetal pituitary or adrenal failure prolongs gestation suggests the involvement of these two glands in human parturition as in other species. Present evidence from the rhesus monkey and the human suggests that endogenous prostaglandins play some part in limiting progesterone production. As in other species there is a dramatic increase in placental estrogen production before parturition. This estrogen is known to stimulate the synthesis of prostaglandin F2a by placenta and uterus and to thereby cause uterine contraction. Estrogen also promotes development of receptors for oxytocin and communication junctions between cells of the uterus. There is firm evidence that prostaglandins increase during labor, and that inhibition of prostaglandin activity delays labor in primates. Prostaglandins clearly have a role in labor and along with oxytocin, they cause the uterine contractions of delivery. Extensive clinical experience in the prostaglandins for induction of labor has revealed no ill effects on the fetus.

 

B. Stages of labor:

1. Preparation stage. Uterine contractions provide the major driving force for this stage of delivery (uterine 90%, abdominal contraction 10%). The preparatory stage is characterized by rhythmic peristaltic and segmental contraction of the uterus which force fetal fluids and membranes against a relaxed cervix causing it to dilate. Uterine contractions are stimulated by extrinsic autonomic neural reflex mechanisms and most importantly, by the local characteristic of automatic contractibility of this smooth muscle.
   
   
2. Expulsion of the fetus. This stage is characterized by violent contractions of the diaphragm and abdominal muscles as well as the myometrium. In ruminants, the fetus is expelled while attached to the umbilical cord and placenta. However, in swine and horses, the placental connections are often broken before delivery. Therefore live birth in these species is dependent on rapid delivery.
   
   
3. Expulsion of the placenta. Peristaltic contraction of the uterus causes inversion of the chorioallantoic placenta and its expulsion. In the pig, placental membranes are sometimes shed between delivered piglets and the remainder at the end of delivery. In ruminants, loosening of the chorionic villi from crypts of the caruncles does not always occur. These are held in place by a swelling or engorgement with blood. Failure of separation results in a retained placenta. These are most frequent in cows that deliver before full term.