Objective
The purpose of this study was to investigate the effect of atosiban (Tractocile; Ferring, Limhamn, Sweden), an oxytocin receptor antagonist, on uterine electrical activity in women with preterm labor and to determine whether this information can assist in the prediction of preterm delivery.
Study Design
Uterine electrical activity was recorded prospectively in 21 women with preterm labor before and during treatment with Tractocile and, for purpose of comparison, in 4 pregnant women without uterine contractions to set the baseline of uterine electrical activity in a quiescent uterus. Uterine activity was recorded with a noninvasive, 9-channel recorder with an electromyography amplifier and a 3-dimensional position sensor with an automatic data analyzer. Uterine electrical activity was quantified by an electrical uterine monitor (EUM) and measured in microwatts per second (μW/s).
Results
The overall pre-Tractocile EUM index was 3.43 ± 0.58 μW/s, which was significantly higher than baseline uterine activity in women without preterm contractions (2.3 ± 0.11 μW/s; P = .001). During the administration of Tractocile, the EUM index gradually decreased in a relatively constant rate from 3.43 ± 0.58 μW/s to 2.56 ± 0.88 μW/s after 330 minutes of continuous therapy ( P < .001). The peak effect of Tractocile was observed 4 hours after the initiation of treatment and was followed by a relative plateau. Women with a latency of <7 days from treatment to delivery were characterized by a distinct EUM-pattern in response to Tractocile, compared with women with a latency of ≥7 days ( P < .001). A similar EUM-pattern after the administration of Tractocile was also observed for women who delivered at <37 weeks of gestation compared with the women who delivered at term.
Conclusion
Tractocile reduces uterine electrical activity in women with preterm labor. This information can provide more insight into the effects of tocolytic agents and to aid in the risk stratification of preterm delivery in women with preterm contractions.
Spontaneous preterm birth is the single most important cause of neonatal morbidity and death. One of the most commonly used interventions for women who are presumed to be at preterm labor is the administration of tocolysis. The newest class of tocolytic therapies is represented by atosiban (Tractocile; Ferring, Limhamn, Sweden), which is a specific oxytocin receptor antagonist and is the only drug specifically registered for this indication. Uterine activity and the response to tocolytic therapy are usually monitored by means of external tocodynamometry, which is limited by a lack of quantitative assessment of uterine contractions and by the provision of only a single measure of global (rather than topographic) uterine pressure. Indeed, external tocodynamometry has been shown to have a relatively low predictive accuracy for preterm delivery. All tocolytic agents, including Tractocile, are of limited proven efficacy in arresting preterm labor and delivery; no specific tocolytic drug is superior to placebo in reducing neonatal respiratory distress syndrome. The reason for this limited efficacy is unclear. Nevertheless, one of the measures that can provide more insight into the mechanism of action of these agents and the reasons for their limited efficacy is the analysis of their effects on uterine activity by alternative means.
Another mode of assessment of uterine activity is measuring electrical activity of the uterine muscle by methods of electromyography (EMG). Initially, this was assessed in animal models by means of invasive uterine EMG, followed by noninvasive EMG recordings from abdominal surface in humans. Several studies have attempted to correlate between term and preterm labor to uterine EMG, with limited success. However, although most traditional EMG devices use only 2 electrodes, new multichannel, noninvasive EMG devices have been introduced recently. Such devices provide not only a quantitative assessment but also a topographic characterization of uterine electrical activity. There are only minimal data available on multiple-electrode uterine EMG systems in animals and humans. However, limited data suggest that multichannel noninvasive uterine electrical activity measurements are as good as internal uterine pressure catheter in the monitoring of uterine activity and that it may be correlated to the risk of preterm labor.
Such an analysis may provide insight into the mechanism of action of tocolytic agents and may assist in the stratification of the risk of preterm delivery. Thus, we aimed to investigate the effect of Tractocile on uterine electrical activity in women with preterm labor by utilizing a novel EMG device and to determine whether this information can assist in the prediction of preterm delivery.
Materials and Methods
Study population
We conducted a prospective study of women who in preterm labor at a gestational age of 24 weeks to 33 weeks 6 days of gestation to the labor and delivery ward in single large tertiary university-affiliated medical center between May 2011 and March 2012 (study group). Preterm labor was defined as the presence of all of the following: (1) uterine contractions: at least 3 contractions in a 10-minute period as reflected by both subjective complaints and by an external tocodynamometer; (2) cervical dilation of ≥1 cm; (3) cervical effacement of ≥50%. Only women who were assigned for treatment with Tractocile were included in the study. Women who were administrated other tocolytic agents or women for whom no tocolysis was indicated, women with preterm premature rupture of membranes, women with cervical dilation of >3 cm, women with suspected placental abruption or chorioamnionitis, and women whose pregnancies were complicated by major fetal anomalies were excluded from the study.
To quantify baseline uterine electrical activity of a noncontracting, nonlabor, quiescent uterus, we also studied 4 women at gestational ages of 28-33 weeks of gestation without subjective or objective evidence of preterm contractions, cervical dilation, effacement, or shortening.
The uterine electrical activity of women who participated in the study was measured using an electrical uterine monitor device (EUM; Electro-Uterine-Monitor-100; OB-Tools Ltd, Migdal Haemek, Israel) before and throughout the administration of Tractocile.
The study was approved by the local institutional review board, and all women provided written informed consent before participating in the study.
Tractocile administration
Tractocile was administered continuously according to a previously published protocol. Briefly, it consists of a 6.75-mg bolus, followed by a first phase of a continuous infusion at a rate of 300 μg/minute over 3 hours. The second stage is a continuous infusion at a lower rate of 100 μg/minute for an additional 15-45 hours.
The EUM device
A novel EMG device, EUM-100, was used to measure the electrical uterine activity. The system is comprised of a multichannel surface EMG, a 3-dimensional position sensor, and a personal computer that provided data analysis and a graphic user interface. The EUM signals are acquired and amplified with the use of a proprietary isolated amplifier box that was based on modified modules (Teledyne A0401; Teledyne Inc, Thousand Oaks, CA). Each EUM channel has a fixed gain of 5000 100-dB common mode rejection, a first-order high-pass filter with a cutoff frequency 0.5 Hz, and a sixth-order antialiasing low-pass filter with a cutoff frequency of 2 KHz. The 9 channels were sampled at 5KHzby DT9804, a 16-bit analog-to-digital USB module (Data Translation, Marlboro, MA). Signals were further filtered to 1-1500 Hz with a a sixth-order digital Butterworth filter.
The surface EMG activity is acquired by 9 electrodes evenly placed on the patient’s abdomen and a tenth common ground electrode on the patient’s left thigh. The electrodes are placed at the level of the pubis, umbilicus, and the uterine fundus with the patient in a supine position. After placement of the electrodes, their exact locations are determined with a 3-dimensional position sensor (miniBird; Ascension Technology, Burlington, VT). If the patient changed position during the EUM monitoring, the relative position of electrodes does not change significantly because the spacing of the electrodes compensates for such movements. The measurement of electrical signals together with their physical location provides an accurate estimation of the uterine activity in the 3-dimensional space.
The electrical signal from the myometrium is recorded and processed with the use of a uterine contractility algorithm. Uterine electrical activity is quantified with the EUM index that was defined as the mean electrical activity of the uterine muscle over a period of 10 minutes and is measured in units of micro-Joule (microwatt per second [μW/s]) with an automatic data analyzer blinded to clinical outcome.
Measurement of uterine electrical activity
Women with preterm labor and for whom a treatment with Tractocile was indicated were given an explanation of the study and signed an informed consent. After demographic and obstetric histories were obtained, baseline uterine electrical activity was measured until the initiation of Tractocile treatment. The recording before Tractocile was administered did not delay the initiation of treatment because there is a preparation period of approximately 30 minutes during which an order is placed for the medication from the hospital’s pharmacy, because routinely Tractocile is not stored in the delivery ward.
After the initiation of Tractocile treatment, uterine electrical activity was recorded continuously throughout administration of Tractocile. EUM-100 recording was stopped when the patient was deemed by the attending physician to be eligible for transfer from the delivery ward to the admission ward because of arrested preterm labor. Alternatively, if the patient has progressed into active preterm labor, treatment with Tractocile was terminated. The decision to stop monitoring or to stop treatment was made only by the treating physician and not by the research team.
Uterine activity was recorded with the EUM-100, concurrently with an external tocodynamometer and electronic fetal heart rate monitoring. EUM data were not available to the treating physician or to the research team. All clinical decisions were solely based on the routinely used external tocodynamometer and other clinical signs and symptoms. Participation in the study did not affect the treatment of participants by any means.
Data collection and analysis
All participants were followed prospectively from the time of EUM recordings until delivery, and delivery outcome was recorded.
The operators of the EUM device and the treating physicians were blinded to the EUM data recordings. EUM data were analyzed by a third party data analyst who was blinded to the clinical data or the nature of the study only after the patient had delivered and had been discharged from the hospital.
We analyzed the effect of Tractocile on uterine electrical activity and compared it with the baseline uterine activity. We also analyzed these data for specific clinical subgroups according to parity, plurality, and gestational age at presentation. To determine whether EUM recordings are correlated to the risk of preterm delivery, we compared the EUM recordings between women who delivered prematurely and those who did not and between women for whom the latency period from presentation to delivery was ≤7 or >7 days.
Statistical analysis
Data analysis was done with the SPSS software (version 15.0; SPSS Inc, Chicago, IL). The Student t test was used to compare continuous variables between the groups; the chi-squared test was used for categoric variables. Differences were considered significant when the probability value was < .05. Comparison of uterine electrical activity between subgroups was performed by a comparison of the average EUM index in specified timeframes previously or during administration of Tractocile.
Results
Overall, 21 women with preterm labor received Tractocile during the study period (study group). The demographic and obstetric characteristics are presented in Table 1 . The mean gestational age at presentation was 30.4 weeks. Almost one-half of the women (47.6%) were nulliparous, and almost one-fifth of the cases (19.0%) involved twin pregnancies.
| Variable | Study group (n = 21) | Reference group (n = 4) | P value |
|---|---|---|---|
| Maternal age, y a | 30.5 ± 6.4 | 29.8 ± 5.5 | .8 |
| Nulliparity, n (%) | 10 (47.6) | 3 (75.0) | .3 |
| Twins, n (%) | 4 (19.0) | 0 | .3 |
| Diabetes mellitus, n | 0 | 0 | N/A |
| Hypertension, n | 0 | 0 | N/A |
| Body mass index, kg/m 2 a | 20.9 ± 2.67 | 22.1 ± 2 .2 | .4 |
| Gestational age at atosiban (Tractocile) administration, wk a | 30.4 ± 2.4 | N/A | N/A |
| <28, n (%) | 3 (14) | N/A | N/A |
| <30, n (%) | 6 (29) | N/A | N/A |
| <32, n (%) | 11 (52) | N/A | N/A |
| Cervical length at atosiban (Tractocile) administration, mm a | 16.6 ± 3.7 | N/A | N/A |
| Gestational age at delivery, wk a | 35.3 ± 3.9 | 39.5 ± 2.4 | .05 |
| ≤34, n (%) | 7 (33.3) | N/A | N/A |
| ≤37, n (%) | 14 (66.6) | N/A | N/A |
| >37, n (%) | 7 (33.3) | 4 (100) | N/A |
| Latency between presentation and delivery, d a | 33.3 ± 20.3 | N/A | N/A |
Uterine electrical activity was measured for an average of 37 ± 19 minutes (range, 20–80 minutes) before Tractocile administration and for an average of 261 ± 107 minutes (range, 30–360 minutes) during the administration of Tractocile. Only 1 participant requested to terminate EUM recordings prematurely after 30 minutes of recorded data.
To determine the basal uterine muscle activity, for a noncontracting, nonlabor, quiescent patient, we also recorded EUM data in a group of women at <34 weeks of gestation without evidence of preterm contractions (reference group). The duration of EUM recording in this reference group was 105 ± 36 minutes (range, 50–150 minutes).
EUM index before Tractocile treatment
The overall EUM index before Tractocile was administered was 3.43 ± 0.58 μW/s, which was significantly higher than that observed in the reference group of women without preterm contractions (2.3 ± 0.11 μW/s; P = .001; Figure 1 ).
For women in the study group, there were no differences in the EUM index before Tractocile between singletons vs twins (3.32 ± 0.55 vs 3.87 ± 0.54 μW/s; P = .1), nulliparous vs multiparous women (3.4 ± 0.62 vs 3.4 ± 0.62 μW/s; P = .9), normal weight vs overweight women (3.59 ± 0.52 vs 3.08 ± 0.59 μW/s), or those who were at <30 or >30 weeks of gestation (3.45 ±0.65 vs 3.41 ± 0.56 μW/s, respectively; P = .9).
EUM index during Tractocile treatment
During the administration of Tractocile, the EUM index gradually decreased from 3.43 0.58 to 2.56 ± 0.88 μW/s after 330 minutes of continuous therapy ( P < .001; Figure 2 ). The rate of decrease in the EUM index was relatively constant and was represented most accurately by a linear regression equation ( r = 0.0172 μW/s/min; Figure 2 ).
We also analyzed the decrease in EUM index as percent of before Tractocile activity ( Figure 3 ). The EUM index after 1, 2, 3, 4, 5 and 6 hours after the initiation of Tractocile decreased by –8.2% ± 8.5% ( P = .34), –11.1% ± 8.6% ( P = .009), –11.9% ± 9.9% ( P = .02), –18.7% ± 10.6% ( P = .004), –16.0% ± 10.4% ( P = .011), and –15.1% ± 10.1% ( P = .046), respectively. The peak effect of Tractocile was observed 4 hours after the initiation of treatment and was followed by a relative plateau ( Figure 3 ).
