Primary Uterine Inertia in Four Labrador Bitches

Introduction

Uterine inertia, a failure of effective myometrial contractility, is reported as the cause for greater than 70% of all canine dystocias.¹ Uterine inertia is generally classified as primary or secondary; however, there does not appear to be a consensus on the precise definitions of either of these classifications. Feldman and Nelson (2004) define primary inertia as failure of sufficient uterine contractions to expel the conceptus when the bitch has a normal birth canal and normal sized fetuses (i.e., small enough to pass through the birth canal). Feldman and Nelson (2004) define secondary inertia as uterine fatigue resulting from a specific cause for dystocia such as fetal obstruction.² Linde-Forsberg and Eneroth (2005) define primary uterine inertia as the failure of the uterus to exhibit effective labor at full-term despite adequate uterine activity to initiate parturition, but insufficient to complete a normal birth of all fetuses, in the absence of an obstruction. Linde-Forsberg and Eneroth (2005) also state that secondary uterine inertia occurs when some fetuses are delivered but exhaustion of the uterine myometrium, caused by obstruction of the birth canal, prevents further delivery of the remaining fetuses. Linde-Forsberg and Eneroth (2005) further postulate that in very small litters (i.e., only one or two puppies) primary inertia occurs because the uterus fails to respond to fetal signals when insufficient to stimulate initiation of labor. Alternatively, Linde-Forsberg and Eneroth (2005) postulate that large litters, excessive fetal fluids, or oversized fetuses can promote overstretching of the myometrium causing primary inertia.³ Darvelid and Linde-Forsberg (1994) define primary complete inertia as gestation that has gone beyond its expected length with no signs of second stage labor noted.¹ It is likely that multiple definitions of primary and secondary uterine inertia exist because actual documentation of myometrial activity is difficult without tocodynamometry. Only by the proactive use of tocodynamometry (uterine monitoring equipment), started before first stage labor is anticipated, can the actual presence or absence of uterine myometrial contractions and their relative strength and frequency be evaluated.⁴

The first stage of labor begins with the onset of organized and progressively frequent and stronger myometrial contractions and ends when the cervix is fully dilated.² During normal stage I labor the myometrium has synchronous contractions. The first stage of labor typically lasts 6–12 hr (up to 36 hr in nervous primiparous bitches) and may be associated with the clinical signs of anorexia, restlessness, apprehension, panting, shivering, and, occasionally, vomiting.⁵ In a normal second stage of labor, the cervix is fully dilated and expulsion of the fetus occurs as a consequence of coordinated uterine myometrial and abdominal contractions.⁴ The third stage of labor results in the expulsion of the placenta.⁵

One hypothesis for the etiology of primary uterine inertia is an absence or incomplete progression of normal hormonal events leading to the initiation of labor. The precise mechanism by which parturition is triggered in the bitch is unclear; however, progesterone levels >2 ng/mL are associated with the maintenance of pregnancy. Progesterone suppresses myometrial activity and one potential cause of primary uterine inertia is a failure of adequate luteolysis at term resulting in persistently elevated progesterone levels.⁶ Failure of adequate luteolysis has been hypothesized to occur with very small litters. In this situation, fetal crowding does not occur, the resultant stress signal is not adequately generated, and the cascade of hormonal events leading to luteolysis and labor fails to occur. Small litter sizes can result from suboptimal husbandry (e.g., timing of breedings, use of a subfertile male), can be a familial trait, or can result from subfertility of the bitch.⁷ In this study, the author investigated four documented cases of primary uterine inertia to determine if failure of adequate luteolysis occurred.

Case Report

Medical and whelping records were reviewed for all bitches diagnosed with primary uterine inertia over a 2 yr period at an assistance dog breeding facility^a. All bitches were examined by a licensed staff veterinarian and deemed healthy and sound for breeding at the onset of proestrus. Pregnancy status was subsequently determined by abdominal ultrasound performed 30–35 days after the day of the luteinizing hormone (LH) surge as determined by ovulation timing (i.e., serial vaginal cytology and serum progesterone determinations). Bitches entered the whelping kennel 1 wk prior to their predicted whelping date (as determined by previous ovulation timing) for 24 hr monitoring by experienced kennel staff. Tocodynamometry and fetal heart rate monitoring were performed on bitches in the whelping kennel daily until the onset of the first stage labor. After the first stage of labor was noted, tocodynamometry was performed serially as clinically indicated during labor until delivery of all fetuses and placentas was completed. Tocodynamometry results were electronically transmitted to and immediately interpreted by a licensed human obstetrical nurse. Variations from either normal uterine activity or fetal heart rates prompted further clinical evaluation by a staff veterinarian at the breeding facility.

Information regarding signalment, parity, whelping histories, and neonatal survival was collected. Primary uterine inertia was defined as the failure of effective myometrial contractility (frequency and/or strength) to ever develop at term gestation that was detected and confirmed using tocodynamometry in bitches with no contributory factors identified (i.e., the bitches were stable and healthy). Term gestation was defined as 64–66 days from the initial rise in the progesterone concentration determined during ovulation timing indicating the LH surge. Prolonged gestation was defined as >67 days gestation.

Primary uterine inertia was diagnosed by documenting an absence of organized, progressive, and regular myometrial contractions at or beyond 64–66 days gestation as determined by periodic (q 4–12 hr based on status of labor) uterine monitoring using tocodynamometry. The uterine monitoring system consisted of a tocodynamometer (sensor), which detected changes in intrauterine and intra-amniotic pressures, a recorder, and a modem^b (Figure 1). The sensor was strapped directly to an area of skin on the caudolateral abdomen that had been shaved and uterine activity was monitored for 30–60 min (Figure 2). The recordings were then transmitted via the modem for evaluation and interpretation^c. Findings were relayed back to the attending veterinarian at the breeding facility by telephone. Fetal heart rates were monitored using a hand held Doppler^d. Obstetrical monitoring using tocodynamometry was routinely performed in all pregnant bitches in the facility at the beginning of the eighth week of gestation.

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Progesterone concentrations were evaluated in each dog from a serum sample obtained at the time of the diagnosis of primary uterine inertia (Table 1). Progesterone concentrations were determined by a chemiluminesence method validated for dogs by a commercial veterinary diagnostic laboratory^e.⁸

Table 1 Preoperative Progesterone Concentration in Bitches with Primary Uterine Inertia

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Approximately 100 bitches whelped annually at the breeding facility. All bitches were screened annually for Brucella canis. Ovulation timing was routinely performed on each bitch in the breeding kennel. The facility had a >95% conception rate after instituting ovulation timing (described below) that was performed by an experienced breeding technician. Specifically, vaginal cytology, vaginoscopy, and progesterone concentrations were used to determine and confirm ovulation, optimal dates for breeding, and predict gestational length. Vaginal cytology was initiated on the first day proestrus (detected based on vulvar swelling and discharge) and repeated and recorded every other day until day 1 of diestrus was determined (i.e., <50% superficial cells on cytology). Vaginoscopy was performed at the time of vaginal cytology until all of the breedings were completed. The degree of mucosal crenulation was recorded. All bitches were bred naturally 3 and 5 days after the initial rise in progesterone concentration. The initial rise (day 0) was defined as the day the progesterone concentration first reached 2.1–3.0 ng/mL. Progesterone concentrations were measured until they were >5.0 ng/mL to confirm ovulation and luteinization. Previous studies at the facility (unpublished) showed that progesterone concentrations of 2.1–3.0 ng/mL, which were all measured at a single commercial laboratory, correlated well with in-house LH testing using a commercial kit^f. The predicted whelping date was calculated as 65±1 day after the date of the initial rise in progesterone levels. Cesarean sections in this study were performed on or within 2 days following the last calculated due date (i.e., 66 days from the initial rise in progesterone level), upon discovery of fetal distress (bradycardia), or intractable uterine inertia that was not responsive to medical management. Fetal bradycardia was defined as a heart rate consistently <170 beats/min.

Medical management of dystocia, when instituted, consisted of the administration of 10% calcium gluconate^g (0.465 mEq/4.5 kg SC), followed by oxytocin^h (0.5–1.0 U.S.P. units/bitch SC) 15–30 min after the calcium gluconate. Tocodynamometry was subsequently performed to evaluate response to therapy. The SC administration of calcium gluconate has been reported to improve uterine contractility in bitches who are known to be eucalcemic.⁴ All four bitches in the colony determined to have primary uterine inertia were included in the study. Serum ionized calcium, PCV, TP, BUN, and blood glucose were normal in these four bitches at the time primary uterine inertia was diagnosed. Details regarding these four cases are provided here.

Discussion

Gestation length has been described in the canine as 58–72 days after a single breeding, 64–66 days after either the serum LH surge or after serum progesterone concentration reaches 1.0–1.9 ng/mL, 63–65 days after serum progesterone concentration reaches 2.0–3.9 mg/dL, 62–64 days after serum progesterone concentration reaches 4.0–10.0 ng/mL, and 57 days after the onset of cytologic diestrus.⁵ Variations in the length of canine gestation have been postulated to be due to breed or litter size differences.⁹ When defined as the period from mating to parturition, Okkens et al. (2001) report that gestation lasts from 58 to 65 days with a mean of 61.4 ± 1.5 days. This group also reports that duration of gestation was negatively correlated with litter size in the total population but not within each breed studied.¹⁰ In studies that measure length of gestation based on the time from the LH peak to parturition, the interval is much less variable ranging from 64 to 66 days and averaging 65.1 ± 0.1 days.¹¹ In this study, all due dates were calculated based on the date of the initial rise of progesterone (i.e., the day the progesterone concentration first reached 2.1–3.0 ng/mL) and therefore would be expected to be less variable. Calculating the expected whelping date based on measuring the LH surge (or initial progesterone rise correlating to the day of the LH surge) is the most accurate method. An accurate due date is important for early recognition and intervention in cases of primary uterine inertia. Without effective intervention, primary uterine inertia may contribute to fetal death secondary to prolonged gestation.⁵

Luteotrophic support is affected by antiprogestagen therapy. This may be the consequence of actions of the progesterone receptor antagonist at the hypothalamic-pituitary level.¹² Prostaglandin F_2α (PGF_2α) causes direct luteolysis and termination of pregnancy.¹³ The antiprogestagen, mifepristone, induces premature termination of pregnancy and decline of progesterone concentration to <1 ng/mL suggesting that luteal function in pregnant bitches is dependent on luteotrophic support blocked by antiprogestagen therapy.¹² The PGF_2α analog, cloprostenol, induced birth in near-term pregnant bitches.¹⁴

Progesterone plays a central role in the sequence of events leading to parturition. Progesterone withdrawal and the resulting increase in the estrogen-progesterone ratio has been postulated to be the major initiating factor of placental detachment, cervical dilation, and increased uterine contractility.¹⁵ In bovine endometrial tissue explants, one study reports that progesterone is capable of suppressing the ability of oxytocin to induce endometrial secretion of PGF_2α. This suppression is reportedly mediated through a direct interference between oxytocin and its own receptor.¹⁶ Levels of the PGF metabolite 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) increase in maternal plasma approximately 48 hr before parturition and continue to increase until parturition.¹⁷ Progesterone concentrations begin to fall 24 hr before onset of whelping and remain low after delivery.⁶ Progesterone withdrawal causes a further increase in PGF_2α, which completes luteolysis and provides a major portion of uterotonic activity leading to the expulsion of pups.¹⁷

During late pregnancy (>50 days) the pattern of uterine electrical activity is characterized by episodes of contractility lasting 3–10 min and recurring at a low frequency (1–2/hr). During the last 7 days of gestation there is a progressive qualitative change in uterine activity, which is correlated with a decrease in plasma progesterone concentration.⁶

Progesterone concentrations must fall below 2 ng/mL in order for parturition or medically induced abortion to occur.^18–20 In six dogs with plasma progesterone concentrations remaining between 4 and 12 ng/mL during the last week of pregnancy, five of the six failed to whelp.¹⁸ In dogs treated with the antigestagen RU 38486, endogenous progesterone levels remained unchanged (i.e., >2 ng/mL) and PGFM levels increased only slightly or not at all. Additionally, only one treated bitch showed signs of labor and all treated dogs required a cesarean section.²¹ The timing of antiprogestagen therapy (i.e., early, mid, or late in the luteal phase) may affect its activity at the hypothalamic-pituitary level. During early luteal development, antiprogestagen therapy is less likely to result in luteolysis. Progesterone levels decline after the death of fetuses. Falling concentrations of progesterone release the inhibitory effect on the myometrium allowing additional prostaglandin synthesis and release from the endometrium.¹⁵ Flunixin meglumine, a prostaglandin synthetase inhibitor, disrupted the normal PGFM profile and neither abolished prostaglandin synthesis completely nor delayed the onset of labor in treated animals.¹⁴ In another study, bitches treated with high doses of the prostaglandin synthetase inhibitor indomethacin maintained high progesterone and basal PGFM concentrations for 2–3 days later than controls and a cesarean was required to deliver the puppies.²²

Conclusion

It is clear that progesterone concentrations must decline in order for normal parturition to commence. This case study suggests that failure of luteolysis is not the only mechanism involved in prolonged gestation. Primary uterine inertia can occur even with appropriate term gestation luteolysis resulting in progesterone concentrations falling below 2.0 ng/mL.² This is in contrast to a single case report describing failure of luteolysis to be a cause of prolonged gestation in a bitch.²³ The presence of primary uterine inertia, defined in this paper as a lack of appropriate uterine contractions (ever) as determined by tocodynamometry, was not documented in that case report. Regardless of litter size, luteolysis occurred in each of the bitches described in this study diagnosed with primary inertia by tocodynomometry. One bitch (case 1) had evidence of placentitis associated with a nonviable fetus; the littermate was viable. Intrauterine pathology can initiate luteolysis; however, normal labor still did not commence in this bitch.

Uterine monitoring (tocodynamometry) must be performed to accurately diagnose primary uterine inertia and to differentiate primary from secondary uterine inertia. Tocodynamometry should be initiated well before term gestation to recognize the true onset of the first stage of labor by the presence of characteristic myometrial activity, or alternatively, the presence of primary uterine inertia. Other factors should be investigated to better define the etiology of primary uterine inertia in healthy bitches with normal clinical evaluation. Histopathology of the uterus in two of the bitches in this report failed to identify any particular abnormality associated with their primary inertia.