Physiology and Clinical Parameters of Pregnancy in Dogs
Patrick W. Concannon, PhD, Dipl ACT (Hon)
Department of Biomedical Sciences, Cornell University
Ithaca, NY, USA
Pregnancy length in dogs is remarkably consistent, being 64-66 days from the preovulatory LH surge to parturition in nearly all instances. The luteal phase of pregnancy involves an initial peak in progesterone around Day 15-25 and a subsequent slow decline, with concentrations comparable to those in non-pregnant cycles. However, there are secondary increases in circulating progesterone beginning between Days 25-35, despite increased progesterone metabolism and fecal excretion, reflecting a pregnancy specific stimulation of progesterone production. Luteal function is terminated by an abrupt prepartum luteolysis.
Ovulation and Fertilization
Ovulation occurs spontaneously about 2-2.5 days after the preovulatory LH surge. Estrus behavior, and copulation, may begin as early as 5 days before ovulation or as late as 3 days after ovulation. Oocytes are ovulated as immature primary oocytes, and become mature after a 2 or 3-day period in the oviducts (uterine tubes). Following oocyte maturation, bitches remain fertile for 2-4 days, or longer. Lengthy fertile life spans of spermatozoa in the female tract and of mature oocytes in the oviducts in this species may explain the high fertility rates (>95%) often obtained in commercial dog breeding facilities. Dog sperm may remain fertile in the female tract for up to 8 days and pregnancies have resulted from single matings at 5 days before ovulation. Having multiple sires for a single litter is not uncommon. Pregnancy rates and litter size decline progressively with matings after Day 6, due to oocytes degeneration and cervical closure. In some cases, matings as late as Day 9-10 have resulted in pregnancies lasting only 56-57 days after mating.
Implantation, Placentation and Timing of Pregnancy Events
Gestation almost invariably lasts 64, 65 or 66 days after the LH surge (Day 0), whereas the interval to parturition following a single mating can range from 56 days (following a "late" mating) to 69 days (following an "early" mating). Implantation is apparently timed by maternal endocrine changes initiated around the time of ovulation. Available data suggests that blastocysts typically enter the uterus around Day 10-12, pre-implantation uterine swellings are grossly detectable around Day 18, trophoblast attachment occurs around Day 21, and implantation around Day 22. Using high-resolution (7 to 10 MHz) ultrasound, embryonic vesicles are first detectable at Day 18-20, embryonic masses at Day 21-23, fetal heart movement at Day 24-25, the zonary placenta at Day 28, and fetal body movement at Day 35. As the placenta and embryo continue to grow, the embryo is shorter than the length of the placental band until Day 38-40 and is obviously longer than the placental girdle after Day 42. The timing of the events of canine pregnancy are also reviewed in Concannon, 2001 (www.ivis.org).
Placentation is endothelial-chorial, zonary and circumferential. The girdle of fetal trophoblast tissue develops marginal hematomas, while the chorioallantoic poles remain thin and transparent. The marginal hematomas develop large pools of stagnant blood from which the extra-embryonic circulation absorbs metabolites and iron. Pregnancy can be diagnosed by manual palpation of discrete uterine enlargements between Day 20 and 35; by ultrasound after Day 25; and by radiography after Day 46. Fetal heart rate (average around 230 bpm) can be monitored readily by ultrasound, beginning at Day 28. Biochemical pregnancy tests have included nonspecific assays of fibrinogen and of c-reactive protein, which are not specific. Serum relaxin assay after Day 30 is diagnostic. An "in-clinic" canine serum relaxin ELISA assay is marketed for this.
Pregnancy Physiology and Endocrinology
Several endocrine differences have been reported for pregnant bitches when examined in comparison to nonpregnant bitches in the same stage of the ovarian cycle. These include (1) a modest secondary increases in progesterone and estradiol secretion after Day 25 to 30; (2) an elevation in relaxin concentrations from about Day 26 to 30 until term; (3) an elevation in prolactin concentrations from Day 30 to 35 until term, followed by suckling related elevations during 6-8 weeks of lactation; (4) pregnancy-related elevations in acute-phase proteins between Days 30 and 50; and (5) changes associated with parturition including, brief a prepartum increase in cortisol., and increased circulating prostaglandin during an abrupt prepartum decline in progesterone and surge in prolactin.
A progressive, normochromic, normocytic anemia starts between Day 25 and 30, becomes maximal near term, recovers over an 8-12 week period post-partum, and can involve 20-40% decreases in PCV to hematocrit values as low as 29-35%. The anemia of pregnancy represents hemodilution due to an increased plasma volume, but actual changes in blood volume have not been determined. Pregnancy causes resistance to exogenous insulin in diabetic bitches, and can cause insulin resistance and hyperglycemia in some normal bitches. The likely cause is an increase in growth hormone secretion by the progesterone-stimulated mammary gland, which can occur in nonpregnant cycles as well. Average litter size declines after 7 years. Studies have documented post-implantation losses of 1 or more fetuses in 6% to 25% pregnancies. Spontaneous resorption or abortion of entire litters can occur. Body weight typically increases 20-55% (average 35%). Absolute requirements for both protein and carbohydrate are increased. It is recommended food be offered at >150% of maintenance levels during the last 3 weeks of pregnancy, and at >200% of maintenance during early and peak lactation.
Post-implantation increases in fibrinogen and other serum acute phase proteins, i.e., C-reactive protein, may reflect reaction to trophoblast invasion of the uterus, are not pregnancy specific, and can be expected in dogs with any inflammatory disease. The induced increase in fibrinogen is compensated by a simultaneous increase in local finbrinolytic activity reflected in increased serum fibrinogen degradation products.
Secondary, pregnancy-related increases in progesterone and estradiol secretion between Days 25 and 40 are not fully reflected in serum concentrations due to increased steroid metabolism metabolism and dilution in an increased plasma volume. Prolactin becomes distinctly elevated above levels seen in most non-pregnant cycles by Day 30-35, increases to near peak level in late gestation, and surges during parturition. Whether relaxin or another placental hormone is the stimulus for the gestational rise in prolactin is not known. Relaxin levels in the bitch increase between Day 27 and 30, peak by Day 40-50, are elevated but declining towards term, and fall at parturition to reach non-detectable levels in 1-6 weeks. Relaxin levels are normal ovariectomized pregnant bitches administered exogenous progestin. Therefore, the placenta is the primary relaxin source in dogs although ovarian production is possible.
Luteal Function and Maintenance of Pregnancy
The corpora lutea are the only known source of circulating progesterone during pregnancy. Both LH and prolactin are required luteotrophins. Dopamine agonists will decrease progesterone at any time. The pregnancy-related increase in prolactin the presumed stimulus for the pregnancy-specific increase in luteal function. Ovariectomy or induction of luteolysis at any time in gestation causes termination of pregnancy or premature parturition. Exogenous prostaglandin F-2-alpha (PGF) is weakly luteolytic in the bitch, but can be used to readily induce luteolysis and terminate pregnancy after Day 30 when administered in low to moderate but sufficient doses (30-100 ug/kg) two or more times a day for a sufficient duration (5-10 days). After Day 30-35, dopamine agonists (DA) such as bromocriptine (30-100 ug/kg, BID) and cabergoline (5 ug/kg daily) are readily abortifacient by virtue of their ability to suppress prolactin secretion and thus progesterone secretion. Combination DA-plus-PGF protocols for pregnancy termination beginning at Day 25 have been developed.
During the 24 h prior to parturition, progesterone falls below the 2 ng/ml required to support pregnancy. The rapid luteolysis is caused by a concurrent increase in PGF concentrations. A transient prepartum hypothermia is caused by rapid withdrawal of the thermogenic effects of progesteronemia and is useful clinically to predict impending parturition. The PGF increase is likely the result of a cascade of fetal-placental endocrine changes initiated by maturation of the fetal hypothalamic-pituitary-adrenal axis, as in other species. However the dog does not have any observable prepartum increase in estrogen as a stimulus for PGF release, and it may be that cortisol can act directly to stimulate prostaglandin release in the placenta or uterus in this species. During the 6-24 h before birth of the first pup, behavior changes typically include seeking of seclusion, digging, scratching at the floor, panting, anorexia, vomiting, and shivering. A potentially copious green mucoid vaginal discharge before, during and after parturition, is normal and includes normal hemoglobin metabolites, termed uteroverdin, from placental blood stores. The prepartum surge in prolactin is followed by somewhat reduced levels for 1-2 days before suckling induces re-elevation to near-maximal values. About 60% of pup births involve anterior presentations. Pups may be delivered within intact membranes or attached to ruptured membranes. Membranes and placenta are typically eaten by the bitch, and the umbilical cord thus severed-punctures of the puppy abdomen and cannibalism can occur. Vomiting of placental material is common. Intervals between pups is normally less than 30 min, but can vary from 15 min to several hours. A litter of 6 to 8 pups can require 4 to 18 hours. Dystocia may involve malposition requiring caesarian section, although manual assistance may suffice. In both species, uterine inertia is treated by administration of oxytocin and/or calcium gluconate at carefully monitored doses and rates. Elective caesarian delivery can be timed based on serum progesterone assay. Prophylactic administration of corticosteroid prepartum has not been reported.
Lactation and Neonatal Period.
Obvious mammary development usually occurs by Day 45, and obvious milk secretion normally begins at or after parturition. However, instances of delayed mammary enlargement or of early milk secretion can occur. Suckling induces prolactin elevations to values similar to those of late pregnancy during peak lactation, and to progressively lower levels later in lactation. Prolactin is required for normal lactation; its suppression by dopamine agonists inhibits lactation. Oxytocin released in response to suckling has been measured. Lactation lasts about 6 weeks, with the dam encouraging weaning beginning about week 5. Neonatal deaths are not uncommon for both pet and laboratory dogs. A moderate to severe transient metabolic acidosis occurs in pups during parturition in normal births. Consequences of acidosis and compromised respiration have not been evaluated. Average neonatal mortalities reported range from 15 to 25%. Causes include respiratory distress following dystocia, and bacterial infection. Puppy fading syndrome is recognized. The contributing factors are not known, but may include hypothermia when e bitches do not retrieve wandering pups, unrecognized infection, congenital abnormalities, and even failure to suckle competitively..
Post-Partum Anestrus, and Interestrus Intervals
Hematocrit returns to near normal by 40 to 90 days post partum. Anestrus typically last 2 to 8 months after parturition, with interestrus intervals being similar to those in nonpregnant cycles. Altered hypothalamic dopaminergic activity and reduced prolactin secretion may play a role in the increased LH pulsatile secretion that initiates proestrus at the end of anestrus.
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Patrick W. Concannon, MS, PhD, Dipl. Am. College of Theriogenology (Hon)