1. No category

Pregnancy and Parturition
Fuller W. Bazer and Neal L. First
J ANIM SCI 1983, 57:425-460.
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PREGNANCY
AND PARTURITION
1
Fuller W. Bazer 2 and Neal L. First a
University of Florida, Gainesville 32611 and University of Wisconsin, Madison 53706
Summary
The establishment and maintenance of
pregnancy in domestic animals requires interactions between the developing conceptus and the
maternal system. These interactions are essential
for maintenance of the corpora lutea (CL),
conceptus development and placentation, regulation of uterine endometrial secretory activity,
placental transport of nutrients and gases,
regulation of uterine blood flow, achievement
of immunological "privilege" for the conceptus,
stimulation of development of the maternal
mammary glands and various other effects on
the physiology and endocrinology of the materhal and conceptus systems. Interactions between
the conceptus and maternal systems are also
responsible for initiating parturition. All of
these events are discussed, on a comparative
basis, with respect to current knowledge
obtained from studies of domestic farm animals
and, where appropriate, data from laboratory
species.
(Key Words: Pregnancy, Parturition, Conceptus,
Physiology, Endocrinology.)
Introduction
Ovulation is the culmination of numerous
endocrinological and physiological events and
usually occurs between 30 and 45 h, depending
on the species of farm animal, after onset of
estrus and the ovulatory surge of luteinizing
hormone (LH). If ova are not fertilized or if
embryonic development is abnormal, the
estrous cycle continues, seemingly uninterrupted, to allow subsequent opportunities for
mating and establishment of pregnancy. If
fertilization is achieved and embryonic development is normal, conceptus-maternal interactions
occur that result in: (1) maintenance of corpora
1The authors wish to thank Julie Busby for typing
and arranging the manuscript and Jan Lohse, Budi
Nara, Bill Thatcher, Dan Sharp and Mike Fields for
their review and helpful suggestions.
2Dept. of Anita. Sci., Univ. of Florida.
a Dept. of Meat and Anita. Sci., Univ. of Wisconsin.
425
lutea (CL) and production of progesterone, (2)
continued development of the uterine endometrium, (3) implantation and establishment
of conceptus membranes to allow nutrient
partitioning (homeorhetic effect, Bauman and
Currie, 1980) between the conceptus and
maternal system during pregnancy and (4)
parturition. Subsequent discussion will consider
current and future research related to conceptus
development, mechanisms whereby the eonceptus prevents regression of corpora lutea and
allows establishment of pregnancy, endometrial
function, conceptus development and parturition.
Establishment of Pregnancy
General. After fertilization, embryos spend a
short period near or at the ampullary-isthmic
junction of the oviduct before entering the
uterus at: 48 to 56 h after ovulation in pigs
(Dziuk, 1977); 72 to 96 h after onset of estrus
in cows (Robinson, 1977); 72 h in ewes
(Robertson, 1977) and about 144 h in the mare
(Nishikawa and Hafez, 1974). Unfertilized ova
are not transported into the uterus of the mare
(see Ginther, 1979). Speculation has centered
around production of a humoral agent by
equine embryos that affects oviductal motility.
Pig (Murray et al., 1971; Pope and Day,
1972) and sheep (Winterberger-Torres, 1956)
embryos fail to develop beyond the early
blastocyst stage if confined to the oviduct.
Failure of embryos to develop beyond the early
blastocyst stage may be due to either the
absence of essential factors for embryonic
development in the oviduct or the presence of
embryotoxic or embryostatic factors.
Brackett (1981) indicated that studies of
oviductal fluid composition led to development
of excellent culture media that allow in vitro
fertilization and development of mammalian
embryos. While embryos of several species can
be cultured through later stages of development
to become biastocysts, it is only in one strain of
mice that one-cell fertilized eggs will reliably
become blastocysts in vitro. This inability to
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BAZER AND FIRST
develop in culture may be due to inadequate
cuhure media and conditions or deficiencies in
eggs resulting from in vitro fertilization. It has
recently been shown that one-cell fertilized eggs
from a hybrid strain of mice, where development does not continue, can be induced to
develop by microinjection of cytoplasm from
two-cell eggs of an inbred strain that does undergo full development in culture (Harris et al.,
1982). It is likely that a true synthetic oviductal
fluid (SOF) will be developed to enhance
progress in studies of in vitro fertilization,
embryo culture and transfer and embryo
manipulation.
Pig. Mating occurs during estrus, which lasts
for 24 to 72 h, and, if the female becomes
pregnant, a gestation period of 114 to 115 d
follows. Hormonal events associated with the
first 14 d of the estrous cycle and pregnancy
are essentially identical. After that time,
however, functional CL must be maintained for
the duration of pregnancy. Loss of CL function
at any stage of gestation leads to abortion
within 24 to 36 h (Belt et al., 1971). Plasma
progesterone (P4) levels of 30 to 40 ng/ml on d
12 to 14 of pregnancy decrease to 10 to 25
ng/ml by d 25 of pregnancy (Guthrie et al.,
1974; Robertson and King, 1974; Knight et al.,
1977), and then remain fairly constant until
about d 100 of gestation. Then, P4 levels decline slowly to parturition (d 114 to 115),
when they decrease abruptly to less than 1
ng/ml.
There are several key events in conceptus
development during pregnancy. The pig embryo
moves from the oviduct into the uterus at
about the four-cell stage, i.e., 60 to 72 h after
onset of estrus. The embryo reaches the blastocyst stage by d 5, and the zona pellucida is shed
(hatching) between d 6 and 7. The exposed
blastocyst expands from .5 to 1 mm diameter
at hatching to 2 to 6 mm diameter on d 10 and
then elongates rapidly to the filamentous form
by d 16 (see Geisert et al., 1982b). Between the
9 to 10 mm spherical stage and the 100 to 200
mm long filamentous stage, pig blastocysts
elongate at a rate of 30 to 45 mm/h, apparently
by cellular remodelling and not cellular hypertrophy (Geisert et al., 1982b). However,
continued elongation and growth of the conceptus from 100 to 200 mm to 800 to 1,000
mm on d 14 to 16 does involve cellular hyperplasia (Geisert et al., 1982b). Coincidental with
initiation of blastocyst elongation there is
initiation of estrogen production that results in
a marked increase in total recoverable calcium,
proteins, PGF 2a, PGE2 and plasminogen
activator (Geisert et al., 1982a,c; Fazleabas et
al., 1982) in uterine secretions. However, the
factor(s) responsible for initiation of blastocyst
elongation are not known. Failure of blastocyst
elongation may lead to death of the embryo
early in gestation or compromise placental
development (see Perry and Rowlands, 1962;
Knight et al., 1977).
Rapid expansion and development of the
allantois occurs between d 18 and 30 of gestation. Fusion of the chorion and allantois takes
place between d 30 and 60 of pregnancy and by
d 60 to 70, placental development is complete.
The pig blastocyst is said to undergo a central
type of implantation; however, there is no
invasion of the maternal uterine endometrium
and the term "placentation" is more appropriate. Placentation in the pig involves interdigitation of microvilli on the surface of the trophoblast and epithelial cells lining the uterine
endometrium. Because placentation is superficial in the pig, as it is in the cow, ewe and
mare, the direct transfer of nutrients or histotroph from endometrial surface and glandular epithelium to the chorioallantois occurs
at least through the second trimester of gestation.
Plasminogen activator (PA) is involved in
invasive growth of cells (Ossowski et al., 1973),
e.g., those of trophoblast, and is produced by
pig blastocysts (Mullins et al., 1980). Pig
blastocysts transplanted to an eetopic site, e.g.,
uterine stroma (Samuel and Perry, 1972) or
kidney capsule (Samuel, 1971) are highly
invasive. Within the uterine lumen, however, pig
blast0cysts do not undergo invasive implantation. Fazleabas et al. (1982) purified and
characterized progesterone-induced protease
inhibitors secreted by the pig uterine endometrium which are believed to protect the uterus
from proteases, such as PA, released by trophoblast. It is possible that the PA may act within
the conceptus to promote cellular remodelling
during blastocyst elongation, but is prevented
from affecting the uterus due to uterine production of protease inhibitors that appear to
coat and be taken up by trophectoderm
(Fazleabas et al., 1982).
Pig blastocysts produce estrogens (see Flint
et al., 1979) and estrogen (E) synthesis begins
at the 10 mm spherical stage (Fischer, 1981;
Geisert et al., 1982a). Estrone sulfate (El 804)
in maternal plasma indicates that E secretion by
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PREGNANCY AND PARTURITION
the pig conceptus is triphasic with peaks on d
10 to 12 (Stoner et al., 1981), 16 to 30
(Robertson and King, 1974; Stoner et al.,
1981) and 60 to term (Robertson and King,
1974; Knight et al., 1977). Pig conceptuses also
secrete a number of proteins, beginning as early
as d 10.5 of pregnancy, which change both
qualitatively and quantitatively as gestation
progresses. Between d 10.5 and 12 of pregnancy
a group of low molecular weight proteins (M r
20 to 25 k; pI 5.6 to 6.2) are most prominent.
Then, between d 13 and 16 the qualitative
changes are marked and the major product is a
basic protein (M r 35 to 50 k; pI -8.0; Godkin
et al., 1982b). This basic protein may be one
initially proposed to have chorionic gonadotrophin-like activity by Wise et al. (1980);
however, more recent data failed to confirm the
preliminary evidence (P.T.K. Saunders, personal
communicaton). Chorioallantoic tissues from d
20 to 35 of gestation also secrete proteins that
differ from those produced earlier in pregnancy.
A high molecular weight glycoprotein (50%
carbohydrate; Mr>660,000) is also produced
by pig trophoblast between d 13 and 16.
Prostaglandins, PGF2a and PGE2, are produced
by pig blastocysts and probably make a substantial contribution to the uterine luminal
milieu of pregnancy (Zavy et al., 1980; Geisert
et al., 1982a; Lewis and Waterman, 1982).
Plasma estradiol (E2) and estrone (El),
both free and conjugated forms, change during
pregnancy in pigs; however, E1SO4 is the
predominant E during pregnancy. This hormone
increases from d 16 (60 pg/ml) to d 30 (3
ng/ml), decreases to d 46 (35 pg/ml), increases
slightly to d 60, and then increases steadily to
parturition (3 ng/ml; Robertson and King,
1974). Knight et al. (1977) reported the same
pattern for unconjugated E1 and E2 in uterine
vein and peripheral plasma and amniotic and
allantoic fluids.
The CL of pigs must be maintained and
secrete P4 if pregnancy is to be established and
maintained to term (du Mesnil du Buisson and
Dauzier, 1957). In the pig, therefore, "maternal
recognition of pregnancy" signals are those,
presumably from the conceptus, that prevent
the uterus from exerting a luteolytic effect on
the CL. A theory has been developed relative to
a mechanism whereby an agent (E) produced
by the embryo prevents PGF2a secretion from
the uterine endometrium into the uterine
venous drainage, where it could gain access to
the CL and cause luteolysis (Bazer and Thatcher,
427
1977).
The following assumptions were made: (1)
PGF2a is synthesized and secreted by epithelial
ceils of the uterine endometrium; (2) PGF2a
can move either into the uterine lumen (exocrine
direction) or toward the endometrial stroma
and associated vasculature (endocrine secretion);
(3) the direction of movement of PGF2a is
determined by local concentrations of E
established by the trophoblast (chorion) in the
pregnant pig and (4) PGF2a is the uterine
luteolysin in swine. Prostaglandin F 2a is
luteolytic in pigs and PGF2a is produced by the
uterine endometrium (see Bazer et al., 1982).
Studies of utero-ovarian vein plasma concentrations of PGF indicated that they are elevated
during the period of luteolysis in nonpregnant
gilts; however, no significant changes were
found in utero-ovarian vein plasma concentrations of PGF in pregnant gilts between d 12 and
25 of gestation (see Bazer et al., 1982). The
13,14 dihydro-15 keto PGF2~ (PGFM) metabolite of PGF2a has also been studied, but in
peripheral plasma of nonpregnant and pregnant
gilts by Shille et al. (1979) and Terqui et al.
(1979). Their results support those previously
noted for utero-ovarian vein plasma PGF in
that PGFM in peripheral plasma was elevated
during the period of luteolysis in nonpregnant
gilts, but was not elevated in pregnant gilts
between d 12 and 20 of gestation.
Kidder et al. (1955) reported that injection
of diethylstilbestrol (DES) on d 11 of the
estrous cycle led to prolonged CL maintenance.
Frank et al. (1977) found that utero-ovarian
vein basal PGF concentrations, PGF peak
concentrations, and number of PGF peaks were
lower between d 12 and 20 after onset of estrus
in gilts treated with estradiol valerate (E2V; 5
mg/d) on d 11 through 15 after onset of estrus
compared with control gilts. The reduced
utero-ovarian-vein PGF levels in E2V-treated
gilts were associated with an interestrus interval
of 146.5 d compared with 19.0 d for control
gilts.
The theory of maternal recognition of
pregnancy in pigs (see Bazer et al., 1982) is
based on evidence that E, produced by blastocysts from about d 12 to 30 of pregnancy or
injected as E2V, reduces the release of PGF2a,
in an endocrine direction. The precise mechanisms whereby E prevents secretion of PGF2a
in an endocrine direction, i.e., toward the uterine vasculature is not known. In pregnant
gilts, however, PGF2a secretion is in an exocrine
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428
BAZER AND FIRST
direction; it is sequestered within the uterine
lumen and prevented from entering the uterine
venous drainage and affecting the CL. That the
luteostatic effect of E is at the level of the
uterus in swine is supported by several lines of
evidence: (1) removal of the uterus from
otherwise intact gilts, without hormone therapy,
allows for prolonged CL maintenance; (2) CL
of pregnant gilts (Diehl and Day, 1974) and
E2V-treated gilts (Kraeling et al., 1975) are
susceptible to the luteolytic effect of PGF2t~;
(3) production of PGF2tx by endometrium
from pregnant gilts is similar to that for nonpregnant gilts (Zavy et al., 1980) and (4)
LaMotte (1977) concluded that PGF2tx is
secreted into the uterine lumen and transferred
from there to uterine venous circulation. Other
evidence suggests a direct effect of embryonic
factor(s) and steroids on luteal function in pigs
(Ball and Day, 1982; Chakraborty et al., 1972).
The fate and role of PGF20I sequestered
within the uterine lumen of pregnant gilts have
not been extensively studied. Walker et al.
(1977) reported that conceptus membranes,
especially the amnion, have a high capacity for
metabolizing PGF2~ to PGFM, which is believed
to be biologically inactive. On the other hand,
Kennedy (1980) suggests that PGF is required
for implantation.
Cow. Chang (1952) described blastocyst
elongation in cattle. Bovine blastocysts are
spherical on d 8 to 9 (.17 mm diameter),
oblong or tubular by d 12 to 13 (1.5 to 3.3 mm
by .9 to 1.7 mm) and then filamentous between
d 13 to 14 (1.5 x 10 mm), 14 to 15 (2 x 18
ram), 16 to 17 (1.8 x 50 mm) and 17 to 18
(1.5 x 160 mm). By d 17 to 18 the bovine
blastocyst occupies about two-thirds of the
gravid uterine horn. It then occupies the whole
gravid uterine horn by d 18 to 20 and extends
well into the contralateral uterine horn by d 24.
Shemesh et al. (1979) reported that bovine
blastocysts from d 13, 15 and 16 of pregnancy
produced P4, some testosterone and limited
quantities of E2-17~, Eley et al. (1979c) also
found conversion of androstenedione to E2-17/3
by d 15 to 17 bovine blastocysts. Extensive
metabolism of P4 and androstenedione to
5~-reduced metabolites by bovine blastocysts
has also been reported (see Thatcher and Bazer,
1983). Bartol et al. (1982) demonstrated
production of a high molecular weight glycoprotein (Mr>720 k) and major low molecular
weight proteins (M r - 24 to 40 k; pI 4 . 6 - 7 . 5 )
by d 16 to 24 bovine blastocysts.
Production of PGE 2 and PGF2a by d 16 and
19 bovine blastocysts in vitro is extensive
(Lewis et al., 1982). This is consistent with
higher levels of PGE 2 and PGF2tx in uterine
flushing from pregnant vs nonpregnant cattle
on d 16 and 19 after onset of estrus (see
Thatcher and Bazer, 1983).
In the pregnant cow, plasma P4 concentrations of about 10 ng/ml are maintained from
around d 14 to 16 of gestation to term. Estrone
sulfate, the major form of E in the pregnant
cow, is present in highest concentrations in
allantoic fluid. Eley et al. ( 1 9 7 9 a ) r e p o r t e d
allantoic fluid E 1SO4 concentrations to increase
from d 33 to 111 of pregnancy. Robertson
and King (1979) extended these observations
and indicated an increase in Et SO4 in allantoic fluid from d 41 to 132 followed by a sharp
decrease on d 170 and a second increase between
d 200 and 250, followed by a decrease to term
(< 100 ng/ml).
The presence of a developing embryo in the
bovine uterus allows for CL maintenance for
the duration of pregnancy. Northey and French
(1980) reported that pregnant cows from which
embryos were removed on d 17 and 19 had
interestrus intervals of 25.0 -+ 1.2 and 26.2 +- .6
d compared with those having embryos removed
on d 13 (20.2 + . 8 d) or not mated (20 to 21
d).
Amoroso (1952) indicated that before
attachment of the bovine conceptus, there is
increased edema, vascularity and glandular
hypertrophy of the uterine endometrium.
Fusion of the trophoblast and endometrium is
followed by a gradual erosion of the endometrial surface epithelium (Melton et al., 1951;
Amoroso, 1952). Elongation of bovine blastocysts is most rapid between d 16 and 20 of
gestation. The trophoblast cells are either
columnar or giant cells. The columnar cells
accumulate lipid material between d 16 and 25
of gestation (Greenstein et al., 1958), which
coincides with increasing amounts of PGF in
the uterine lumen (Bartol et al., 1982). Lewis et
al. (1982) demonstrated synthesis of PGF20I
from arachidonic acid by d 16 and 19 bovine
blastocysts.
Bovine blastocysts recovered on d 15, 16
and 17 of pregnancy can convert androstenedio n e to E2 in vitro (Eley et al., 1979a). The
physiological importance of this observation is
not known. As indicated earlier, E have a
luteolytic action in the cow whether administered in the unconjugated (Greenstein et al.,
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PREGNANCYAND PARTURITION
1958; Wiltbank et al., 1961) or conjugated
(E1SO4) form (Eley et al., 1979b). Extensive
metabolism of androstenedione to 5~reduced
compounds by the conceptus, and the role of
these compounds in regulating the bovine
endometrium warrants further study (Eley et
al., 1979c).
Thatcher et al. (1979) reported that E2-17/3
given iv on d 13 of the estrous cycle caused an
acute increase in plasma PGFM levels at 6 h
postinjection, and complete luteolysis occurred
earlier in treated vs control heifers. Using this
approach, the antiluteolytic effect of the
bovine conceptus was tested (see Thatcher and
Bazer, 1983) using crossbred beef. heifers.
Pregnant animals received E2-17/3 on either d
18 or 20 and nonpregnant cows were treated on
d 18. The PGFM response to E2-17/3 challenge
was lower in pregnant compared with nonpregnant cows. Results suggested that the conceptus
alters the temporal pattern of secretion of
PGF2t~ in response to E2-17~ and are consistent
with in vitro observations that endometrium
from d 17 pregnant cows synthesizes less
PGF2t~ than that from nonpregnant cows.
Considerable research is needed to establish
maternal recognition of pregnancy mechanisms
in the cow.
Ewe. Sheep blastocysts are basically spherical
between d 4 (.14 mm diameter) and 10 (.4 mm
diameter) and then elongate to the filamentous
form b y d 12 (1.0 x 33mm) a n d 1 4 ( 1 . 0 x 68
mm) according to Bindon (1971). Chang and
Rowson (1965) reported that d 15 sheep
blastocysts were 150 to 190 mm long x 1 mm
diameter and located in one uterine horn, while
the trophoblast extended through the uterine
body and into the contralateral uterine horn by
d 16 to 17.
Data concerning steroid production by sheep
blastocysts is circumstantial. Steroid production
by ovine blastocysts between d 12 and 15 of
pregnancy has not been established. Ellinwood
(1978) measured E2 -17B and E1 in utero-ovarian
vein plasma on d 13, 15 and 17 of the estrous
cycle and pregnancy. These E values were not
significantly different, but El concentrations
were consistently higher for pregnant ewes. In
contrast, Reynolds et al. (1982) reported no El
or E2 differences in uterine arterial and venous
blood between pregnant and nonpregnant ewes
on d 11, 13 and 15 after onset of estrus.
Sheep blastocysts secrete proteins of which
one major protein is a high molecular weight
glycoprotein (Mr>660,O00) and the other
429
major protein, ovine trophoblast Protein 1
(oTP1), is of low molecular weight (Mr - 17k;
pI - 5.5) and secreted between d 12 and 21 of
pregnancy (Godkin et al., 1982a). Martal et al.
(1979) found a "protein" termed "trophoblastin" in homogenates of sheep blastocysts,
which may be comparable to oTPl and suggested
that this protein, when infused into the uterine
lumen, caused prolonged CL maintenance.
Godkin et al. (1982a) reported that oTPl is
taken-up by uterine epithelial cells. But, there is
no evidence that oTPl directly stimulates
progesterone production by luteal cell suspensions or luteal slices, although it does appear to
bind to luteal cell membranes. There is no
evidence that oTPl has prolactin-like activity.
These results are consistent with those of
Ellinwood (1978), which indicated no LH or
prolactin-like activity in homogenates of sheep
conceptuses collected between d 14 and 15 of
pregnancy.
Available data on the ovine uterus-CLhypothalamic-pituitary axis is extensive and has
been reviewed recently by Horton and Poyser
(1976). As with other farm animals, the ovine
uterine endometrium appears to control CL life
span in nonpregnant females (Wiltbank and
Casida, 1956).
McCracken (1971) obtained evidence that
PGF2a was released into the uterine vein of the
ewe and elevated levels were temporally associated with CL regression. Goding (1974) reviewed
evidence for and against the proposition that
PGF2a is the ovine uterine luteolysin and
concluded that PGF2 'v does serve that role.
The question of how the embryo prevents
luteal regression is applicable to the ewe. A
functional CL is required for at least 60 d of
the 145 to 150 d gestation period. After that
time, placental Pa production is adequate to
allow maintenance of pregnancy (Casida and
Warwick, 1945).
Moor and Rowson (1966a,b) removed
embryos from mated ewes between d 5 and 15
of pregnancy. No effect of the embryo on the
interestrus interval was detected until d 13 of
gestation. About one-third of the ewes from
which embryos were removed between d 13
and 15 had interestrus intervals greater than 25
d. The pregnancy rate for nonmated ewes to
which embryos were transferred on either d 12,
13 or 14 was 60 to 67, 22 and 0%, respectively.
These data indicated that the conceptus influences CL maintenance between days 12 and 15
of pregnancy. Continuous intrauterine infusion
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BAZER AND FIRST
of homogenates of 14- to 15-d ovine embryos
also extends CL life span in sheep (Moor and
Rowson, 1967; Ellinwood, 1978); however,
infusion of the homogenate into the uterine
vein was not effective (Ellinwood, 1978).
In comparing utero-ovarian vein plasma for
differences in PGF20~ concentrations between
pregnant and nonpregnant ewes, results have
been conflicting (see Bazer et al., 1981b). This
may be due to PGF2a production by the
conceptus that masks changes in endometrial
PGF20I production during pregnancy.
There are data to indicate that PGF20t in
utero-ovarian vein plasma and PGFM in peripheral plasma are markedly lower in pregnant vs
nonpregnant ewes (see McCracken et al., 1981).
Recently, Moore et al. (1982) reported that
pulsatile release of oxytocin-neurophysin and
PGFM occurs in nonpregnant ewes during the
period of luteolysis, but is suppressed during
the comparable period of pregnancy. The
possibility that oxytocin may be synthesized
and secreted by luteal tissue and neurohypophysis (Sheldrick and Flint, 1981; Wathes and
Swann, 1982) adds a new dimension to control
of luteolysis in the ewe. McCracken et al.
(1981) proposed that oxytocin initiates events
leading to increased PGF2ol production by
uterine endometrium and that the role of E is
to induce oxytocin receptors on endometrial
cells so that they can respond to oxytocin.
They indicated that endometrial oxytocin
receptor concentrations are lower in pregnant
than nonpregnant ewes. Moore et al. (1982)
suggested that a product of the conceptus may
be acting to suppress the pulsatile release of
oxytocin. Because oxytocin and neurophysin
may be of posterior pituitary and(or) CL origin,
further research is needed to indicate why
oxytocin-neurophysin are suppressed in pregnancy.
Data are not available to resolve the following
questions relative to the mechanism of maternal
recognition of pregnancy in the ewe. First, are
PGE2 and(or) PGE1 luteotrophic as suggested
by numerous investigators because PGE2 is produced by sheep blastocysts (See Bazer et al.,
1981b). Second, is trophoblastin and(or) oTP1
the blastocyst luteotropic signal that is mediated via the uterine endometrium to prevent
luteolysis. Third, is there a transient period of
estrogen production, not yet detected, by ovine
conceptuses that may be important in establishment and maintenance of pregnancy. Evidence
for a factor emanating from the gravid uterus
that affects the CL directly was reported by
Mapletoft et al. (1975). Results of Pratt et al.
(1977) indicated that CL of pregnant ewes were
less susceptible to PGF2a than those of nonpregnant ewes.
During the course of pregnancy in ewes,
plasma P4 concentrations are similar to those
found during the luteal phase of the estrous
cycle up to about d 60 of gestation then
increase between d 60 and 140 due to placental
P4 production. After d 140, plasma P4 levels
decline to time of parturition (145 to 150 d).
Estrone concentrations in peripheral plasma are
low from d 20 to 110 of gestation and then
increase three- to fourfold by term (see Bazer et
al., 1981b). Estradiol values follow the s a m e
pattern, but are about 50% lower than those for
El.
Estrone sulfate is the major form of E in the
pregnant ewe and the highest concentrations
are present in allantoic fluid. Estrone sulfate
concentrations in allantoic fluid increase from d
20 to a first peak on d 46, then decrease to d
55. A second EISOa peak occurs between d
100 and 120, which is followed by a decline to
d 140.
Mare. Equine embryos do not undergo a
rapid elongation process. Rather, they remain
spherical until around d 50, possibly due to the
prominent yolk sac and fluids present by d 12
of pregnancy that do not regress until after d
25 or 30 of gestation when the developing allantoic sac and fluids began to fill
the extra-embryonic coelom (see Ginther,
1979).
Zavy et al. (1979) incubated equine conceptus membranes in vitro for 120 min and reported
that El and E2 production increased from d 8
to 20. The possible effect of these E on the
uterine luteolytic agent is worthy of further
study.
Maternal recognition of pregnancy signals
are poorly understood in the mare. It appears
that the primary CL of the mare must be
"protected" from the luteolytic effect of the
uterine endometrium if pregnancy is to be
established. Kooistra and Ginther (1976)
demonstrated that removal of the equine
conceptus on d 24 of pregnancy results in an
extended interestrus interval. Ovulation did not
occur for 34.8 + 5.8 d after conceptus removal. This period of prolonged CL maintenance or pseudopregnancy of 50 to 60 d was
shorter than CL life span for hysterectomized
(70 to 140 d) or pregnant (140 to 210 d)
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PREGNANCY AND PARTURITION
mares. It is possible that the equine conceptus
protects the CL from a uterine luteolysin.
Diethylstilbestrol (DES), was administered
daily to three mares by Nishikawa ( 1 9 5 9 ) f o r
14, 15 or 20 d beginning either on d 7, 8 or 9
postovulation. Ovaries were removed either on
d 24, 32 or 47 and contained CL believed to
have been present at the time of initiation of
treatment. Similarly, mares given 5.0 mg DES,
but not .5 mg E2-1713 or vehicle alone, had
prolonged interovulatory intervals (Berg and
Ginther, 1978).
Ginther and First (1971), Stabenfeldt et al.
(1972) and Squires et al. (1974) have provided
evidence to indicate that the primary CL is
maintained for up to 140 d in bilaterally
hysterectomized mares. In pregnant mares, the
primary CL and accessory CL, i.e., CL formed
between d 40 and 50, regress between d 140
and 210 of gestation, and primary CL weight at
d 140 is greater for pregnant than for hysterectomized mares (Squires et al., 1974). The
gestation period in mares is about 335 d.
Progesterone or pregnanes of placental origin
are adequate for pregnancy maintenance
after CL regression. The hormone maintaining
late pregnancy has not been established.
The presumed equine luteolysin PGF2a
causes luteolysis when injected into mares (see
Allen and Rowson, 1973) in doses as small as
1.25 mg. This dose of PGF2t~ given on d 32 of
pregnancy or pseudopregnancy is luteolytic
(Kooistra and Ginther, 1976).
Three independent studies indicate that
endometrial production, uterine fluid content
and uterine vein plasma concentrations of PGF
are elevated when degeneration of the equine
CL is occurring (Van Niekerk et al., 1975;
Douglas and Ginther, 1976; Zavy et al., 1978)
and plasma P4 concentrations are decreasing
during the late luteal phase of the estrous
cycle.
Inferential evidence (Vernon, 1979) suggests
that the embryonic signal for CL maintenance
probably acts at the level of the uterus. First,
endometrial production of PGF by the pregnant
uterus in vitro increases steadily between d 8
and 20 of gestation and, therefore, PGF must
be prevented from reaching the CL. Second,
luteal-cell membrane PGF2a-binding capacity
between d 14 and 18 of pregnancy is equal to
or greater than that on d 12 of the estrous
cycle, which also suggests that the uterine
luteolysin must be prevented from reaching the
CL of pregnancy. Both PGF in uterine venous
431
blood (Douglas and Ginther, 1976) and PGFM
in peripheral blood (Kindahl et al., 1982) are
lower in pregnant than in nonpregnant
mares. Contrary to data of Vernon (1979),
Berglund et al. (1982) reported lower recoverable PGF in uterine flushings of pregnant mares
and indicated that the conceptus may reduce
PGF production by the endometrium.
Pregnant mare serumgonadotropin (PMSG)
is produced by chorionic cells of the endometrial cups. It is detectable in maternal plasma by
d 37, reaches peak values around d 60, and then
declines to undetectable levels by d 140 of
pregnancy. Kooistra and Ginther (1976) suggest
that the longer period of CL maintenance in
pregnant (140 to 210 d) compared with hysterectomized (70 to 104 d) and pseudopregnant
mares (about 50 d) may be due to effects of
PMSG. However, data are not available to
suggest that PMSG is present between d 12 and
14 of pregnancy when CL maintenance must be
established.
Potential Role of Hormones of Conceptus Origin
Prostaglandins. Prostaglandins may affect
changes in blood flow through their effects on
arterioles and the capillary bed supplying the
uterus and ovary. Prostaglandin E1 and PGE2
are vasodilatory while PGF2~ causes vasoconstriction (see Ford, 1982). There is evidence for
interactions between PG, E and norepinephrine.
As reviewed by Ford (1982), E stimulates
production of PG and PGF2a may cause release
of norepinephrine, a vasoconstrictor, which
would have a marked effect when P4 is high
and neuronal stores of norepinephrine are high,
but little effect when E levels are high and
neuronal norepinephrine stores are low. The
interplay between sex steroid, PG and catecholamines may allow regulation of uterine blood
flow to the gravid uterus to meet conceptus
needs as well as affect blood flow to ovarian
structures during the esrous cycle and pregnancy. Uterine blood flow is known to increase
to the gravid uterus of cows, ewes and pigs beginning early in gestation and during periods
when E production by the conceptus membranes is increasing. Ford (1982)suggested
that E2 may decrease t~-adrenergic receptor
activity in the arterial vasculature to increase
uterine blood flow after it is converted to a
catechol estrogen that could interact with
a-adrenergic rece~otors. Presumably, there is a
progressive reduction in function of periarterial
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432
BAZER AND FIRST
adrenergic nerves that would eventually lead to
maximum arterial vasodilation and uterine
blood flow during late pregnancy.
Prostaglandins may also affect changes in
permeability of the endometrial vascular bed
(Kennedy, 1980) and fluid and electrolyte
transport across epithelia (Biggers et al., 1978)
that would enhance nutrient availability to the
developing conceptus. The conceptus may also
be affected by PG since they promote cellular
proliferation as mediated by cAMP (MacManus and Whitfield, 1974) and they stimulate
steroid biosynthesis (Batta, 1975).
Steroids. Estrogen and P4 have numerous
effects on the hypothalamic pituitary axis and
the pregnant uterus (see Clark et al., 1977). The
patterns of change in these sex steroids have
been described for each species and will be
discussed further relative to potential involvement in specific aspects of conceptus development.
The bovine conceptus produces primarily
53-reduced metabolites of P4 and androgens
while the uterine endometrium produces
primarily the 5t~-reduced metabolites of those
steroids. These metabotites of P4 and androgens
cannot be aromatized to E. Rather, there is
evidence that 53-reduced metabolites have their
own unique roles in stimulating erythropoiesis
and hemoglobin synthesis in tissue forming
blood and in suppressing uterine myometrial
contractility (see Thatcher and Bazer, 1983).
Placental Lactogen. Placental lactogen has
been identified in the ewe and cow, but not the
mare and sow. Ovine placental lactogen (oPL)
and bovine placental lactogen (bPL) are produced by chorion (Martal and Djiane, 1977;
Carnegie et al., 1982). This hormone has
prolactin and growth-hormone activity (Martal,
1978; Reddy and Watkins, 1978). Martal and
Djiane (1977) and Martal and Lacroix (1978)
suggested that oPL may be a component of the
"luteotropic" complex in pregnant ewes, but
this has not been demonstrated.
The oPL concentrations in maternal plasma
are detectable by d 48 and increase about
400-fold by d 140 and then decrease to term.
Although undetectable in plasma before d 45 to
50 with current assay techniques, oPL has been
extracted from trophoblast tissue of d 16 and
17 blastocysts (Martal and Djiane, 1977) and
detected by d 14 in trophoblast tissue by
immunofluorescent microscopy (Carnegie et al.,
1982).
Bovine placental lactogen (bPL) is present in
peripheral serum in concentrations less than 50
ng/ml before d 160 and then increases to
approximately 1,000 ng/ml between d 200 and
285 of gestation (Bolander et al., 1976).
Concentrations of bPL in serum were lower in
beef (X - 6 5 0 ng/ml) than dairy (X -1,103
ng/ml) cows during the last trimester of pregnancy. Other studies using bioassay (Buttle and
Forsyth, 1976) and radioreceptor assay (Kelley
et al., 1976) indicate very low levels of bPL in
the maternal circulation.
Placental lactogens have been implicated in
stimulation of mammary gland development,
steroidogenesis by the ovary and placenta and
fetal growth (see Talamantes et al., 1980).
Because of the potential economic importance
of bPL relative to milk production and oPL and
bPL on conceptus development, considerable
research is needed to define the role(s) of this
hormone.
Pregnant Mares Serum Gonadotropin. Pregnant mares serum gonadotropin (PMSG) is
produced between d 40 and 160 of gestation by
chorionic girdle cells of the endometrial cups.
Ginther (1979) reviewed evidence for the likely
stimulatory effects of PMSG on formation of
accessory CL and production of P4 by primary
and secondary CL, which may be essential
to maintenance of pregnancy. He also noted
that considerable PMSG is found in exocrine
secretion from endometrial cups. A possible
immunosuppressive role for PMSG has also
been proposed (Allen, 1979).
Tbyrotropic Hormone Acitivity. Avivi et al.
(1982) reported extraction and purification of
a thyroid stimulating hormone-like protein
(thyrotropic protein) from bovine placenta
collected between d 40 and 120 of gestation.
This thyrotropic protein-bound TSH had membrane receptors and induced specific TSH biological effects, but it is structurally and immunologically distinct from TSH and pituitary and
placental gonadotropins. This observation and
those demonstrating synthesis and secretion of
numerous proteins by ovine, bovine and porcine
conceptuses suggest that we know very little
about potential regulatory proteins of conceptus
origin in farm animals.
Maintenance of Pregnancy
Pig. The CL appear to be autonomous until
about d 14 after onset of estrus and then
require only basal LH support until d 40 to 50.
After that time, prolactin has been suggested to
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PREGNANCY AND PARTURITION
assume an essential role in CL maintenance (see
du Mesnil du Buisson and Denamur, 1968;
Heap et al., 1973). However, recent data
suggest that prolactin may not be required for
CL maintenance during the last one-half of
pregnancy. In an experiment with three sows
(R. R. Kraeling, unpublished data), bromocryptine (CB154) was administered at doses up to
480 mg/d between d 75 and 80 of pregnancy,
but none of the sows aborted and all had CL
that appeared normal. In a related study
Whitacre and Threlfall (1981) treated five sows
with CB 154 for 10 d before farrowing and
compared them with controls with respect to
concentrations of prolactin and progesterone
in peripheral plasma. Treated sows had lower
mean plasma prolactin concentrations, no
prolactin surge prepartum and they did not
lactate. Progesterone concentrations were not
different between control and treated sows.
From these studies, it does not appear that
reduced prolactin concentrations cause premature regression of CL in sows after d 70 of
gestation.
Sbeep. In sheep, LH and(or) prolactin are
required for maintenance of pregnancy until
about d 60 when the conceptus appears to
assume the capability of maintaining the CL.
This assumption is based on the fact that
neither hypophysectomy nor ovariectomy lead
to abortion in sheep if performed after d 50 of
gestation (see Heap et al., 1973). Ovine placental lactogen (oPL) is produced from about d 14
of pregnancy, but its effect on CL maintenance
is not known and trophoblastin is not produced
beyond d 21 of gestation (see Bazer et al.,
1981b). Therefore, the nature of the endocrine
signals allowing pregnancy maintenance in
hypophysectomized-ovariectomized ewes remains to be elucidated.
Cow. In the cow, LH and, to a lesser extent,
prolactin are considered to provide the stimulus
for CL maintenance during pregnancy (see
Heap et al., 1973). However, Anderson et al.
(1979) indicated that luteal support and
pregnancy were maintained to term in cows
hypophyseal stalk-transectioned at midgestation. The effect of bovine placental lactogen on
CL function is not known.
Mare. The primary CL is necessary for the
establishment of pregnancy and additional CL
are formed around d 40 to 50 of gestation. All
of these CL regress by d 150 to 180 and placental P4 or pregnanes acting locally on the pregnant uterus appear to be adequate for pregnancy
433
maintenance until term (about d 335 of gestation; see Heap et al., 1973; Ginther, 1979).
There is a strong temporal relationship between
CL function and PMSG production between d
40 and 150 to 180 of gestation (Ginther,
1979).
Uterine Secretions During Pregnancy
General. According to Amoroso (1952),
Grosser (1924) introduced the term histotroph
to refer to secretions (histopoietic material) and
detritus (histolytic material) present within the
uterine lumen for nourishment of developing
conceptuses. In domestic animals, implantation
is noninvasive and uterine endometrial gland
secretion of histotroph appears to be required
for a major portion of pregnancy. Uterine
secretions comprise a complex nutrient-rich
"culture medium" for the developing conceptus
(Roberts and Bazer, 1980).
Pig. The most extensively studied protein in
uterine secretions of domestic animals is
uteroferrin. Uteroferrin is a P4-induced glycoprotein secreted by pig uterine gland epithelial
cells. The protein has a molecular weight of
about 35,000, a pI of 9.7, acid phosphatase
enzymatic activity and contains one molecule
of iron. The primary role of this protein appears
to be transport of iron from uterine glands to
the conceptus (see reviews by Roberts and
Bazer, 1980; Bazer et al., 1981c). Uteroferrin
will be discussed with respect to how it transports a nutrient to the conceptus because it
provides a model for study of other components
of uterine secretion in pigs and other species.
Uteroferrin is transported from uterine
glands across the placental areolae by nonreceptor mediated (fluid phase) pinocytosis and
released into the placental venous system
(Renegar et al., 1982). Upon entering the
umbilical vein it is transported to the fetal liver
where ceils of the reticuloendothelial system
bind and endocytose uteroferrin by a receptor
mediated process involving coated pits, coated
vesicles and receptosomes (Renegar et al.,
1982). Binding of uteroferrin by endothelial
and(or) Kupfer cells appears to depend upon
the mannose residues in the carbohydrate
portion of the molecule (P.T.K. Saunders,
unpublished data). Presumably, uteroferrin is
directed to lysosomes where the iron is released
to ferritin and transferred to erythroblasts by a
process called ropheocytosis (Policard and
Bessis, 1958) for synthesis of hemoglobin.
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434
BAZER AND FIRST
The fetal liver of piglets is the primary site of
erythropoiesis throughout gestation.
Uteroferrin not bound by liver is cleared
through the kidney, into the fetal bladder and
then into the allantoic sac via the urachus
(Renegar et al., 1982). Allantoic f u i d is known
to be a rich source of uteroferrin (see Bazer et
al., 1981c). Buhi et al. (1982) reported that
iron bound to uteroferrin was transferred to
transferrin in allantoic fluid. Transferrin is
then taken up by the allantoic epithelium and
enters the fetal circulation (Ducsay et al., 1982)
where it can provide iron for hematopoiesis and
meet other metabolic needs for iron.
Other transport proteins, e.g., (retinol and
retinoic acid binding proteins), hydrolytic
enzymes (lysozyme, cathepsin activities B, D
and E, leucine aminopeptidase and proteases)
and regulatory proteins (protease inhibitors)
have been found in uterine secretions of ovariectomized pigs treated with progesterone.
Glucose phosphate isomerase and plasminogen
activator are the only proteins studied to date
in pig uterine secretions that appear to be
regulated by E (see Bazer et al., 1981c).
Murray et al. (1980) and Moffatt et al.
(1980) identified riboflavin as the compound
causing pig uterine flushings collected between
d 6 and 8 of either the estrous cycle or pregnancy to have a distinct yellow color. The high
riboflavin content of uterine flushings occurs
during the period of initial blastocyst expansion;
however, the significance of this association is not understood because riboflavin may
affect many aspects of cellular function. Active
immunization of rats against a chicken riboflavin
carrier protein results in reversibly suppressed
embryonic survival during the preimplantation
period (Murty and Adiga, 1982). Riboflavin
transport protein, which may be essential for
transplacental ribofavin transport, has also
been described for the cow (Merrill et al.,
1979).
Glucose is found in uterine flushings of the
pregnant pig, mare, cow and ewe and fructose is
detectable after d 12 of pregnancy in gilts and
mares (see Zavy et al., 1982). Both of these
sugars increase in the pregnant uterus with
advancing gestation. Glucose phosphate isomerase enzymatic activity is responsible for the
interconversion of glucose-6-PO4 and fructose6-PO4 and appears to be modulated in endoinertial tissue by estrogen (Zavy et al., 1982).
Fructose is produced by the trophoblast and
chorion from glucose via sorbitol. Fructose
may be important because it can be sequestered
in the reproductive tract and it may be preferentially metabolized through the phosphogluconate pathway to generate NADPH H + and
ribose sugars essential for biosynthesis in
rapidly proliferating tissues (see Zavy et al.,
1982).
Ascorbic acid is also present in uterine
secretions of pregnant gilts and mares and
increases quantitatively as pregnancy advances
(Zavy et al., 1982). Ascorbic acid is known to
affect collagen synthesis, catecholamine and
indolamine biosynthesis, iron absorption and
metabolism and it has a sparing effect on
B-complex vitamins and vitamins A and E due
to its antioxidant role.
Ewe. Sheep uterine milk collected from the
nongravid uterine horn of unilaterally pregnant
ewes on d 140 of gestation contains two basic
polypeptides of 57,000 and 59,000 molecular
weight. These proteins are P4-induced (see
Bazer et al., 1981c) and may be immunosuppressive (Segerson et al., 1982). These proteins
are not detectable in uterine flushings collected between d 0 and 16 of the estrous cycle.
Roberts et al. (1976) reported activities of
several glycosidases in sheep uterine flushings.
These glycosidases were present in small
amounts and are not likely to be uterine
specific.
Cow. Proteins secreted by bovine endometrial epithelium have not been well defined (see
Bazer et al., 1981c). Dixon and Gibbons (1979)
obtained uterine secretions from ovariectomized
cows that received 300 mg progesterone daily
for 2 to 3 mo. Total recoverable protein varied
from 494 to 660 mg and appeared to contain at
least nine "nonserum" proteins. Seven of these
proteins were very minor, but two were major
proteins determined to be an acid phosphatase
and lactoferrin. Bovine acid phosphatase has a
pI of 9.7, which is identical to that of uteroferrin
from pigs. Lactoferrin may serve as a bacteriostatic agent in bovine uterine secretions. Roberts
and Parker (1974a,b) detected a-L-fucosidase,
/3-D-galactosidase,
a-N-acetylgalactosamidase
and ~N-acetylglucosaminadase in increasing
amounts between d 0 to 3 and 19 to 21 of
pregnancy in cattle uterine flushings. They
suggested that the glycosidases may affect
blastocyst development or the process of
adhesion between trophoblast and endometrial
surface epithelium.
Horse. Equine uterine secretions contain a
number of proteins similar to those found in
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PREGNANCY AND PARTURITION
the pig, including uteroferrin (see Bazer et al.,
1981c). This is of interest because both the pig
and mare conceptus have diffuse, epitheliochorial placentae.
Immunobiology of Pregnancy
General. Beer and Billingham (1979) indi-
cated that the dam and conceptus exist in a
state of immunological coexistence or tolerance
and suggested mechanisms whereby the maternal immune system may be influenced to
allow immunological tolerance of the conceptus.
One mechanism involves nonspecific immunosuppressive or immunoneutralizing properties
of uterine and(or) trophoblast secretions. For
example, sheep, pig and cow blastocysts secrete
a large glycoprotein (Mr>660,000), which may
coat the conceptus and prevent maternal
lymphocytes from recognizing conceptus antigens (Masters et al., 1983). It has also been
argued that human chorionic gonadotropin
(hCG) and PMSG may play an immunosuppressire role (see Allen, 1979).
Beer and Billingham (1979) suggested that:
(1) excess antigen shedding by trophoblast may
lead to blocking of T and B cell immune
responses; (2) antigen-antibody complex production during pregnancy may block T and B
cell immune responses and (3) suppressor T
lymphocyte production may be enhanced
during pregnancy. Recent data suggest that
uterine secretions of the cow (Roberts, 1977),
pig (Murray et al., 1978) and sheep (Segerson,
1981) contain an irnmunosuppressive factor(s).
In addition, porcine allantoic and amniotic
fluid protein(s) is immunosuppressive. These
conclusions are based on evidence that the
immunosuppressive protein(s) inhibit phytohemagglutinin (PHA) induced mitogenic activity
of maternal lymphocytes and increased mitogenie activity resulting from mixed lymphocyte
cultures (Segerson, 1981). Segerson's (1981)
data suggest that the conceptus enhances
immunosuppressive activity of sheep uterine
flushings. The ovine pregnancy associated
antigens described by Staples et al. (1978) and
Staples (1980) are possible candidates for
immunosuppressive activity.
In addition to immunosuppressive proteins
of uterine and(or) conceptus origin, P4 may
enhance immunological tolerance of the mother
to the fetoplacental unit. Staples et al. (1982)
described a complete utero-ovarian lymphatic
network in sheep and reported P4 concentra-
435
tions in lymph to be 10- to lO00-fold higher
than in jugular vein plasma between d 15
and 45 of gestation. These findings indicate
that leucocytes in the lymphatic network of the
reproductive organs and the lumbo-aortic and
medial iliac nodes would be exposed to a high
P4 concentration that may have an immunoprotective function relative to the conceptus
allograft.
Godwin and Webb (1980) reviewed evidence
for regulation of the immune system by prostaglandins. Prostaglandins El, E2 and A, and F I ~
have been shown to inhibit[3H]thymidine
incorporation into PHA stimulated human
lymphocytes. Prostaglandins El and E2 may
act as local feedback inhibitors of T-cell activation and prostaglandins of the E and F series
appear to modulate hormonal immune responses
such as 3-cell activation and antibody production
(Godwin and Webb, 1980). Because the uterine
endometrium and conceptus tissues produce
prostaglandins of the F and E series, they
may also play a role as immunoprotective
agents.
The Fetal-Placental Unit
General. The embryological development of
the fetal membranes of domestic animals has
recently been reviewed by Perry (1981).
Specialized structures on the epitheliochorial
placentae include coytledons, areolae, chorioallantoic cysts and petrifactions (Amoroso,
1952). The placental cotyledons of the sheep
and cow are assumed to be sites of transport of
gases and small molecules from dam to conceptus, while the areolae are sites of absorption of
components of glandular secretions or histotroph. The significance of chorioallantoic cysts
and petrifactions, areas of deposition of calcium salts, has not been elucidated.
Fetal fluids, i.e., amniotic and allantoic
fluids, have been of interest for many years. It
was originally thought that allantoic fluid was
derived from the mesonephros and served as a
reservoir for fetal waste. Neither of these
notions are supported by available facts. First,
the mesonephros does not produce water, but
only redistributes that available to it. Second,
the allantoic fluid of pigs contains a substantial
pool of nutrients, including all proteins found
in uterine secretions, glucose, fructose, water,
minerals, electrolytes and vitamins (see Bazer et
al., 1981a).
Transport of nutrients across the placenta
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436
BAZER AND FIRST
may be by fluid-phase pinocytosis of macromolecules, e.g., proteins, as occurs within the
areolae (Friess et al., 1981). Active transport
processes, for water and glucose, may be
modulated by El, P4 and(or) lactogenic hormones (see Bazer et al., 1981a). Increasing
allantoic fluid volume between d 20 and 30 and
50 and 60 of pregnancy in pigs appears essential
for expansion of the chorioallantoic membranes
and support of their apposition to the uterine
wall. Amniotic fluid is also important in that it
allows the embryo/fetus to develop symmetrically in a liquid environment independent of
the forces of gravity (see Bazer et al., 1981a).
The general roles of fetal fluids, as described for
the pig, appear to apply to all domestic animals.
Research is needed to: (1) define the hormonal
regulation of placental transport mechanisms,
(2) determine environmental effects, e.g., those
causing hyperprolactenemia, on fetal fluid
volume and placental surface area, (3) define
rates of turnover of nutrients in fetal fluids and
(4) determine when placental-fetal fluid nutrient
reserves are deposited and extensively utilized
by the fetus.
Embryonic-Fetal Mortality
General. The classic studies of Hammond
(1914, 1921) indicated that the number of
potential offspring, as indicated by the number
of corpora Iutea, was much greater than that
realized at term. Since that time, effects of
environment, nutrition, genetics, age, disease
and endocrine factors have been studied in
relation to embryonic death (see Boyd, 1965
and Wrathall, 1971). There has been no single
factor identified that can be manipulated to
consistently alter embryonic survival. This
should not be surprising because successful
establishment and maintenance of pregnancy
represents the results of many endocrinological,
morphological, physiological and immunological
events.
Within the last 10 yr it has become evident
that the developing conceptus may, in part,
control its own destiny through production of
chemical agents. Perry and Rowlands (1962)
reported that most embryonic mortality in pigs
occurs before d 12 of gestation. We now know
that the pig blastocysts begin to produce E on d
11 of pregnancy and that these E stimulate a
synchronized secretion of histotroph from the
uterine gland epithelium by a mechanism that
may be calcium-mediated (Geisert et al.,
1982a,c). In addition, there is an increase in
uterine blood flow in response to either the E2
or PGE2 produced by the conceptus (Ford and
Christenson, 1979). In the past, emphasis has
been placed on the possibility that a "hostile"
uterine environment leads to pregnancy wastage.
However, it now seems likely that blastocysts
of domestic animals must develop and elongate
at a rate adequate to ensure that they produce
their signals, e.g., E on a critical day to ensure
CL maintenance (Bazer and Thatcher, 1977)
and nutrient availability (Ford and Christenson,
1979; Geisert et al., 1982a,b). This concept
suggests that pregnancy wastage is a function of
conceptus deficiencies rather than maternal
deficiencies in untreated females mated in a
conventional manner. The concept is consistent
with the fact that synchrony must exist between
conceptus and endometrium to ensure that
embryonic signalling occurs after the uterine
endometrium has acquired the ability to
produce histotroph, but before it begins releasing luteolytic material into the uterine venous
drainage. Also it allows for the fact that some
embryos survive while others die within the
same uterine environment of the pig, cow and
sheep having multiple embryos. In monotocous
species, failure of conceptus development is
represented by a return to estrus without
substantially lengthening the estrous cycle (see
Northey and French, 1980).
Genetic Factors. Genetic abnormalities appear to account for only a small percentage (0
to 4%) or embryonic mortality in domestic
animals (Boyd, 1965). In humans, however,
about 90% of spontaneous abortions occur
before the eighth week of pregnancy and, of
these, about 62% have abnormal karyotypes
(see Short, 1979). Monosomy, trisomy and
triploidy represent the most common genetic
defects in human embryos that are aborted.
Genes affecting early embryonic development
have been identified recently (see Goldbard and
Warner, 1982). Goldbard and Warner (1982)
reported that genes both within and outside the
H-2 complex influence the rate of blastomere
cleavage and, therefore, the rate of embryonic
development. They found that an H-2 associated gene named Ped (preimplantation embryo
development) controlled either fast or slow
embryonic development. Goldbard and Warner
(1982) reported a gene interaction in BALB.K
mice in which the background genes from the
BALB/c strain and the slow H-2 associated gene
from the H-2 k haplotype combined to produce
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PREGNANCYAND PARTURITION
"superslow" developing BALB.K embryos.
Studies similar to these for mice may have great
potential in livestock in determining immunohistocompatability factors associated with
conceptus development and perhaps embryonic
survival.
Another aspect of genetic factors affecting
conceptus development and the maternal
system during the prepartum and postpartum
periods has been reviewed recently by Thatcher
et al. (1979). Because the genotype of the fetus
and its membranes is determined by genotype
of the dam and sire, both parents influence
production of protein and steroid hormones
by the placenta. These hormones influence
conceptus development and survival in utero,
maternal adaptations to pregnancy, mammary
gland growth and lactation and postpartum
events related to uterine involution and resumption of the reproductive cycle. Future
research may indicate how the use of certain
sire-dam matings will lead to a high level of fertility, birth of viable offspring and maximum
production of milk to ensure a high rate of
development of offspring from birth to weaning.
Parturition
Parturition is initiated by the fetus. This was
established by designed experiments following
observations in the 1960's that defects of the
fetal brain or adrenal glands prolonged gestation
in sheep, goats and cattle. These observations
led to pioneering studies in sheep and goats
followed by confirming studies in cattle, swine
and horses to identify the sequence of coordinated hormonal signals originating with the
fetal brain and terminating in maternal behavior,
expansion of the birth canal, parturition and
lactation. The extent to which these processes
are understood and occasional differences in
one or more of the messages differ for each
species. For example, mechanisms terminating
progesterone (P4) production differ between
species where P4 is produced by the placenta in
sheep and by the ovaries in pigs and goats.
Recent investigations have focused on the
hormone relaxin and its role in expansion of
the birth canal, as well as on the contraction of
uterine smooth muscle and the way in which
the endocrine and nervous systems influence
this contraction.
From the applied view, studies of the past
15 yr have resulted in ways to control the day
or hour of delivery, an understanding of the age
437
limits in each species for induction of premature
delivery and they may someday result in ways
to prevent stillbirth and retained placentas.
Because there are differences between
species each will be considered separately in
terms of description of parturition and application of methods for induction of parturition to
the livestock industry. They will be compared
in terms of hormonal mechanisms initiating
parturition, uterine contraction and cervical
expansion.
A Description of Parturition
Swine. The length of gestation in swine is
reasonably precise, being approximately 112 to
116 d depending on the breed, size of litter and
season (Cox, 1964; Bichard et al., 1976;
Aumaitre et al., 1979). Parturition occurs
slightly more frequently in late afternoon and
at night (Bichard et al., 1976; Boning, 1979).
The entire parturition process requires 2 to 5
h with piglets being delivered at approximately
12 to 16 min intervals (Sprecher et al., 1974).
Piglets are delivered randomly from the two
uterine horns (Dziuk and Harmon, 1969;
Taverne et al., 1977). They sometimes pass
each other in birth order (Taverne et al., 1977)
and the placentas are delivered either in part
after the emptying of one uterine horn or
within approximately 4 h after the last piglet is
delivered (Jones, 1966). This is at a time when
plasma levels of oxytocin are elevated (Taverne
et al., 1979a). Parturition is normally preceded
by udder edema, attempted maternal nest
building and a milk ejection response (First and
Bosc, 1979).
Parturition is not without complications.
Body temperature increases 13 + 4.1 h before
delivery of the first piglet, reaches a peak of .6
to 1.2 C above normal of 38.3 + .3 C and in
healthy sows returns to near normal within 24
h (Elmore et al., 1979).
Not all piglets survive farrowing; at least 6%
are born dead (Randall, 1972; Sprecher et al.,
1974; Leman et al., 1979) and the last piglet in
each uterine horn has less than a 50% chance of
survival (Bevier and Dziuk, 1976). Factors
influencing piglet survival were reviewed
recently by Leman et al. (1979) and Dziuk
(1979), who indicated that pre- and postpartum losses of piglets may be as high as 20 to
25%.
Understanding the birth process and mechanisms controlling parturition should result in
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438
BAZER AND FIRST
ways o f reducing this loss and o f controlling
the m o m e n t of delivery so that attendants
might be present. The presence of an attendant and resuscitation of piglets has been shown
to save as many as one additional piglet per
litter (Milosavljevic et al., 1972; Hammond
and Matty, 1980). Synchronization of the
m o m e n t of farrowing also results in increased
efficiency of production b y allowing management of groups rather than individual litters.
Sheep. The length of gestation in sheep
depends on breed, age of dam and litter size.
The gestation period is approximately 149 to
151 d for fine wool breeds, 144 to 147 d for
down breeds and 142 to 145 d for high litter
size breeds such as the Finnish Landrace. The
standard deviation within breeds is approximately 2 d. Gestation length is shorter for twins
than singles and increases with age of the dam.
Lambing occurs at all times of the day or night
(Terrill, 1968).
Intrauterine contraction waves increase in
frequency about 12 h before delivery (Hindson
and Ward, 1973) and at about the time the ewe
begins to show uneasiness and isolates herself
from others. Delivery normally lasts for 20 to
30 rain for single births and 40 to 60 rain when
twins are born. The placenta is usually expelled
2 to 4 h after birth. In lie-de-France sheep,
Bosc (1973) found that 17% of the lambs die at
birth if birth is unattended whereas the loss is
only 4% when birth is assisted. This difference
may not be so great for ewes on range. The
most common difficulty is malpresentation of
the lamb for singles and twins and low weight,
weak lambs if triplets or quadruplets are
born.
Cattle. The length of gestation in cattle
ranges from 270 to 292 d. It depends on the
number, breed and sex of fetuses in utero.
Twins cause gestation to be 3 to 6 d shorter
than the usual single birth and male calves are
carried 1 to 2 d longer than female (Jainudeen
and Hafez, 1980). When embryos of short
gestation breeds are transferred into recipients
of long gestation breeds, gestation is of a length
identical to the breed of the embryo. The
reciprocal transfers produce a long gestation in
cows of short gestation breeds (Lampeter et al.,
1980; King et al., 1982).
There is little evidence that cows normally
give birth to calves at one time of day more
frequently than at others. However, in one
study the frequency of calves delivered between
0600 and 2200 h was increased from 57 to 79%
b y feeding the cows at 2200 h rather than at
0900 h (Lowman et al., 1981).
The most frequent birth related problems in
cattle are dystocia and retained placentas.
Approximately 6.4% of the potential calves die
around the time of parturition (Bellows et al.,
1979). Most of these, 72%, die from dystocia
(Anderson and Bellows, 1967). This is usually
due to disproportion between the size of calf
and cow and occurs most commonly when the
sire or transferred embryo are of a large breed
or the dam is a heifer (Price and Wiltbank,
1978).
Because the unborn calf at the end of pregnancy is increasing in weight by at least .5
to .7 kg/d (Lasley, 1981), one solution to dystocia is to induce parturition preterm when
calves are smaller; however, this solution leads
to retention of placentas. In fact, the frequency
of retained placentas is high whenever gestation
is shorter than normal. The frequency of
cows with retained placentas when parturition
is induced can be as high as 50 to 75% (First,
1979; Chew et al., 1979a,b).
Parturition in cattle can occur within a few
hours or as long as a day after the cow becomes
restless and attempts to seclude herself from
the herd. The first stage of labor lasts 2 to 6 h.
The period of delivery is approximately 30
to 40 min and the placenta is normally shed
2 to 6 hr after delivery is completed, but retention for as long as 12 h is considered normal.
Horses. The length of gestation in horses is
highly variable, between and within breeds,
ranging from 330 to 335 d in ponies to 338 + 5
d in light and heavy horses. Mares foal predominately at night (Jeffcott, 1972; Rossdale and
Ricketts, 1980) and have the ability to delay
parturition for several days when disturbed or
constantly observed. In spite of this, late
pregnancy is precariously maintained and small
increases in oxytocin during the last week will
induce delivery (Pashen, 1980).
Impending parturition is usually preceded by
colostrum oozing from the teats as a wax-like
material 2 to 3 d before foaling. Parturition in
mares, as in other domestic animals, can be
divided into three stages. In the mare, the first
stage is characterized by restlessness and
abdominal pain and is likely comparable to the
period of increased uterine contraction described
for sheep and swine. The second stage is delivery
of the foal and begins with straining by the
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439
PREGNANCY AND PARTURITION
mare followed b y appearance and rupture of
the amnion and expulsion of the foal covered
by amnion and with the umbilical cord still
attached. The cord breaks as the foal and mare
move. The third stage is expulsion of the
placenta (see Ginther, 1979). The first and
third stages of labor each last approximately 1
h while the second or delivery stage requires
only 10 to 15 min (Jeffcott, 1972). Parturition
in mares is usually without complication.
However, occasional malpresentation or prolonged retention of the placenta will occur.
Initiation of Parturition and Hormonal
Changes Associated with Parturition
Parturition in farm animals is initiated b y
the fetus, however, in some cases such as horses
the mother possesses the ability to postpone
delivery until undisturbed, although, she cannot
prevent eventual delivery. The exact hour of
delivery can also be influenced by light in rats
and feeding in sheep and cattle. Models for the
sequence of events and endocrine controls
initiating parturition in swine, a species with
pregnancy maintained by the ovaries and,
sheep, a species with pregnancy maintained by
the placenta, are shown in figures 1 and 2.
The specific mechanisms will differ slightly
between species, and the existence of some
steps or mechanisms may be unknown for one
or more species. The reader is encouraged to
compare the domestic species.
In general, the hormonal changes associated
with parturition are those involved with final
maturation of the fetus, termination of pregnancy, expansion of the birth canal, initiation
of uterine contraction, maternal behavior,
HYPOTHALAMUS
F
E
T
A
L
ANTERIOR~PITUWA~
ACTH+
~, ADRENALCORTEX
~
CORTISOL+
PLAC~ENTA
1
M
A
T
E
R
N
A
L
POF =/
GRAVID UTERUS
POSTERIOR
PITUITARY
PGF2oc+
f
OVARIES (CL)
PROGESTERONE
OXYTOCI
+ -N~ ' ~ ~
MYOMETRIUM
(CONTRACTION AND DELIVERY'}
RELtXIN
CERVIX
Figure 1. A suggested sequence of events leading to and associated with parturition in the pig. Hormones having a stimulatory effect on a target are designated with a (+); unknown steps or compounds are indicated by a
(?). From First and Bose, 1979.
Downloaded from www.journalofanimalscience.org by guest on June 11, 2014
440
BAZER AND FIRST
synthesis of milk and the ability to eject milk.
These events are normally coordinated by the
endocrine system with the perfection of a great
symphony. The mechanisms differ slightly
depending largely on differences between
species in the way in which pregnancy is
maintained.
A profile of hormonal changes preceding
parturition in swine is shown in figure 3 and for
cattle in figure 4. For extensive reviews of the
hormonal changes and mechanisms controlling
initiation of parturition the reader is referred to
reviews by First et al. (1982) and Taverne
(1982) for swine; First (1979), Challis (1980),
Challis and Mitchell (1981) and Evans et
al. (1981b) for sheep; Thorburn and Challis
(1979) and First (1979) for goats; Hoffmann et
al., (1979a), First (1979) and Johnson (1981)
for cattle and First (1979), Rossdale and
Ricketts (1980) and Allen and Pashen (1981)
for horses.
There is strong evidence that signals initiating
parturition in goats (Thorburn and Challis,
1979) sheep (Challis, 1980) swine (First et al.,
1982) and cattle (First, 1979 and Hoffmann et
al., 1979a) originate in the hypothalamo-pituitary axis. This evidence comes from absence of
parturition when the fetuses have congenital
pituitary defects or after ablation of the fetal
pituitary gland (First, 1979). Studies in sheep,
swine and goats either involving ACTH administration to fetuses and premature birth or ACTH
replacement after fetal hypophysectomy in
sheep (Jones et al., 1978) suggest that the essential pituitary product is ACTH. Its target is
the fetal adrenal gland where it is known in
sheep and swine that ACTH initially causes
growth of the fetal adrenals followed by a
stimulated change in adrenal steroid production
from other steroids to production of cortisol
SHEEP
HYPOT~LAMUS
ANTERIOR PITUITARY
A~H§
F
E
ADRENAL CORTEX
COR,~I~OL+ "
T
AL
PLACENTA
PROGESTERONE ( ~ O G s
M
GRAVID UTERUS ' ~
A
RN
A
L
\
OXYTOCIN
§ "
.....
II
MYOMETRIUM
(CONTRACTION AND DELIVERY)
CERVIX
(SOFTENING)
Figure 2. A suggested sequence of events leading to and associated with parturition in sheep. From First,
1979.
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PREGNANCY AND PARTURITION
441
parturition is less clear and the appropriate
experiments are yet to be done. T h e r e is good
evidence in sheep (Flint et al., 1975, J o h n and
Pierrepoint, 1975; A n d e r s o n et al., 1978a,b)
and f r o m f e t e c t o m y experiments in rabbits
(Chiboka et al., 1977) that the target for fetal
cortisol in initiation of parturition is the
placenta.
Here the mechanisms initiating
parturition appear to differ across species
( G l i c k m a n and Challis, 1980; Lohse and First,
1981; Lohse and Nara, 1982; Rose et al.,
1982). Cortisol or its synthetic analogues
effectively initiate parturition w h e n administered in large doses to the m o t h e r in all five
domestic species or by infusion or fetal administration of small doses in three o f these species
where studied (First, 1979). F o r horses the role
of the fetal brain and adrenals in initiation of
ENDOCRINE CHANGES PRECEDING
PARTURITION IN SWINE
IO0
--
nglml
CORTICOSTEROIDS
80-
A~
MATERNAL
0
I
pq/ml
~
I
I
.L
I
I
I
I
.~ ........~...~,:~
~
20
T
%
"" .,
OESTRADOL
cpq x.a3/m~'/...~
\'~
_j 15
~ ,.~---.-A," _...,m
uJ
>
i
LU
.
I0
..~TOTAL
OESTROGENS
<
(P9 X333/mD
(h
<
/
n
",.\~
OESTRONE"
(pgXIOO/mD ~,
5-0
I
I
I
ng/ml
I
I
I
I
145 6 n(:j/ml @
9
TIT
RELAXIN
:
/
(X2)~ ~'~
25-
/
ZO- PROGESTERONE
/
//
-
,o_
_ METABOLITE
-7
I
-6
-5
I.
Nt',d
...li"
.._
I
~J~
I
/X
_
_
%'. ~J
......--
I
I
I
I
~
UDDER EDEMA-UI~\\X\K\\\\\\\\\\\\\\\\~I
MILK EJECTION
-4
-3
-2
-I
DAYS PERIPARTUM
,,t
0
..FI
Figure 3. Endocrine changes preceding parturition in pigs. (a) Corticosteroids: - o - o - o - fetal cortisol,
- -a- -A- -A- - maternal corticoids; (b) --m--B--I-- total estrogens (pg X 333/ml), - -a--A--a-- estradiol-173 (pg •
.33/ml), e . . . 9
9 estrone (pg X 100/ml); (c) . . 9 9 .. 9 relaxin (X2) - R - i - m - progesterone and
- -a- -a- -a- - PGFz~ metabolite. From First et al., 1982.
Downloaded from www.journalofanimalscience.org by guest on June 11, 2014
442
BAZER
AND
depending on the way in which pregnancy is
maintained and the mechanisms for reversing
the maintenance. In the sheep where pregnancy is maintained by placental P4, cortisol
stimulates the rate limiting enzyme 17~ hydroxylase and causes the placenta to secrete
predominantly E rather than P4. Complete
decline of maternal P4 is not essential for
parturition in sheep; however, delivery progresses to the second stage only if P4 is reduced
FIRST
(Currie, 1977). The elevated E also stimulates
secretion of PGF20~ and development of receptors for oxytocin. In species requiring the
corpus luteum for maintenance of pregnancy,
swine, goats and cattle, its production of P4
must be terminated for parturition to occur
(First, 1979; First et al., 1982). Cortisol causes
elevation of maternal PGF2~ resulting in
regression of the corpora lutea, but how this is
accomplished is less clear (First et al., 1982).
CHANGES P R E C E O i N G
PARTUIIITION IN CATTLE
ENDOCRINE
BOVINE
MATERNAL
PLASMA
gl
I
]
I
MATERNAL PLASMA
300
2SO
PROGESTERONE
E 20O
if. 71
~
6
150
I00
O
B.
a.
4
SO
l.S
1.0
2
LN
O.S
1
26
,,
~;
642o
DAYS PRECEDING PARTURITION
DAYS PRECEDING PARTURITION
BOVINE FETAL PLASMA
BOVINE MATERNAL SERUM
2S00
'2DO0
80
E
1500 ~
70
iooo ~_ ~ so
20
30
IS
25
M
M
4DO .".
~s
80
,o
300
~- ~. 30
200
20
100
10
20 ~"
is
0
20
19
9
6 4 2 0"2"4"6"8
DAYS PERIPARTUM
26
19
9
6 4 2 0
DAYS PERIPARTUM
Figure 4, Endocrine changes preceding parturition in cattle. From First, 1979.
Downloaded from www.journalofanimalscience.org by guest on June 11, 2014
PREGNANCYAND PARTURITION
Increased maternal concentrations of E from
the placenta occur in response to the fetal
cortisol and maternal concentrations of PGF2a
increase in response to E in cattle and goats but
not in swine. In swine and sheep experiments
involving inhibition of prostaglandin synthesis
and replacement with a glucocorticoid or
PGF2a have shown that luteolysis and uterine
contraction depend on elevated PGF2~ and
that glucocorticoids cause parturition by
causing increased concentrations of PGF2~
(First, 1979; Nara and First, 1981a,b). In swine
there is evidence that the elevated PGF2a
causes pituitary release of oxytocin and prolactin
as well as ovarian release of relaxin (First et
al., 1982). In horses the mechanisms are less
clear, in part because the appropriate ablation
and replacement experiments have not been
done and because pregnancy maintenance and
hormonal changes associated with parturition
differ from other species (First, 1979; Allen
and Pashen, 1981). Ovarian P4 is not required
for maintenance of equine pregnancy after
about d 50 (First, 1979; Ginther, 1979). The
principal progestational hormones of late
pregnancy are three pregnanes and especially
20a-dihydroprogesterone. The equine placenta
produces increasing amounts of E in late
pregnancy, but apparently from dihydroepiandrosterone derived from the fetal gonad, rather
than a placental precursor (Allen and Pashen,
1981). As in the other species maternal blood
levels of PGF2a increase rapidly at parturition
in association with uterine contraction (First
1979; Allen and Pashen, 1981). If the foal does
initiate its own birth, the mare may have the
ability to modulate this fetal influence. Mares
are known to foal when secluded and undisturbed, and they foal predominantly at night
(Rossdale and Short, 1967; Jeffcott, 1972; Bain
and Howey, 1975). Circumstantial evidence
that the equine fetus can control initiation of
parturition comes from study of the length of
gestation for donkey-horse crosses. In these
cases, length of gestation is near that of the
paternal component of the fetus (Rossdale and
Ricketts, 1980). On the fetal side, there is
evidence that fetal adrenal glands undergo rapid
hypertrophy immediately before parturition
(Comline and Silver, 1971). Fetal plasma
cortisol concentrations increase slightly near
term (Nathanielsz et al., 1975), and a greater
increase occurs in cortisol content of amniotic
fluid (Pashen and Allen, 1979). However, no
spectacular rise occurs as seen in the other
443
domestic species just before birth (Bassett and
Thorburn, 1969). Plasma concentrations of
glucocorticoid in the mare remain unchanged
before parturition. The most positive evidence
for involvement of a product of the fetal
adrenal gland in initiation of parturition in the
mare comes from the observation that administration of a large dose of dexamethasone
induces premature parturition and milk ejection
(Aim et al., 1974, 1975). Prostaglandin F2a
(Sharma, 1975; Barnes et al., 1978; Pashen and
Allen, 1979) and oxytocin (Barnes et al., 1978;
Pashen, 1980) appear to be involved in delivery
of the fetus, but are not required for luteolysis
because the ovaries can be removed without
interfering with delivery. Rapid increases in
plasma levels of these two hormones occur
during parturition, but not before. There is
likely synergism in their action and exogenous
oxytocin causes a rapid increase in PGF2a
metabolites in blood (Pashen, 1980). Hormonal
control of gap junction formation and oxytocin
receptors are unknown for the mare. Because
the mare has four progestins at the end of
pregnancy and four E their specificity in
affecting myometrial oxytocin receptors and
gap junctions should be determined. It may be
that alteration of the E:P 4 ratio to promote
oxytocin receptor and gap junction formation
is achieved by conversion of P4 to its inactive
20a-dihydro metabolite that becomes the predominant progestin at parturition (Seren et al.,
1981). This shift in E:P4 ratio may also be
enhanced by increases in E2 in maternal blood
(Barnes et al., 1975) while the other E, El,
equilin and equilenin are falling.
Uterine Contraction
Parturition depends on the coordinated
rhythmic contraction of uterine smooth muscle
and on involuntary contractions of abdominal
muscles as well as on softening or opening of
the birth canal. The physiology of uterine
contractions at parturition has not been extensively studied in domestic animals. Drawing on
information from several species, including rodents it is apparent that unstimulated
uterine smooth muscle undergoes spontaneous
arythmic uncoordinated contractions during
late pregnancy, which consist of irregular
episodes of prolonged activity in uterine
segments containing a fetus, and relative
inactivity in empty parts of the uterus (reviewed
by Liggins, 1979). With approaching parturition,
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444
BAZER AND FIRST
the frequency, amplitude, propagation and
coordination of electrical impulses associated
with uterine contractions increase and seem to
be brought about through establishment of
intercellular electrical coupling by formation of
nexuses or gap junctions (Garfield et al., 1979a,
1982).
Gap junctions provide low resistance coupling
for communication between cells (Peracchia,
1980). In rats, uterine gap junctions increase
dramatically on the day of parturition (normally
d 21). In pregnant rats, ovariectomized on d 16
and treated with E, premature delivery on d 18
was accompanied by an increased number of
gap iunctions, but both events could be prevented by P4 administration (Garfield et al.,
1982). In ovariectomized, postpartum rats,
either E or uterine distension with a balloon
increased numbers of gap junctions somewhat,
but both treatments together were required to
increase gap junctions to parturition levels
(Wathes and Porter, 1982). In sheep, the
number of gap junctions is also correlated with
the prepartum decrease in maternal P4 and
increase in E (Garfield et at., 1979b). Gap
junctions form spontaneously in myometrium
cultured in vitro and their formation is increased
by E, but reduced by P4. In addition, E given
to immature rats in vivo increases the number
of gap junctions formed by their uteri in vitro.
Gap iunction formation is prevented by inhibitors of RNA or protein synthesis (Garfield et
al., 1980b), inhibitors of PG or thromboxane
synthesis and by the prostacyclin (PGIz) analog
earbacyclin. The effect of the PG synthesis
inhibitor indomethacin (that inhibits synthesis
of all PG's, thromboxanes and prostacyclin)
could be overcome by the PG precursor arachidonic acid, or by a stable endoperoxide of
PGH2, but not by PGE, PGH2, PGF2c~ or
thromboxane B2 (Garfield et al., 1980a).
Oxytocin had no effect on gap junction formation, but the /~ adrenergic analog isoxuprine
decreased their number and increased their
size. Dibutyryl cAMP, but not monobutyryl
eGMP also increased gap junction size (Garfield
et al., 1980b). Garfield et al. (1980b) proposed
that steroid hormones regulate synthesis of gap
junction proteins, called connexine, that gap
junction assembly may depend on connexin
crossqinking by PG and that gap junction
function is further regulated via cAMP and(or)
calcium.
Contraction of smooth muscle involves an
increase in intracellular free calcium, which
causes formation of a calcium-calmodulin
complex. This complex binds to and activates
myosin kinase, which phosphorylates myosin,
enabling myosin to interact with actin to cause
contraction (reviewed by Adelstein and Eisenberg, 1980). Ionized calcium (Ca 2+) can be
either liberated from intracellular binding sites
or it may enter the cell from the extracellular
fluid. Mitochondria can act as a Ca 2 + sink that
binds Ca 2+ when cytoplasmic concentrations
are high. The sparse sarcoplasmic reticulum and
vesicles associated with the inner surface of the
plasma membrane also bind some Ca~ + at lower
concentrations (Janis et al., 1977).
Uterine smooth muscle in which the contractile mechanisms have been developed by
exposure to E contracts rhythmically and
spontaneously. The rhythmicity of these
contractions is due to slow fluctuations in the
magnitude of the electrical potential across the
cell membrane, often referred to as pacemaker
potentials. In relaxed muscle, the pacemaker
potentials remain below a threshold whieh,
when exceeded, cause a burst of spike potentials
superimposed on the pacemaker potentials. The
spike potentials are associated with a sharp
increase in intracellular Ca: + resulting partly
from influx through pores in which the resistance to Ca 2+ falls with each burst of spike
potentials and partly from liberation of Ca2+
bound to surface vesicles. During relaxation
Ca2+ is both pumped out of the cell through
the pores and bound again at the various
intracellular sites.
Hormones that influence smooth muscle
activity act on either or both of the mechanisms
regulating intracellular Ca 2+ concentrations.
Oxytocin lowers the threshold potential for
initiation of action potential activity and also
has a direct action on the rate of Ca ~ + influx.
Prostaglandins act mainly by liberating Ca2+
from intracellular binding sites, but in addition
to having this effect on tonic contraction, they
cause a slow membrane depolarization that
increases the frequency of bursts of action
potentials and phasic contractions (Liggins,
1979). Uterine contractions forcing delivery in
domestic species are likely initiated by increased
intracellular Ca2 + in myometrial smooth
muscle and by the formation of gap junctions,
but the factors causing the change in Ca 2+ and
gap junction formation are not well understood
for these species.
Similar patterns of myometrial electrical
activity seem to exist prior to parturition in the
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PREGNANCY AND PARTURITION
sheep (Naaktgeboren et al., 1975a,b; Prud'
homme and Bosc, 1977; Krishnamurti et al.,
1982); cow (Taverne et al., 1979a) and goat
(Scheerboom and Taverne, 1981). In sheep,
increased electrical spike activity coincided
with increasing uterine pressure prior to parturition. Until 10 d before parturition, uterine
electrical activity consisted of irregular trains of
action potentials of variable amplitude, but
predominantly low. This is considered to be the
pattern of response expected from uncoordinated contraction of isolated groups of cells.
Long bursts of spike activity with high amplitude are considered to represent coordinated
and rhythmic activity of several groups of cells
and usually occur after the formation of gap
junctions (Garfield et al., 1979a). The long
bursts of spike activity increased 48 h preparrum and at a time when P4 withdrawal and E
and PGF2~ increases are seen in blood plasma.
This activity increased even more rapidly from
12 h before parturition until parturition, a time
when ewes exhibit external signs of impending
parturition and uterine pressure increases
(Hindson and Ward, 1973). These patterns were
reversed after parturition. Bursts of electrical
activity first appeared at the uterotubal junction. The existence of uterine cells that increase
in activity before others and act as a uterine
pacemaker has been proposed (Sakaguchi and
Nakajima, 1973).
In the pig, myometrial activity during late
pregnancy has been shown to consist of irregular
episodes of prolonged activity in those uterine
segments containing a fetus, while empty parts
of the uterus remain relatively inactive (Taveme
et al., 1979a). At this time, plasma concentrations of oxytocin remain below 1.3 /~U/ml and
plasma concentrations of Pa and E remain
unchanged (Forsling et al., 1979; Taverne et al.,
1979a). Between 24 to 10 h before expulsion
of the first piglet, when concentrations of P4
have significantly decreased and E has increased,
myometrial activity is still similar to that
recorded on the previous days. Only between 9
and 4 h before birth of the first piglet does
myometrial activity increase in all parts of the
uterus. This increase in myometrial activity
coincides with elevated concentrations of
oxytocin in peripheral plasma. Uterine contractions are most frequent during delivery when
oxytocin concentrations are highest (Taverne et
al., 1979a). Release of oxytocin seems to be
related to decreased concentrations of P4 as
well as increased levels of E (Forsling et al.,
445
1979).
Multiple implantation of intrauterine catheters (Zerobin, 1968) or surface electrodes
(Taverne et al., 1979b) demonstrated that
myometrial contractions in all segments of a
sow's uterine horn are synchronized during
delivery. Unlike the sheep (Krishnamurti et al.,
1979, 1982), contractions were initiated
preferentially at both ends of the uterine horn
and subsequently propagated in either a tubocervical or cervicotubal direction. These contraction waves echoed to return in the opposite
direction upon reaching the end of the horn
(Taverne et al., 1979c; Taverne, 1982). Cervicotubally-directed contractions stopped when a
horn was emptied and they seemed to be
related to the presence of piglets close to the
cervix. Taverne (1982) proposed that this
bellows effect shortens the distance traveled by
succeeding piglets and prevents piglets from
piling up at the cervix where placental attachments might be disassociated and cause fetal
anoxia and death.
In support of this idea, it is known that
piglets dying in the process of delivery are
predominantly the last ones born (Randall,
1972) and usually the last piglet in each uterine
horn (Bevier and Dzink, 1976). It is also known
that surgical inversion of the uterine horn
impairs normal expulsion of piglets from that
horn (Bosc et al., 1976). Little is known about
the synchrony of contraction of the two horns
except that expulsion of piglets from the two
horns is random (Dziuk and Harmon, 1969;
Taverne et al., 1977).
Little attention has been given to possible
influences of the nervous system on uterine
contractions in domestic animals. Beta-2
sympathetic blocking drugs will temporarily
block uterine contraction and delivery (Zerobin
and Kundig, 1980; Grunert and Verhulsdonk,
1980; Greene, 1981).
Studies of their function suggest that oxytocin and PGF2ct should be capable of inducing
labor. In intact animals they do and they can
act separately or in concert (Chan, 1977). This
interaction is made more complex in the whole
animal by evidence that PGF2~ causes release
of oxytocin in swine (Ellendorff et al., 1979a)
and that increased plasma levels of PGF2a or its
metabolite are present after administration of
oxytocin (Mitchell et al., 1975; Chart, 1977;
Mitchell and Flint, 1978b).
Oxytocin is not effective until uterine
receptors for oxytocin are developed. Oxytocin
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446
BAZER AND FIRST
receptors are developed in rats and guinea pigs
by a shift in the E:P 4 ratio. This shift is accomplished prior to parturition in rats predominantly
by luteal regression and termination of P4
production (Alexandrova and Soloff, 1980a,b)
whereas it occurs in the guinea pig due to a
dramatic increase in E (Alexandrova and Soloff,
1980c).
The effect of steroid hormones on oxytocin
receptors and the impact of development of
oxytocin receptors on parturition in domestic
animals needs to be established. Oxytocin
receptors do exist in the pig uterus in late
pregnancy (Soloff and Swartz, 1975). Each
species seems to first respond to oxytocin
administration with uterine contraction and
delivery at approximately the same time that
milk can be ejected or streams from the nipples.
The existence and hormonal control of uterine
oxytocin receptors needs to be established for
the other domestic species.
Species differences and sometimes differences
within species exist regarding the ability of P4
to suppress uterine contractions and whether
parturition can occur while plasma levels of P4
are elevated. In goats, swine and cattle, where
pregnancy maintenance is dependent on functional CL, plasma levels of 14 normally decline
to minimal levels during the 2 d preceding
parturition (First, 1979). Parturition is prevented if plasma P4 is sufficiently elevated
without the major daily fluctuations often
caused when P4 is administered once per day,
or when administration is started before oxytoein receptors are developed. Such is the ease
for swine, goats and cattle. Prevention of
luteolysis and uterine contraction with inhibitors of PG synthesis also prevents or delays
parturition in swine (Nara and First, 1981a,b;
Gooneratne et al., 1982; Taverne et al., 1982).
This is untested in cattle and goats.
In sheep, where pregnancy is maintained by
P4 from the placenta, P4 decreases at parturition
but the absence of P4 from blood plasma does
not seem to be essential for parturition (Liggins
et al., 1973), and inhibition of PG synthesis
interferes with delivery in sheep with only
partial reduction in plasma levels of P4 (Mitchell
and Flint, 1978a). Presumably the effect of the
inhibitors is on PG stimulation of uterine
contraction either directly, by stimulation of
oxytocin release or both. One may speculate
that development of receptors for oxytocin in
ewes is dependent on elevated plasma levels of
E as in the guinea pig.
In the mare exogenous P4 does not prolong
gestation (Alto et al., 1975), and maintenance
of late pregnancy may not be dependent on P4,
(see Moss et al., 1979; First, 1979; Rossdale
and Ricketts, 1980). The hormonal regulation
of development of receptors for oxytocin is
unknown for the mare. In spite of the need in
some species for elevated E levels to develop
oxytocin receptors, the situation in sheep may
be different. It is known that E levels are
elevated prepartum in ewes (Nathanielsz et al.,
1982) and exogenous E causes premature
delivery (Bosc et al., 1975; Hindson et al.,
1967). Elevation of E alone may not be prerequisite for formation of oxytocin receptors or
parturition in sheep because immunization of
ewes against E did not prevent parturition or
alter levels of P4 or PGF2a (Rawlings et al.,
1978). It is possible that immunization against
E was not complete. In estrual sheep E promotes
a high frequency of uterine contractions and
causes contractions to originate in the posterior
uterus (Croker and Shelton, 1973; Hawk,
1975a,b; Rexroad, 1980). This E stimulation of
uterine contractions requires protein synthesis
and is not blocked by inhibition of prostaglandin
synthesis with indomethacin (Rexroad, 1980).
The initiation of parturition by the fetus
culminating in uterine contraction would be a
futile effort unless the birth canal was prepared
to allow exit of the fetus.
Expansion of the Birth Canal
The cervix presents a formidable block to
expulsion of fetuses until its connective tissue
becomes soft and capable of distension. This
softening or increased distensibility is regulated
hormonally. Softening of the cervix is dependent on changes in the structure of its connective tissue. The principal changes at the time of
parturition are a separation or scattering of
tightly packed collagen fibers, and an increase
in the proteoglycan intercellular matrix and in
water content. The principal component of the
proteoglycans that increases at this time in
humans is keratin sulphate (Danforth et al.,
1974) although an increase in total glycosaminoglycans also occurs (Danforth, 1980). There is
also a softening of the collagen fiber network.
This appears to result from physical separation
or proteolytic depolymerization of collagen
because collagenase does not increase (Veis,
1980).
Little is known about the biochemistry of
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PREGNANCY AND PARTURITION
cervical softening in domestic animals. More is
known about the hormones influencing cervical
distensibility and the necessity for development
of distensibility before parturition. This is best
evidenced for swine from experiments of
Kertiles and Anderson (1979) and Nara et al.
(1982). Kertiles and Anderson (1979) found
that injections of relaxin caused premature
dilatation of the cervix in late pregnant gilts.
Removal of CL on d 110 resulted in premature
delivery and prolonged parturition whereas
relaxin therapy to gilts without CL resulted in
premature deliveries, but parturitions of short
duration and with cervical dilatation. Nara et al.
(1982) used P4 to maintain pregnancy in
ovariectomized gilts and found that in the
absence of the source of relaxin, i.e., the CL,
delivery was prolonged and there was a high
incidence of stillborn piglets. Relaxin therapy
resulted in plasma concentrations of relaxin,
duration of delivery and frequency of live
births comparable to that of ovary intact gilts.
Several hormones including E, PG, oxytocin
and relaxin have been implicated in stimulation
of cervical distensibility. Species differences
appear to exist in describing the hormonal
stimulator. However, our base of information
from experiments designed to directly determine
hormonal interactions and the sequence of
hormonal signals preparing the cervix for
distension is insufficient to draw conclusions
across species. Certainly species such as the
cow, ewe and mare in which the ovaries can be
removed before parturition without interfering
with birth raise questions about the source or
essentiality of relaxin for cervical distension
(cow: Estergreen et al., 1967; Chew et al.,
1979a,b; Hoffmann et al., 1979b; Wendorf et
al., 1983), (ewe: Casida and Warwick, 1945;
Denamur and Martinet, 1955) and (mare: First
and Aim, 1977). It has been suggested that
relaxin may act to maintain late pregnancy in
some species by suppressing uterine contraction
(Taverne et al., 1979a; Porter, 1979). However,
there is, as yet, no definitive evidence for this
effect in domestic animals.
Swine. In swine where relaxin seems to be
the principal hormone promoting cervical
distensibility, the source, synthesis and control
of relaxin are best understood. This hormone,
its structure, source and functions in swine have
been reviewed recently by Sherwood (1982)
and Anderson (1982).
The porcine CL of late pregnancy is a rich
source of relaxin (Fevold et al., 1930, Hisaw
447
and Zarrow, 1948), and the absence of release
of relaxin into the blood plasma after ovariect o m y indicates that the CL is the principal
organ producing relaxin in this species (Nara et
al., 1981, 1982). Relaxin is secreted by lutein
cells of CL (Belt et al., 1971; Kendall et al.,
1978). It is stored and concentrated in CL
throughout pregnancy (Anderson et al., 1973b).
This accumulation is not dependent on pregnancy because CL of gilts hysterectomized
early in pregnancy are maintained and accumulate relaxin through 124 d (Anderson et al.,
1982). Additionally, in the absence of mating,
relaxin was accumulated in CL that had their
life span prolonged by exogenous E (Anderson
et al., 1973b).
Relaxin is released into the blood as sustained
surges starting approximately 2 d before
parturition with peak release at 14 to 22 h
before parturition and this activity is rapidly
lost after parturition (Sherwood, 1982). Release
is dependent on PG synthesis and is stimulated
either directly or indirectly by PGF2a (Sherwood et al., 1979; Nara and First, 1981b).
While normally associated with luteolysis, the
release of relaxin by PGF2a is not dependent
on luteolysis (Nara et al., 1982). In fact, there
is evidence based on hysterectomy that the
timing of relaxin release may be dependent on
the life span of CL and not on pregnancy or
parturition (Anderson et al., 1982). This is
supported by the observation that sows containing decapitated (Sherwood, 1982) or
hypophysectomized (Kendall et al., 1980)
fetuses have prolonged gestation and release
relaxin into their blood on random days around
the time of expected parturition.
It may be that the release of relaxin induced
by PGF2a is actually caused by oxytocin after
stimulation of oxytocin release by PGF2&. If
this is the case, small changes in either hormone
extrinsic or intrinsic to CL could cause release
of relaxin. Prostaglandin F2a is known to cause
oxytocin release at the same time that release
of relaxin occurs (Ellendorf et al., 1979a).
Nevertheless, the specificity of PGF2a activity
needs to be tested with the ovary isolated in
vivo or in vitro or CL isolated in vitro.
Relaxin appears to be associated with
increased distensibility of the cervix in rodents
as evidenced by ovarian ablation and relaxin
replacement. The effectiveness appears dependent on prior exposure to E or P4 followed by
E (see Sherwood, 1982). Zarrow et al. (1956)
reported that relaxin would cause cervical
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448
BAZER AND FIRST
dilatation, increase water content and cause
depolymerization of cervical glycoproteins
when injected into E-treated ovariectomized
nonpregnant gilts. As previously indicated,
Kertiles and Anderson (1979) found that
relaxin therapy prepartum stimulated cervical
distensibility in ovariectomized gilts, and cervical diameter of intact gilts increased when relaxin release into blood occurred. While E or E
and P4 may aid in preparing the porcine cervix
to respond to relaxin (Zarrow et al., 1956),
P4 does not inhibit release of relaxin (Sherwood
et al., 1978).
Research is needed in swine to identify the
effects of relaxin on specific components of
cervical softening such as changes in specific
glycosaminoglycans. Research is also needed to
establish the interaction of relaxin with other
hormones and the sequence of cervical events
and hormonal controls required to prepare the
cervix to respond to relaxin.
Relaxin therapy alone or in combination
with steroids has been shown to cause cervical
changes in humans, monkeys and cattle (see
Sherwood, 1982). Cervical changes in the other
domestic species may be more dependent on
hormones other than relaxin.
Cattle. In cattle, relaxin also has been
isolated from CL during late stages of pregnancy
(Wada and Yuhara, 1960; Fields et al., 1980)
and from bovine placenta (Wada and Yuhara,
1960). The activity is much less than in the pig.
Small amounts were identified in blood from
cattle of late pregnancy by biological assay
(Wada and Yuhara, 1961), but not by the
porcine RIA (Sherwood et al., 1975). Little is
known about hormonal regulation of cervical
distensibility or changes in the cervix of cattle
at parturition.
Sheep. There is no RIA for ovine relaxin.
Using a porcine relaxin RIA Chamley et al.
(1975) found episodic bursts of relaxin throughout the estrous cycle. They found a rise in
plasma relaxin and prolactin just before parturition and observed correlated changes in both
hormones. Both hormones were present and
again exhibited correlated, abrupt increases
within 1 to 5 min after initiation of machine
milking. Relaxin levels dropped within 2 min,
but prolactin remained elevated. Similar changes
occurred when Iambs suckled ewes (Chamley et
al., 1976). This release of relaxin may be caused
by oxytocin, because infusion of oxytocin to
Pa-E primed anestrous ewes stimulated release
of relaxin (Chamley et al., 1976), or by PG,
which were stimulated to be released into the
blood by oxytocin. The source of relaxin
must be other than CL or placenta of ewes
because they are not present during lactation.
Infusion of PGF2a directly into the cervix
of sheep has been reported to cause cervical
softening (Fitzpatrick, 1977). However, Fitzpatrick and Liggins (1980) suggested that it
may be a prostacyclin rather than a PG that
promotes cervical softening. The activity of
prostacyclins in the cervix may be from their
local synthesis. The prostacyclin 6-oxo-PGF1
is produced in the cervix of sheep and in
increased quantity at labor (Ellwood et al.,
1980; Evans et al., 1981a,b). Estrogens have
been shown to promote cervical softening or
dilatation in ewes during late pregnancy (Stys
et al., 1980; Fitzpatrick and Liggins, 1980).
This effect of E on cervical softening occurred
even though P4 levels were elevated. In fact,
administration of 200 mg of P4/d failed to
inhibit the prepartum cervical softening of ewes
with parturition induced by dexamethasone
(Stys et al., 1980). Experiments involving
maternal hypophysectomy, ovariectomy and
fetectomy are needed to isolate and allow
replacement of the hormones suspected of
influencing cervical softening.
Horses. Little is known concerning the
regulation of cervical dilatation in horses.
Relaxin from the placenta is present and
elevated in the blood of mares before parturition (Stewart and Stabenfeldt, 1981; Stewart
et al., 1982).
The Induction of Parturition
Knowing the steps and hormonal messengers
involved in the initiation of parturition, it
should be possible to administer one or more of
these messengers to cause early and perhaps
precisely timed delivery. Indeed such can be
done. The most effective hormonal messenger
differs some among the species. Unfortunately
parturition cannot be induced much before
term in some species without interfering with
birth weight and survival of the offspring. These
critical periods are less than 3 d for swine, 5 to
7 d for sheep, 1 wk for horses and for cattle.
Sheep. From the practical point of view,
parturition can be induced in sheep most
effectively by either glucocorticoid or E administration. Parturition can be induced by ACTH
infusion or by continuous infusion of cortisol
after approximately d 120 (Liggins, 1968), and
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PREGNANCY AND PARTURITION
abortions can be caused even earlier by E
(Hindson et al., 1967); however, practical
systems for induction of parturition require
that the hormones be used at a stage when
postpartum fetal survival and growth will be
normal. The efficacy and limitations of glucocorticoid, estrogen and prostaglandin induction
systems for sheep have been reviewed by Bose
et al. (1977).
Swine. If the proposed model for the steps
and mechanisms initiating parturition in swine
is valid, it should be possible to induce parturition before term by exogenous hormones which
elicit the sequence of events leading to parturition. This is possible for four hormones: ACTH
to the fetus (Bosc, 1973); cortisol analogues to
fetuses or the mother (North et al., 1973; First
et al., 1982); PGF2a and its analogues to the
mother (First et al., 1982); and within the last
12 h of gestation, oxytocin to the mother
(Welk and First, 1979).
This knowledge has provided the basis for
development of methods for the induction of
parturition. The potential benefits derived from
induced parturition in swine at a precise time
are: a) more efficient use of farrowing facilities
and labor, b) avoidance of parturition on
weekends, holidays or at late hours of the
night, c) more efficient cross-fostering of litters,
d) more uniformity in the time of estrus for
lactating sows after weaning and in the age and
weight of piglets in feedlots and e) reduction in
the length of gestation.
Unfortunately, the latter is of limited
feasibility. Attempts to cause delivery before d
109 have resulted in death of the piglets by d 1
postpartum (Wierzchos and Pejsak, 1976; N. L.
First, unpublished). Piglets born as late as d 110
(Jainudeen and Brandenburg, 1980) or in some
cases d 111 (Bosc and Martinat-Botte, 1976;
Hammond and Carlyle, 1976; Gilchrist-Shirlaw
et al., 1978; Aumaitre et al., 1979) have reduced
survival and reduce birth and weaning weights.
However, piglets born 2, and in some experiments, 3 d before term have normal survival
and normal birth and weaning weights (Aumaitre
et al., 1979).
The most effective, efficient and widely
accepted method to date for inducing parturition
in pigs is an im injection of PGF2a or one of its
analogues. Experiments involving the use of
PGF2a to induce parturition in swine have been
reviewed and summarized recently (First et al,
1982).
There have been two attempts to develop
449
methods for making the time of PGF2cx-induced
parturition more precise. When oxytocin was
injected on the expected day of cloprostenolinduced parturition and at a time when milk
could be ejected, the interval from injection of
PG to delivery of the first piglet was 27.2 + 2 h
and the variance in time of delivery was significantly reduced from that due to cloprostenol
alone (Welk and First, 1979). This combination
of drugs allows synchronization and supervision
of farrowings during a specified half day. Long
acting oxytocin preparations are now available
(Veznik et al., 1979), but they are untested for
that purpose in swine.
In a second attempt, the treatment involved
daily administration of 100 mg of P4 on d 112,
113 and 114 and 200/lg of cloprostenol on d
115 (Goonerame et al., 1979). Here 80% of the
sows farrowed between 0800 and 1700 h on d
116. A precise time of parturition, 25.4 -+ 1 h,
after injection of cloprostenol was achieved.
Although this study was without a control
group in which cloprostenol alone was used, the
initiation of lactation, piglet survival and
weight, and postpartum reproductive performance of the sows were not different from
untreated controls.
Cattle. There are several reasons for considering the induction of parturition as an aid in
management of calving. A successful method
could be used to 1) advance the calving date in
late conceiving cows, 2) condense the herd
calving interval, 3) group parturition at a
precise time so that attendants, shelter and care
could be provided at parturition, 4) shorten
the length of gestation thereby reducing the
size of the calf and incidence of dystocia and 5)
terminate pregnancy if desired.
The greatest use of methods for induction of
parturition has been in dairy cattle of New
Zealand where parturition has been induced in
over one million cows (Welch and Scott, 1979).
It has been used there primarily to synchronize
the beginning of lactation with the beginning of
lush pasture without great regard for stage of
pregnancy or survival of the offspring.
Parturition in cattle has been induced
prematurely in a number of experiments by a
single im injection of either a glucocorticoid or
PGF2a and sometimes by E (see First, 1979;
Hoffmann et al., 1979a; Johnson, 1981).
When parturition is to be induced after
maternal plasma levels of E are elevated, the
effective drugs are either glucocorticoids or
PGF2 a, Glucocorticoids used include dexa-
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450
BAZER AND FIRST
methasone (Day, 1977; Davis et al., 1979),
dexamethasone trimethyl acetate (Welch et al.,
1977; Welch et al., 1979), flumethasone (Davis
et al., 1979) and betamethasone (Diskin, 1982).
The prostaglandins most commonly used are
the tham salt of PGF2~ (Lauderdale, 1975;
Henricks, et al., 1977; Diskin, 1982) and the
PGF2~ analogue, cloprostanol (see Johnson,
1981).
The frequency of cows calving has been
increased, the frequency of dystocia and
retained placentas reduced slightly and the
interval from treatment to parturition shortened
by the use of two separate drugs. Most commonly, this has involved an initial treatment
with a long acting glucocorticoid, followed 8 to
11 d later in cows not calving by a short acting glucocorticoid or a PGF2~ preparation
(MacDiarmid, 1980).
Retained placentas commonly occur when
cows are induced to calve before full term
gestation is completed. The frequency seems
reduced, the closer to term calving occurs
(Welch et al., 1977, 1979; MacDiarmid, 1980;
Johnson and Jackson, 1980). Estrogens have
been used with glucocorticoids to reduce
retained placentas, but without much effect
(Barth et al., 1978; Davis et al., 1979). The
frequency of retention does seem to be reduced
slightly by the use of a short acting glucocorticoid after initiation of events leading to parturition by a long acting glucocorticoid (Davis et
al., 1979).
The success with oxytocin for induction of
parturition has been varied and sometimes less
than desirable (Adams, 1969). More recently
for cows previously treated with a glucocorticoid
or cows 1 or 2 d prepartum, a long acting
carboanalog of oxytocin has effectively induced
labor and delivery (Veznik et al., 1979). It may
be that the effectiveness of oxytocin in cattle is
only for cows with well developed oxytocin
receptors and safely only after the cervix has
softened.
For cows beginning labor, and with cervical
distension, long acting drugs that stimulate B2
adrenergic receptors, such as clenbuterol, delay
delivery for at least 5 h (Arbeiter and Thurnber,
1977; Grunert and Verhulsdonk, 1980; Zerobin
and Kundig, 1980; Greene, 1981).
Effective methods for inducing early parturition in cattle are available. Unfortunately calf
survival is reduced if calving is induced more
than approximately 1 wk preterm. More
research is needed to determine the physio-
logical mechanism involved in retention of
placentas associated with early delivery and to
develop ways to prevent placental retention.
Horses. Parturition can be induced in mares
by glucocorticoids, PGF2~ or oxytocin. The
preferred method for mares close to term is a
low dose of oxytocin. A dose of 100 mg of
dexamethasone/d for 4 d was required to
induce parturition in large saddle-type mares.
These mares gave birth to live foals 6.5 to 7 d
after initiation of dexamethasone treatment
(Aim et al., 1974, 1975). The same treatment
regimen applied to p o n y mares resulted in a
more immediate response, with most mares
foaling between the third and fourth days of
dexamethasone injection. When treatment
started on d 321, five pony mares foaled on d
324 + .1 compared with d 334 + 1.2 for seven
controls. All foals were born live and survived,
and their mothers produced adequate milk
(First and Aim, 1977).
Prostaglandin F 2 a will also cause premature
parturition and abortion in the mare. While in
ponies a single dose as low as 1.25 mg induced
abortion in early pregnancy, a dose of 2.5 mg
administered every 12 h for approximately 2 d
is required to cause abortion at later stages of
pregnancy (Douglas et al., 1974). A larger dose
of PGF20t may be required in saddle and draft
mares, in which multiple doses of P G F 2 a were
not consistently effective (Aim et al., 1975),
but a single dose of the potent analog Fluprostenol was effective (Rossdale et al., 1976,
1979).
Estrogen treatment alone does not cause
premature parturition (Aim et al., 1975). When
combined with oxytocin, however, E has
caused dilation of the cervix and facilitated the
birth process (Hillman, 1975). When signs of
impending parturition were obvious, i.e., udder
enlargement, presence of milk, and cervical
distension, oxytocin has induced parturition. When administered im, 20 IU of oxytocin
induced parturition, but more slowly than
doses up to 188 IU (Hillman, 1975). However,
Pashen (1980) found that small doses of 2 to
10 IU were effective and suggested a second
treatment, when the first fails, may be more
effective than a high dose. While there is much
to be learned yet about mechanisms controlling parturition in the mare, it is evident
that pregnancy can be terminated at early
stages with an appropriate dose of PGF2a.
Parturition can be induced after d 320 with a
P G F 2 a analog or dexamethasone and after signs
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PREGNANCY AND PARTURITION
o f p a r t u r i t i o n are evident, o x y t o c i n will i n d u c e
hbor.
T h e s t a t u s o f o u r p r e s e n t k n o w l e d g e conc e r n i n g t h e w a y in w h i c h p r e g n a n c y is initiated,
recognized, m a i n t a i n e d a n d t e r m i n a t e d a n d
aspects of t h e s e processes n e e d i n g f u r t h e r s t u d y
have received t h e p r i n c i p a l f o c u s of this review.
A p p r o x i m a t e l y 35% o f fertilized eggs in
f a r m a n i m a l s do n o t result in live b i r t h . R e l a t e d
to t h e s e processes, b u t n o t discussed in detail in
this review, are t h e p r o b l e m s o f early e m b r y o n i c
d e a t h loss, genetic a n d e n v i r o n m e n t a l i n f l u e n c e s
o n e m b r y o survival a n d d e v e l o p m e n t a n d
i n f l u e n c e s o f t h e f e t u s o n t h e d a m ' s m i l k production.
Literature Cited
Adams, W. M. 1969. The elective induction of labor
and parturition in cattle. J. Amer. Vet. Med.
Assoc. 154:261.
Adelstein, R. S. and E. Eisenberg. 1980. Regulation
and kinetics of the actin-myosin-ATP interaction.
Annu. Rev. Biochem. 49:921.
Alexandrova, M. and M. S. Soloff. 1980a. Oxytocin
receptors and parturition. I. Control of oxytocin
receptor concentration in the rat myometrium at
term. Endocrinology 106:730.
Alexandrova, M. and M. S. Soloff. 1980"o. Oxytocin
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