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BOR - Papers in Press, published online ahead of print October 23, 2002.
Biol Reprod 2002, 10.1095/biolreprod.102.005900
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BIOLOGY OF REPRODUCTION 68, 536–542 (2003)
DOI: 10.1095/biolreprod.102.005900
© 2003 by the Society for the Study of Reproduction, Inc.

Pregnancy

Cervical Dilatation Related to Uterine Electromyographic Activity and Endocrinological Changes During Prostaglandin F2{alpha}-Induced Parturition in Cows

V.N.A. Breeveld-Dwarkasing1,a, P.C. Struijkb, F.K. Lotgeringb, F. Eijskootb, H. Kindahlc, G.C. van der Weijdena, and M.A.M. Tavernea

a Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands b Department of Obstetrics and Gynaecology, Erasmus University, Rotterdam, The Netherlands c Department of Obstetrics and Gynaecology, Swedish University of Agricultural Sciences, Uppsala, Sweden


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The temporal relationship between changes in cervical dilatation, uterine electromyographic (EMG) activity, and maternal plasma concentrations of estradiol 17ß (E2), progesterone (P4), and 13,14-dihydro-15-keto-prostaglandin-F2{alpha} (PGFM), was investigated in six parturient cows. Calving was induced with a single injection of a synthetic analogue of prostaglandin F2{alpha} (PG) on Day 274 of gestation. Cervical dilatation was measured continuously by measuring the transit time between two implanted ultrasound crystals while at the same time uterine EMG activity was measured through two silver electrodes sutured on the myometrial surface until the expulsive stage of calving had been reached. In blood samples collected at 4-h intervals, starting at the moment of PG injection, the mean plasma E2 concentration gradually increased and was significantly elevated at 28 h after PG injection. At 4 h after PG treatment, the mean P4 concentration had dropped significantly and continued to decrease until a value of around 1 ng/ml was reached, where it stayed until the onset of expulsion. Mean plasma PGFM concentrations increased steadily after PG injection, reaching significantly elevated concentrations at 20 h after treatment. In the five cows that delivered calves in anterior positions, uterine EMG activity, expressed as root mean square (RMS in µV), started to increase at a mean interval (± SD) of 13.1 ± 3.7 h following PG treatment. The increase in EMG activity was significantly correlated with changes in plasma PGFM concentrations. In these cows, dilatation of the caudal cervix started after a mean (± SD) interval of 28.5 ± 1.5 h following PG treatment and dilatation progressed at a mean (± SD) rate of 2.25 ± 0.24 cm/h. In one cow with a calf in the posterior position, uterine EMG activity and dilatation started at 15.8 h and 31.8 h, respectively, after induction of calving. We conclude that a predictable sequence of physiological changes occurs around induction of calving, which allows specific timing of future studies on cellular and biochemical changes within the cervix during parturition.

cervix, female reproductive tract, parturition, steroid hormones, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Our understanding of the mechanisms involved in cervical ripening and dilatation has been hampered by the lack of studies in which the onset of labor has been well defined with respect to simultaneous changes in uterine activity and plasma hormone concentrations. Most clinical studies on the relation between uterine activity and cervical dilatation in women may have been flawed because they depended on an arbitrary starting point [1–4] (i.e., the time of admittance, patient recall of the start of uterine contractions, or both). Consequently, the latent phase of cervical dilatation; that is, the stage of parturition in which there is no appreciable dilatation [3], could not be accurately defined in these women. As a result, the acceleration point at which dilatation starts to speed up [1–3, 5] could not be accurately determined. In one report, serial blood sampling was performed in an attempt to describe the temporal relationship between cervical dilatation, uterine activity, and hormonal changes in women [6]. Unfortunately, this report may have been biased because it was based on digital, and thereby subjective, measurements of cervical diameter that were repeated at various intervals in the women who were studied. It has been claimed that the use of digital measurements may cause artifacts in the partograms of women that could lead to falsely assumed phases during cervical dilatation [3, 7], including the deceleration phase proposed for women by Friedman [1, 2], during which the cervix is still dilating but at a considerably slower rate. Attempts to combine measurements of uterine activity with cervical dilatation have been made only in women [3–8] and cows [9–11]. Similar to the studies in women, the two studies of spontaneous calvings in cows [9, 10] did not adequately define the beginning of parturition.

Dilatation of the cervix depends on the resistance caused by the viscoelastic properties of the cervix on the one hand and the force induced by uterine contractions on the other hand. Softening of the cervix is an important prerequisite for cervical dilatation. Recent studies in rats suggest that both cervical resistance and collagen concentration within the cervix start to diminish slowly by the end of the second trimester and reach a nadir at the two-thirds point of the third trimester [12]. During labor additional structural changes may take place before the onset of dilatation. It has been shown that cervical dilatation is more closely related to the concentration of collagenolytic enzymes in cervical tissue than to the duration of labor per se [13]. This implies that local changes in the cervix that are unrelated to uterine activity may play a role in dilatation during labor [13]. In fact, cervical effacement in parturient sheep takes place independent of uterine contractility or pressure when the uterus is surgically separated from the cervix [14] or when uterine activity is suppressed with ß2 mimetics [15]. Nonetheless, cervical dilatation does not occur without uterine activity. According to Lindgren [16], the speed of dilatation depends on the frequency and strength of the uterine contractions, whereas the head-to-cervix pressure may serve as an expression of the tissue resistance of the cervix against the intra-amniotic fluid pressure changes during uterine contractions. In addition, van Dessel et al. [3] claim that more contraction work (i.e., the sum of all active pressure areas over 1 cm of cervical dilatation) is needed for cervical dilatation before than after the acceleration point, which implies that, even during parturition, changes take place in the cervix that influence its resistance against uterine contractions. The observation that the relationship between intra-uterine pressure and head-to-cervix force varied widely between women, whereas a close correlation between the two variables did not consistently result in faster dilatation [17], indicates that the relationship between the uterine contractile force and cervical dilatation is not a simple one. In ruminants in which the pregnant uterus does not rest upon the pelvic floor, the mechanics of cervical dilatation can be expected to be different than those in women.

Over the years, several instruments have been designed to continuously measure cervical dilatation [18, 19], but they have not been used in combination with electromyographic (EMG) recordings of uterine activity and serial blood sampling, probably because of ethical restrictions (in women) and anatomical restrictions (in small laboratory animals) in the species that were under study. The objective of the present study was to design an experimental model that would allow us to investigate the temporal relationship between changes in cervical dilatation, uterine EMG activity, and endocrinological changes in cows. To this end, a previously described method of ultrasound cervimetry [11] was combined with recordings of uterine EMG activity and measurements of maternal plasma hormone concentrations in term pregnant cows during prostaglandin F2{alpha} (PG)-induced parturition at term.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Surgery

Six multiparous Holstein Friesian cows with singleton pregnancies were used in this experiment. During the experimental period the cows were housed in individual stands and subjected to a normal daylight cycle. Food and water were given ad libitum according to the feeding standards of dry cows. The protocol was approved by the Animal Research Committee of the Faculty of Veterinary Medicine of Utrecht University. After a 48 h fast and 24 h of water deprivation, surgery was performed under general anesthesia at least 10 days before the induction of parturition, as previously described [20]. In short, with the cow in a dorsal recumbent position, a midventral laparotomy was performed during which two bipolar silver electrodes were sutured approximately 30 cm apart on the surface of the pregnant uterine horn. Two electrodes were placed to ensure that at least one recording of good quality could be obtained. Subsequently, the cow was turned to the right lateral position for cathetherization of the left circumflex artery. The wires and catheter were tunneled s.c. to the dorsal area of the sublumbar fossa, wrapped in alcohol-soaked gauze pads, and kept in a plastic bag until experimentation. Ampicillin (12 mg/kg body weight; Praxavet Ampi-15, Boehringer-Ingelheim, Alkmaar, The Netherlands) was given i.m. once a day during the first 5 days following surgery.

Experimental Protocol

Starting at Day 270 of gestation, daily blood samples were collected between 0800 and 1000 h in heparinized tubes for later analysis of maternal plasma concentrations of progesterone (P4) and estradiol-17ß (E2). On Day 274 of gestation, two ultrasound transducers, a transmitter and a receiver, were sutured on the vaginal cervical rim as previously described in detail [11]. The change in transit time of the ultrasound signal was used to measure the distance between the transducers. Calibration in water was used to check the linearity of the recorded distance and the distance between the transducers.

Simultaneous, continuous, and uninterrupted recordings of cervical dilatation and uterine EMG activity were started between 1200 and 1400 h, approximately an hour after the ultrasound transducers had been inserted, and the cow had received 7.5 mg Luprostiol i.m. (Prosolvin; Intervet, Boxmeer, The Netherlands). A cervimeter as described earlier [11] was used to measure cervical dilatation. A universal amplifier (model 13-4615-56; Gould Inc., Cleveland, OH) was used to measure uterine EMG activity; the bandpass filter was set between 1 and 10 Hz. A sampling rate of 40 Hz was used to continuously acquire and display the multichannel data (Labview 5.0; National Instruments, Dublin, Ireland) and the digitalized signals were stored on a personal computer. From the moment of PG treatment (T0) onward, arterial blood samples were collected every 4 h through an extension of the catheter that was placed in the left circumflex artery and into heparinized tubes for later analysis of maternal plasma concentrations of E2, P4, and PGFM. During the measurements, the cows remained undisturbed in an individual pen of 4 x 2 m with free access to food and water. Recordings took place in an adjacent room while the cow was observed via a television camera. At the onset of the expulsive stage, when the amniotic sac had become visible outside the vulva, recordings were discontinued and the ultrasound transducers were removed from the dilated cervix to prevent damage during expulsion of the calf.

Hormone Analysis

P4 concentrations were measured by a validated, direct, solid phase 125I RIA as previously described [21]. The sensitivity of the assay was 47 pg/ml; the interassay coefficient of variation (CV) was 11% (n = 16), and the intraassay CV was 7.5% (n = 20). E2 concentrations were measured by RIA as previously described [22] following double diethylether extraction. The sensitivity of the assay was 32 pg/ml and the interassay and intraassay CVs were both 9% (n = 20). PGFM concentrations were measured by homologous double antibody RIA as previously described [23]. The sensitivity of the method was 30 pmol/L, the interassay CV was 14% and the intraassay CV ranged between 6.6% and 11.7% for the different ranges of the standard curve.

Data Analysis and Statistical Analysis

The data were analyzed with INSTAT software (1990; Graph Pad Software, San Diego, CA) and are presented as means ± SEM. The blood samples obtained the morning of Day 274 were designated as control values prior to PG treatment. The plasma hormone concentrations and E2:P4 ratios were analyzed for the effect of time both before and after treatment using a repeated measures ANOVA (RM-ANOVA) having assured a Gaussian distribution. If a significant effect of time was present, post hoc analysis was performed by comparing mean values with pretreatment controls using the Dunnett test. A P value < 0.05 was taken as significant.

Cervical Dilatation

The data were analyzed with SPSS software (1997, Chicago, IL). For each cow, the mean dilatation (in centimeters) within each hour following PG treatment was calculated and the values were plotted relative to T0. Because we were primarily interested in the onset and speed of cervical dilatation, we used nonlinear regression (NLR) analysis to identify the point of transition from the latent phase with no appreciable increase in cervical diameter into the dilatation phase. The following model was used:

If time <T1, then the predicted value (of dilatation at a given time during latent phase) = S1 x (time - T1) + Y1.
If time >=T1, then the predicted value (of dilatation at a given time during dilatation phase) = S2 x (time - T1) + Y1.
T1 represents the transition point of the latent phase into the dilatation phase (the onset of dilatation) in hours after T0 (PG treatment), Y1 is the average cervical dilatation (in centimeters) during the latent phase, and S1 is the rate of dilatation (cm/h) during the latent phase. S2 is the rate of dilatation during the dilatation phase. It was assumed that cervical dilatation progressed in a linear fashion until maximum dilatation was reached; the deceleration phase, if present, was not included in the calculation.

From the results obtained for individual cows the overall mean interval (± SD) from PG treatment to the onset of cervical dilatation was calculated, as well as the overall, mean (± SD) dilatation rate. A mean dilatation curve from the values obtained for the individual cows was plotted as the mean dilatation per hour (± SEM) relative to T0. A maximum follower procedure as previously described [11] was used to find the absolute maximum diameter of the cervix that was reached before the transducers had been removed from the cervix.

Uterine EMG Activity in Relation to Cervical Dilatation and PGFM Concentrations

For each of the two EMG electrodes, RMS values were calculated for each hour after PG injection. Because the onset of electrical uterine activity was unrelated to the position of the electrode, the data from the two electrodes were pooled for cows 1, 2, 4, and 5 before they were further analyzed together with the data of the other two cows in which only one of the two electrodes functioned properly. The nonlinear regression model that was used to determine the transition point of cervical dilatation was also used to find the transition point between the phase of almost complete uterine quiescence that is associated with PG-induced luteolysis [24] and the onset of uterine activity, with the following adaptations:

If time <T1e, then the predicted value (of EMG activity at any given time during quiescence) = S1e x (time - T1e) + Y1e.
If time >=T1e, then the predicted value (of EMG activity at any given time during increasing activity) = S2e x (time - T1e) + Y1e.
T1e is the transition point for electrical activity in hours after T0, Y1e is the mean RMS value (µV), and S1e is the electrical activity rate (slope, µV/h) during the phase of relative uterine quiescence. During this period, occasional spikes of electrical activity may be registered but there are no contractures. In addition, there was no increase in the frequency of these spikes. Therefore, it was assumed that the slope (S1e) was zero. S2e is the electrical activity rate during the phase of uterine activity. The first 4 h of EMG recordings were not included in the analysis because immediately after PG injection a period of 1–2 h increase in uterine activity may follow [24, 25]. The interval between the transition points of uterine electrical activity and cervical dilatation was calculated for each individual cow, from which the overall mean (± SD) was calculated. A mean curve for electrical activity was constructed from the values obtained for the individual cows by plotting the mean RMS values per hour (± SEM) relative to T0.

Mean PGFM concentrations were also plotted and analyzed to determine an effect of time with RM-ANOVA followed by the Dunnett test to compare mean values against T0 as a control value. The Pearson correlation test was used to study the relation between uterine electrical activity, cervical dilatation, and PGFM concentrations. A P value < 0.05 was taken as significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Outcome of Calvings

All six cows had normal vaginal deliveries. Five cows delivered their calves in an anterior presentation between 35.3 and 41.2 h after PG treatment (mean, 37.7 ± 2.5 h after PG), whereas one cow delivered a calf in a posterior presentation 52.9 h after the injection. Recordings were discontinued at the onset of the expulsive stage, between 33.6 and 40.4 h after PG treatment in the five cows with anterior presentations (mean, 36.9 ± 2.8 h after PG) and 51.9 h after PG treatment in the cow with the posterior presentation.

Maternal E2 and P4 Concentrations, and E2:P4 Ratio

Mean hormone concentrations were calculated only up until 32 h after PG treatment because from the next sampling moment (36 h after PG) on, one or more of the cows had already calved.

Plasma E2 concentrations before PG treatment showed a significant effect of time (P < 0.0007). At Days 270 and 271 (186 ± 31 pg/ml and 217 ± 38 pg/ml, respectively) they were significantly lower (P < 0.01 and P < 0.05, respectively) than controls at Day 274 (308 ± 53 pg/ml). After PG treatment, E2 concentrations further increased with a significant time effect (P < 0.001) and were higher than those of the control (P < 0.01) from 28 h (486 ± 80 pg/ml) onward (Fig. 1A). The P4 concentrations gradually decreased in the period before PG treatment from 5.7 ± 0.4 ng/ml to 4.9 ± 0.5 ng/ml, but there was no significant effect of time. A significant effect of time on P4 concentrations was present in the period after PG treatment (P < 0.0001). Within the first 4 h after PG treatment, P4 concentrations had dropped significantly (1.6 ± 0.1 ng/ml, P < 0.01) compared to that of the control on Day 274, and thereafter they decreased slowly and gradually until a new steady state of around 1 ng/ml was reached (Fig. 1B). With the ratios being significantly lower at Days 270 and 271 (0.04 ± 0.01 and 0.04 ± 0.02, respectively, P < 0.05) than the control values (0.06 ± 0.01), there was a significant effect of time on the E2:P4 ratio (P < 0.0007) in the period before PG treatment. There was also a significant time effect in the period after PG treatment (P < 0.0001) and from 4 h (0.22 ± 0.03) until 32 h (0.41 ± 0.09) after PG injection, the E2:P4 ratios were significantly higher than the control value at Day 274 (P < 0.01, Fig. 1C).



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  		FIG. 1. Maternal plasma concentrations of E2 (A), P4 (B), and the E2:P4 ratio (C) as a function of gestational age (days) and after injection of 7.5 mg Luprostiol, a synthetic PGF2{alpha}. Mean values (± SEM) are presented. The significance of time effect (RM-ANOVA) in the before-treatment and after-treatment periods is indicated in the figures. n.s., Not significant. Asterisks indicate significant differences compared to the before-treatment control at Day 274 (Dunnett test; *P < 0.05, **P < 0.01)

Cervical Dilatation

The presentation of the calf clearly influenced the characteristics of the dilatation curves (Fig. 2). Therefore, the cow with posterior presentation was excluded from the calculation of the mean cervimetry data. For reasons of comparison, however, the data obtained from this single cow will be mentioned in the text. The maximal diameter of the caudal cervix that had ever been reached before the transducers were removed from the caudal cervix varied between 11.4 and 20.2 cm in the cows with anterior presentations and was 15.5 cm in the cow with the posterior presentation. Figure 2 shows the dilatation curves based on the mean dilatation per hour for each cow. The mean dilatation rate of the latent phase was close to zero (0.014 ± 0.012 cm/h for the cows with calves in anterior presentations and 0.006 cm/h for the cow with a calf in the posterior presentation). The point at which the dilatation phase started was calculated at 28.5 ± 1.5 h after PG injection. After this point, the dilatation increased almost linearly at a rate of 2.25 ± 0.24 cm/h. The time from the onset of dilatation to the expulsion of the calf was 9.3 ± 2.1 h. In the case of the posterior presentation calf, dilatation started at 31.8 h with a dilatation rate of 1.57 cm/h, a plateau was reached at 40.9 h, and the calf was born 12.1 h later. Data for individual cows are shown in Table 1.



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  		FIG. 2. Dilatation curves: mean dilatation per hour as a function of time (in hours) after PG injection. The straight lines represent the cows with a calf in the anterior position. The broken line represents the dilatation curve of the cow that delivered a calf in a posterior presentation


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  		TABLE 1. Onset of increase in uterine activity and cervical dilation (hours after PG injection) and the dilatation rates (cm/h)

Uterine EMG Activity in Relation to Cervical Dilatation and PGFM Levels

Five of the 6 cows showed a period of increased uterine activity immediately after PG treatment that lasted <=4 h. Thereafter, all cows showed a period of almost complete myometrial quiescence during which the caudal cervical diameter could temporarily increase from approximately 1–1.5 cm independent of uterine activity. During the latent phase of cervical dilatation uterine EMG activity gradually increased, and some hours later the cervical diameter began to respond to uterine contractions (Fig. 3A). However, the excursions in cervical diameter were rather small and not always synchronous with uterine contractions. During the dilatation phase, uterine activity increased even more, whereas cervical reactions became more synchronized with uterine EMG activity, showing larger excursions of the diameter during uterine contractions (Fig. 3B). Uterine activity expressed as RMS values started to increase 13.1 ± 3.7 h after PG treatment. In the cow with posterior presentation, RMS values started to increase at 15.8 h after PG treatment (Table 1). The mean interval between the onset of uterine activity and the onset of cervical dilatation was 15.3 ± 2.7 h. Figure 4 illustrates the relationship between mean PGFM concentrations, mean uterine activity per hour, and mean cervical dilatation per hour for the cows with a calf in anterior position. Plasma PGFM concentrations started to increase gradually from 8 h after PG treatment onward, there was a significant time effect (P < 0.0001), and at 20 h after PG treatment onward they were significantly higher (325 ± 17 pg/ml, P < 0.01) than at T0 (115 ± 18 pg/ml, Fig. 4). The PGFM concentrations also showed a significant correlation to uterine EMG activity from T0 until 32 h after PG treatment (R = 0.97, P < 0.01). However, no relation was found between the rate of increase in uterine activity and the rate of dilatation (data not shown).



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  		FIG. 3. Examples of synchronous recording of cervical dilatation and EMG taken from cow 2. A) Shortly after the onset of the dilatation phase (29.0–29.5 h after PG): high intensity, short-term electrical bursts, occurring frequently on which the cervix begins to react. B) During the dilatation phase (32.2–32.7 h after PG): increasing intensity of electrical bursts on which the already dilated cervix reacts more synchronously and with larger excursions



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  		FIG. 4. Plasma 15-keto-dihydro-PGF2{alpha} concentrations (n = 6) as a function of time (in hours) after PG injection, related to myometrial activity and expressed as root mean square values (RMS, n = 5) and to cervical dilatation in cm/h (n = 5). Values represent means ± SEM. Mean PGFM concentrations with asterisks are significantly higher than at 0 h after PG injection (**P < 0.01)


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results from this study demonstrate that in PG-induced calvings, a well-defined sequence of events takes place with respect to changes in the maternal plasma concentrations of E2, P4, and PGFM, and myometrial activation and dilatation of the caudal cervix. The interval between the increase in myometrial activity and the expulsion of calves in this experiment is in agreement with published data for spontaneous [26] and PG-induced calvings [25]. We found a progressive increase in plasma E2 concentrations and a progressive reduction in P4 concentrations toward term as has been earlier reported for spontaneous calving cows [27–31]. The significantly greater E2:P4 ratio at Day 274 compared with that at Day 270, and an additional significant increase of this ratio shortly after PG injection, is also in agreement with the findings of Fuchs et al. [32] for the plasma E2:P4 ratio of term pregnant and spontaneous calving cows. Therefore, we conclude that the cows used in the present study were very close to term before PG was injected to induce luteolysis. The rise in E2 concentrations that already started a few days before the induction of parturition may have played a role in the formation of gap junctions in the myometrium [33] and in this way may have prepared the myometrium for coordinated uterine activity. It may also have stimulated the synthesis of PGE2 receptors in the cervix during the last few days of pregnancy as has been reported for the baboon [34], thus sensitizing the cervix to PGE2. PGE2 may have stimulated the final functional changes in the cervix, including greater water content and changes in the content or composition of proteoglycans, shortly before or even during parturition, as has been found in several other species, including ruminants [35–39].

The classical description of cervical dilatation for women by Friedman [1, 2] includes a latent phase, an acceleration phase, a phase of maximum slope, and a deceleration phase and is often referred to in studies of cervical dilatation. In a previous study [11] we demonstrated that an acceleration phase and a deceleration phase are not always present during cervical dilatation in cows. A detailed study of Figure 2 reveals that dilatation in all cows started gradually before it progressed into the rapid dilatation phase, which is equivalent to an acceleration phase. Obviously, the outcome of cervimetry experiments are influenced by the method of analysis as illustrated by the fact that when the present data were analyzed, using a maximum follower procedure followed by a search for transition points, as we did previously [11], we found an acceleration phase in only two and a deceleration phase in only four of the six cases. Because in this study our main interest was to find the onset and rate of cervical dilatation, we chose to assess the point of intersection of the slope of the latent phase (S1) and the slope of the dilatation phase (S2) with a two-compartment model, assuming linear progression of cervical dilatation in both compartments. With the use of this model, we observed only a small variation in transition points of cervical dilatation and in dilatation rates in the five cows with anterior presentation.

The results of this study and our earlier results [11] demonstrate that differences in the presentation of fetal parts between anterior and posterior presentation of the calf have implications for the progress of parturition and on the mechanical part of cervical dilatation, which may influence the forms of the dilatation curves. In addition, the large variation in the maximal diameter that was found between animals that calved with anterior presentations may also be explained from small physiological variations in fetal part presentation at the beginning of the expulsion.

The temporary increase in myometrial activity shortly after PG injection as observed in five of the six cows has been reported earlier [24, 25]. This increase in activity is probably due to a direct effect of synthetic PGF2{alpha} on the myometrium, and not by uterine PGF2{alpha} production, because PGFM levels were not significantly elevated at that time. Injections of synthetic PGF2{alpha} have also been shown to induce greater myometrial activity, even in late-pregnant cows with progestagen-releasing ear implants [24]. Plasma PGFM concentrations, however, may not only reflect the PGF2{alpha} turnover. The enzyme 9-keto-prostaglandin E(2) reductase, which has been shown to convert PGE2 to PGF2{alpha} is present in bovine endometrium [40], and for rats it has been suggested that progesterone withdrawal during estrogen exposure stimulates the production of the enzyme [41]. Thus, it is possible that a greater production of PGE2 in the uterus and cervix after conversion to PGF2{alpha} has also contributed to the rise in maternal plasma PGFM concentrations.

We did not find a relation between the rate of increase in uterine activity and the rate of dilatation of the caudal cervix, which is in accordance with the observations by Almann et al. [17]. The absence of a linear relationship does not mean that uterine contractions are unnecessary for cervical dilatation. Rather, it suggests that the timing of the final structural changes in the cervical tissue during parturition plays a decisive role in the response of the cervix to uterine contractions. It has been postulated that the period of myometrial quiescence associated with prepartum luteolysis in cows is an important moment for the final biochemical and morphological preparation of the cervix and myometrium for labor [20, 24]. The duration of the time interval between the onset of uterine activity and dilatation of the caudal cervix as found in this study allows the cervix to undergo further structural changes while uterine activity increases in order to prepare for the phase in which it can give in to the forces induced by the contractions. Taking cervical biopsies during this time should reveal what these changes are and which factors are involved.

Nitric oxide (NO) might be one of the candidates that plays a role in the cervix during parturition. In rats, the concentrations of nitric oxide synthase and its mRNA in the cervix specifically increase between the initiation of parturition and the delivery of the first pup [42, 43]. NO may induce connective tissue changes through the stimulation of glycosaminoglycan synthesis, metalloproteinases, and PGE2 synthesis via cyclooxygenase II [13, 35, 36, 44], which may take place during the latent phase of cervical dilatation. In addition to its role in the regulation of structural changes in the connective tissue, it might be hypothesized that NO also induces relaxation of the cervical muscles during parturition such as might occur in the myometrial muscles during gestation. EMG activity has been observed in the cervix of several species during parturition [45–47] and combined measurements of cervical EMG and mechanical activity (by way of strain gauges) of the cervix indicate that an active muscle component is involved in the functional changes of the cervix during parturition in sheep [47]. The observations that cervical EMG activity in unripe cervices is significantly greater than in those of women in labor that were already ripened [45] in addition to the observation that electrical activity in the cervix reduces during softening [8] suggest progressive muscle relaxation during the final ripening stage of the cervix, in which NO may have a regulatory role.

Besides EMG activity, there are other indications that cervical muscles are active during the early stage of cervical dilatation. The temporary increases in cervical diameter in the absence of uterine electrical activity during the latent phase as observed in the present and previous study [11] may be postulated to reflect contractions of longitudinal muscles in the cervix that pull the vaginal cervical rim backward and open. The reductions in cervical dilatation that occur synchronously with uterine contractions as reported during the early stages of dilatation in women [4, 46] may than reflect contractions of the more circular oriented muscles of the cervix. These observations made by us and by others indicate that an active muscle component is present in the cervix during parturition, which may also be influenced by NO. The possibility of obtaining biopsy samples of the cervix during different, previously defined and identifiable periods of the parturient process as offered by this experimental model may lead to more insight in the regulation of structural changes and muscle activity in the parturient cervix.

Our study has demonstrated that three different episodes can be recognized in the temporal relationship between cervical dilatation and uterine EMG activity in parturient cows: 1) the period between luteolysis and the onset of uterine activity, 2) between the onset of uterine activity and cervical dilatation, and 3) the dilatation phase. This model provides a basis for future studies of structural changes in the cervix relative to the stage of labor as defined by objective physiological and endocrinological landmarks of parturition.


   ACKNOWLEDGMENTS
 
We thank Dr. A.C.S. Bajcsy (Department of Obstetrics and Reproduction, University of Veterinary Science, Budapest, Hungary), Ms. R. van Oord (Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University), and Ms. R. de Jong (veterinary student), for their assistance during the preparations of the experiment and data collection. We also thank Dr. S.J. Dieleman and Ms. T. Blankenstein (Department of Farm Animal Health) for performing the E2 and P4 assays and Dr. E. Mulder (Wilhelmina Children Hospital, Utrecht, The Netherlands) for help with the statistical analysis of the hormonal data.


   FOOTNOTES
 
1 Correspondence: V.N.A. Breeveld-Dwarkasing, Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 7, 3584 CL Utrecht, The Netherlands. FAX: 31 30 2521887; v.n.a.dwarkasing{at}vet.uu.nl Back

Received: 28 March 2002.

First decision: 25 April 2002.

Accepted: 22 August 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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