A prospective randomized clinical trial comparing two oxytocin induction protocols Peter R. Muller, MD, Thomas M. Stubbs, MD, and Sherry L. Laurent, PhD Charlotte, N orth Carolina OBJECTIVE: Our objective was to compare the safety and efficacy of two accepted oxytocin induction protocols that differ in oxytocin dose increments. STUDY DESIGN: At the Carolinas Medical Center in Charlotte, North Carolina, 151 women with indications for induction of labor were prospectively randomized into one of two oxytocin induction protocols. Safety and efficacy of the two protocols were analyzed with two-tailed t tests and x2 • RESULTS: Time from induction to establishment of a regular labor pattern was significantly shorter in the experimental group compared with the traditional group (p = 0.03) . However, no significant difference was seen from onset of induction to time of delivery. Incidences of hyperstimulation were not significantly different between the two protocols , but there was a trend toward a higher incidence of fetal heart rate changes in the experimental group (p = 0.08). CONCLUSION: These data suggest that induction with larger dose increments will shorten time to adequate labor without an associated increase in uterine hyperstimulation or poor neonatal outcome . The differences in heart rate changes are concerning and merit further investigation . If confirmed by further studies, an increased risk of cord compression could outweigh the benefit of a faster onset of contractions . (AM J OeSTET GVNECOL 1992;167:373-81 .)
Key words: Ox ytocin , labor Since Theobald et al. I first de scribed the use of continuous intravenous oxytocin in 1948, multiple protocols have been advocated by various authors for the use of oxytocin in the induction of labor. These oxytocin induction protocols var y in the initial dose, the time interval between dose increases, and the size of the dose increase. Seitchik et al." demonstrated in vivo that oxytocin concentrations reach steady state after 30 to 40 minutes. This finding has led to the formation of oxytocin induction protocols with int erval increases of ~30 minute s," including the protocol listed by The American College of Obstetricians and Gynecologists (ACOG) Technical Bulletin No. 110." The Uni versity of Texas Health Science Center in San Antonio presented a similar time interval between increases of continuous ox ytocin, but it varied from the ACOG protocol by its larger rate increments." The question arises as to whether the se lar ger rate increments, which obtain higher ox ytocin dosages sooner, may shorten the time from in-
Fromthe Department of Obstetrics and Gynecology, CarolinasMedical Center. Presented as Invited Guestat the Fifty{ourth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Palm Beach, Florida, January 26-29, 1992. Reprint requests: Thomas M. Stubbs, MD, Department of Obstetrics and Gynecology, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232. 6/6/38061
duction to labor and delivery without increasing the risk to the fetus . The purpose of our study was to compare two oxytocin induction protocols: the one listed by ACOG and one similar to that presented by the University of Texas Health Science Center in San Antonio. Safety and efficacy were assessed for each protocol by comparing hyperstimulation, fetal distress, time from induction to labor, and time from induction to delivery. Material and methods This randomized, prospective study was performed at the Carolinas Medical Center after the approval of the Institutional Review Board of the medical center. A total of 151 patients with indication for induction of labor consented to participate in the study and were randomized to one of the two induction protocols described below. Randomization was performed only after the patient agreed to be in this clinical trial and was by computer-generated random assignment with sealed, opaque envelopes. Clinical management was by house officers with immediate inhouse consultation available at all times . Inclusion criteria were a gestational age of 37 to 42 weeks, cephalic presentation, an adequate pelvis by clinical pelvimetry, no more than one prior lower segment cesarean section, and premature rupture of membranes with patient not in labor. Patients not in labor who received prostaglandin gels for cervical ripening
373
374 Muller, Stubbs, and Laurent
were randomized after receiving the gels. Labor was defined as regular contractions with evidence of cervical change (dilatation or effacement)." Excluded from the study were women with an abnormal presentation, abruptio placentae, placenta previa, previous vertical cesarean section, unknown uterine scar, previous myotomy, twins, polyhydramnios, active genital herpes, magnesium sulfate therapy, estimated fetal weight ~4500 gm , nonreassuring fetal testing results, and regular uterine contractions (patients already contracting were considered augmentation of labor). A total of 76 patients were randomized to the traditional protocol, which was modeled after ACOG Technical Bulletin No. 1106 and which is currently used at our center. This will be referred to as the traditional protocol. Oxytocin was started at I to 2 m U / min and was gradually increased in dose increments of 1 to 2 mU /min at 30-minute intervals as needed. The rate was increased as needed according to the judgment of the nurses and physicians at the bedside. A total of 75 patients were randomized to the experimental protocol , a protocol similar to that described by Blanco and Finley.' This will be referred to as the experimental protocol. Oxytocin was started at 1 to 2 m U / min, and each new oxytocin rate was doubled from the preexisting rate (for example, 1,2,4,8,16 mU /min). An interval of 40 minutes between increases was used. After a level of 8 mU/min was reached, less than doubling the rate was acceptable if progression to hyperstimulation was feared (for example, 8, 10, 12 mU/min). For both protocols 20 IU of synthetic oxytocin (Lyphomed, Fujisawa USA , Deerfield, 111.) was mixed in 1 L 5% dextrose in lactated Ringers' solution and delivered by a secondary intravenous line . Oxytocin infusion rate was controlled by continuous electronic infusion pump. Continuous electronic fetal heart rate (FHR) and contraction monitoring were performed in all patients. Amniotomy was performed and an intrauterine pressure catheter was placed by the supervising physician when clinically indicated. Oxytocin was decreased for hyperstimulation, defined as five or more contractions in 10 minutes, contraction duration > 90 seconds , or baseline uterine tone of 25 mm Hg. Ox ytocin was temporarily discontinued for nonreassuring fetal heart rate changes, which included severe variable decelerations, re current late decelerations, prolonged decelerations, or loss of beat-to-beat variability. After 8 to 10 hours of ox ytocin, if the membranes were intact and the cervix was still unfavorable, ox ytocin was discontinued and the patient was scheduled for a second or third day of induction to be performed the following day. A Bishop score was documented at the beginning of each induction day." Epidural anesthesia was not withheld from patients participating in this study. The same group of house
August 1992 Am J Obstet Gynecol
officers used the same continuous-infusion , lumbar epi dural technique for patients in both protocols. Assisted vaginal deliveries were done onl y for clinical indication. Patient demographics, such as age, race, gravidity, parity, and gestational age and clinical criteria (indication for induction, Bishop score, membrane status, cervical dilatation, prostaglandin gels application) were obtained from each patient on admission to the study. Obstetric outcome (number of days for induction , method of delivery, complications associated with delivery) and neonatal outcome (Apgar scores and cord pH) were recorded at completion of induction. Type and frequency of hyperstimulation episodes and FHR patterns were noted by reviewing each fetal monitor strip. Temporal data on each patient included onset of induction to time of delivery and to time oflabor. Labor was defined as > 150 Montevideo units as measured by an intrauterine pressure catheter. When technical consideration prevented the use of an intrauterine pressure catheter, labor was defined as three palpably strong contractions each lasting 60 seconds during a 10-minute interval. Timing of rupture of membranes and placement of epidural anesthesia were recorded. For analysis the timing of epidural placement was categorized according to placement before or after a regular labor pattern was established. If patients required more than 1 da y of induction , then time to labor and time to delivery were calculated with data from the last da y of induction onl y. Sample size determination was based on the detection of a 2-hour difference in total length of labor between the two groups. Assuming a standard deviation of 4 hours in total length of labor, an 80% power, and an alpha level of 0.05, a total of 63 women in each group was needed." A 10% failure rate was assumed, which necessitated increasing the enrollment to a minimum of 70 women in each group for a total sample size of 140. Two-tailed t tests were used to determine significant differences between the two treatment groups for all continuous variables. Significant associations between categoric variables was determined with X2 analysis. Once significant univariate associations were determined, then stepwise multiple regression was used to examine temporal outcomes multivariately. Stepwise logistic regression was used to examine the outcomes of h yperstimulation and abnormal FHR patterns. Throughout all analysis a p value of 0.05 was used for the level of significance. Results
A total of 151 patients were randomized according to the protocol, but there were 13 patients who had to be deleted from the study because of patient withdrawal, placement on regimen of intravenous magne-
Comparison of two oxytocin induction protocols 375
Volume 167 Number 2
Table I. Patient demographics comparing ox ytocin induction groups Traditional protocol (n
= 68)
Experimental protocol (n
= 70)
Table II. Indications for oxytocin induction Traditional protocol
Age (yr,
22.3 :!: 5.3
22.7 :!: 5.7
0.72
Gestational age (wk, mean:!: SO) Race (No.) Nonwhite White Parity (No.) Primigravid Multiparous Previous cesarean section (No.) Yes No
40.6 :!: 1.5
40.5:!: 1.6
0.89
43 (63.2%) 25 (36.8%)
37 (52.9%) 33 (47.1%)
0.24
45 (66.2%) 23 (33.8%)
46 (65.7%) 24 (34.3%)
0.95
4 (5.9%) 64 (94.1%)
4 (5.7%) 66 (94.3%)
0.56
me an x SO)
(n
P Value
siu m sulfate for worsening preeclampsia, or failure to meet the inclusion criteria. Of the deleted individuals eight had been assigned to the traditional protocol and five to the experimental protocol. A total of 138 patients met the inclusion criteria for the stud y, with 68 assigned to the traditional protocol a nd 70 assigned to the ex perimental protocol. Patient demographics shown in T able I indicate that there were no significan t differences between the two study groups with respect to age , estimated gestational age, race, parity, or vagina l birth after cesarean delivery. The indications for induction of labo r are listed in Table II. The most frequent indications in both groups were postdates and premature rupture of membranes, whereas gestational diabetes was more freque nt in the traditional protoco l group compared with the ex perimental grou p. The clinica l characteristics presented in T able III demonstrate no significant differences between the two gr oups with relation to the Bish op score at the time of enrollment in the study, the Bishop score at the time of induction on the da y of deli ver y, th e cervical dilatation at onset of induction , or the status of the membr anes on entry to the study. The use of epidural an esthesia , prostaglandin gels for cervical ripening, and intrauterine pressure cathete rs was similar between the two gro u ps. The ob stetric outcomes outlined in Table IV show that the groups were similar in terms of mean infant birth weight, cord pH, and Apga r scor es. There were no 5-minu te Apgar scores < 8 in either of the two gr oups. Seventy-five percent of the patients in each gro up delivered on the first da y o f induction, with the rem ainder delivered on the second and third days of induction. The number of second- and third-day inductions were similar between the two protocol groups (Table IV). Exam ination of the I-day inductions as
I
(n
= 70)
I
%
No.
25 23
36.8 33.8
30 20
42.9 28.6
4
5.9
7
10.0
No.
Postdate pregnancy Premature rupture of membranes Maternal medical indications Intr auterine growth retardation Impending macrosomia Gestational diabetes Oligohydramnios
= 68)
Experimental protocol
1.5 2
13
o
2.9
19.1
o
%
1.4
o 9 3
o
12.9
4.3
co mpared with the 2- and 3-day inductions indicated that the I-day inductions achieved adequate labor and delivery sooner, and required significantly less oxytocin. There was no difference, however , in FHR changes or cases of hyperstimulation (not shown). There was a significant difference between the two study groups in the method of delivery (Table IV ). Although the cesarean section rates were similar with th e two protocols, there was an increased incidence of assisted vaginal deliveries in the experimental group. In re viewing the labor data on the 24 patients who had assisted vaginal deli veries, 11 patients (one in the traditional group and 10 in the experimental group) underwent assisted deliveries for second stage FHR changes (i.e., severe variables or persistent bradycardia). There were 11 patients (four in the traditional group and seve n in the experimental group) who underwent assisted deliveries for maternal exhaustion and two patients in th e traditional group who ha d assisted deliveries for persistent occipitoposterior presentation. Neonatal outcome was not signifi cantly different between the two protocols in the assisted and spontaneous vaginal deliveries with respect to cord pH , birth weight or 5-minute Apgar scores (not shown). The most frequent ind ication for cesarean section in both groups was secondary arrest of dilatation or arrest of desc ent, although feta l distress occurred in five patients and face presentations in five patients (Table IV) . Complications were similar between the protocols, and there were a total of five patients who had failed inductions in the study. Three of these patients delivered vaginally 7 to 10 days later (two in the traditional protocol and one in the experimental protocol), and the remaining two required cesarean sections at the time of the failed induction (one in each protocol). Mild shoulder dystocia occu rred in four patients, with three of the four occurring in the experimental group. There were no adverse neonatal outcomes from these four de liveries. Meconium staining and nuchal
376 Muller, Stubbs, and Laurent
August 1992 Am J Obstet Gynecol
Table III. Clinical characteristics of oxytocin induction groups
Status of membranes at onset of induction (No.) Intact Ruptured Cervical dilatation at onset of induction (em, mean :t SD) Prostaglandin gels used before induction (No.) Yes No Bishop score at onset of induction (mean :t SD) Bishop score on day of delivery (mean :t SD) Intrauterine pressure catheter (No.) Yes No Epidural anes thesia (No.) Yes No
cord were the most frequent complicating events; these occurred equally in the two groups. According to the stringent definition of uterine hyperstimulation used in this study, there were 38 (60.3%) women in the traditional protocol and 43 (62.9%) in the experimental protocol who were classified as having hyperstimulation (Table V). The types of hyperstimulation are shown in Table VI, with five or more con tractions occurring in IO minutes being the most frequent hyperstimulation pattern. A description of FHR patterns is included in Table VI, with the most commonly occurring FHR change being variable deceleration. Normal FHR patterns throughout labor induction were seen in 41.2% ofthe women in the traditional protocol group and in 27 .1 % of the experimental group, with a tre nd toward significance (p = 0.08) (not shown). Although the incidence of uterine hyperstimulation was greater than expected, it was associated with changes in FHR patterns in only 10 of the 40 patients in the traditional group and 15 of the 43 patients in the experimental group (Table V). Table VII shows that the mean maximum dose of oxytocin in the two groups differed but was not statistically significant (p = 0 .07). The oxytocin dose at the time labor was attained was similar in the two protocols. The number of patients who had the oxytocin dosage modified by either decreasing or temporarily discontinuing the infusion due to perceived hyperstimulation or FHR changes did not significantly differ according to oxytocin protocol. If the oxytocin was discontinued temporarily, the average length of time it was off was 1.8 hours -in the traditional protocol group and 1.7 hours in the experimental group (not shown). If the oxytocin was temporarily turned off, the mean number of times this occurred during the induction was 1.9 times in each group. The temporal in tervals of labor are presented in
Traditional protocol (n = 68)
Experimental protocol (n = 70)
42 (66.8%) 26 (38.2%) 1.8 :t I.l
44 (62.9 %) 26 (37.1%) I. 7 :t I.l
38 (55.9%) 30 (44.1%) 5.4 :t 2.3 5.5 :t 2.3
41 (58.6%) 29 (41.4 %) 5.1 :t 2.2 5.3 :t 2.1
54 (79.4%) 14 (20.6 %)
59 (84.3%) II (15.7 %)
0.46
43 (63.2%) 25 (36.8%)
40(57.1 %) 30 (42.9%)
0.47
P Value 0.90 0.64
0.75 0.40 0.61
Table VIII. These data are only from patients who were delivered vaginall y. Excluded were patients who were delivered by cesarean section (13 in the traditional protocol group and 16 in the experimental protocol group) and those three patients with failed inductions who were delivered vaginall y at a later date. This part of the analysis used a total of 106 patients with 53 women in each group. The time from induction to labor was significantly different between the two groups (p = 0.03). However, the time from onset of induction to delivery time was not significantly different (p = 0.33). There was not a significant difference between the two groups in comparing the timing of epidural anesthesia or rupture of membranes with time of delivery. On examination of potential confounders it was de termined that the time required to establish a regular labor pattern was significantly decreased for women with ruptured membranes but was not significantly affected by epidural anesthesia, the timing of epidural placement, parity, use of prostaglandin gels, or Bishop score. The total length of labor from induction to de livery was significantly decreased for women who were multiparous, had ruptured membranes, did not have epidural anesthesia, or did not have prostaglandin gels placed (not shown) . Bishop scores at time of induction and use of epidural anesthesia did not affect the total length of labor. In the multivariate analysis higher oxytocin dosages at the time of labor, ruptured membranes, timing of the epidural placement, and being assigned to the experimental protocol were all associated with a significantly reduced time for establishment of a regular labor pattern. The total oxytocin dose for the study, use of epidural anesthesia, use of prostaglandin gels, presence of hyperstimulation, and parity were not significantly associated with th e time required to achieve a regu lar
Comparison of two oxytocin induction protocols 377
Volume 167 Number 2
Table IV. Obstetric outcome of oxytocin induction groups
Birth weight (gm, mean ± SD) Cord pH (mean ± SD) Arterial (No.) Venous (No.) Source unknown (No.) Not obtained (No.) 5 min Apgar score Days of induction (No.) I
2 3
Delivery method (No.) Vaginal Assisted vaginal Cesarean section Indication for cesarean section (No.) Dystocia Fetal distress Failed induction Face presentation Complications of delivery* (No.) Shoulder dystocia Meconium staining Nuchal cord Othert No complications
Traditional protocol (n = 68)
Experimental protocol (n = 70)
3386 ± 566 7.27 ± 0.07 56 6
0.96 0.39
8.9 ± 0.37
3391 ± 531 7.26 ± 0.07 57 5 I 7 8.8 ± 0.41
51 (75.0%) 6 (8.8%) 11 (16.2%)
53 (75.7%) 9 (12.9%) 8 (11.4%)
0.58
48 (70.6%) 7 (10.3%) 13(19.1%)
37 (52.9%) 17 (24.3%) 16 (22.8%)
0.05
6 (46.1%) 2 (15.4%) 1 (7.7%) 4 (30.8%)
II (73.3%) 3 (13.3%) 1(6.7%) 1(6.7%)
0.36
I 6 9
3 8 10 9 40
2
4
II
42
p Value
0.42
*More than one complication may be reported for some patients. tIncludes pregnancy-induced hypertension (n = 6), postpartum hemorrhage (n = I), malpresentation (n = 4), suspected chorioamnionitits (n = 6), uterine inversion (n = I), precipitate delivery (n = I), anxiety (n = I). labor pattern. The only variables that contributed significantly toward the reduction in total length of labor were higher total oxytocin doses for the study, ruptured membranes, and parity. Epidural placement and use of prostaglandin gel did not significantly affect the total length of labor in the adjusted analysis. Multiple logistic regression was used to adjust for potential confounders while assessing the relationship between oxytocin protocols and the outcomes of hyperstimulation and FHR patterns. In a stepwise procedure the likelihood ratio test indicated that none of the independent variables contributed significantly to the incidence of hyperstimulation. The placement of an epidural anesthetic was the only variable that contributed significantly to FHR changes.
Comment The yearly oxytocin induction rate of 5.3% (239/4552) in this center suggests that each year approximately 200,000 American women undergo oxytocin induction of labor. An additional large number of patients undergoes oxytocin augmentation of labor each year. Considering the large number of patients involved, surprisingly few papers have reported clinical trials comparing the several options in technique. Part of the explanation may be that several of the options have proved acceptably safe and effective during ex-
tensive clinical usage in particular centers. Nonetheless, in our view there is no reason why these protocols should necessarily be equivalent in any way, and a multiplicity of techniques suggests a need for comparisons to determine which is best. Considering the relative paucity of data comparing several widely used protocols, in our opinion the recent revision of ACOG Technical Bulletin No.157 1 1 (1991, revised from no.llO,1987) appropriately expanded its list of proffered techniques. Even so, that Technical Bulletin does not list all protocols that have seen extensive and satisfactory clinical application. Among the various options in oxytocin induction administration, the time interval between increases can be varied, and also the rate at which the dosage is increased can be varied independently of whatever time interval is chosen. Several recent reports have compared shorter versus longer time intervals between dosage increases." In contrast, we have sought to compare slower versus faster rates of dosage increase for labor induction, with the time intervals approximately the same. Both of our study arms had "longer" intervals between doses, as suggested by Seitchik," because of the time necessary for a given dose to reach its maximum effect. We are unaware of any previous randomized trials making such a comparison. There are several points to be made concerning the
378 Muller, Stubbs, and Laurent
August 1992 Am J Obstet Gyne col
Table V. Uterine hyperstimul ation and FHR patterns of oxytocin induction groups
Presence of uterine hyperstimulation (No.) Yes No Uterine hyperstimulation resulted in FHR alterations (N o.) Yes No No hyperstimulation occurred
Table VI. Contraction and FHR patterns of oxytocin induction groups
Contraction pattern (No.)* Normal ~5 cont ractions per 10 min Prolonged contractions Baseline ~ 25 min Coupling Other FHR pattern (No.j] Normal Variable Late de celerations Prolonged decelerations Decreased variability Other
Traditional protocol (n = 68)
Experimental protocol (n = 70)
27 29
26 32
10 3 8 0
II
28 29 3 14 10 2
19 34 7 14 10 4
8 8
It
*More than one contraction pattern may be reported for some patients. t One patient experienced dysfun ctional labor with no hyper stimulation. :l:More than one FHR pattern may be reported for some patients.
methods. First, the randomization worked quite well, with patient demographics and clinical characteristics similar between the two groups. Second, this study concern ed induction of labor, and all patients with indications for induction were evaluated for inclusion into the study. Because there are a multitude of indications, we felt this would be more clinically valuable to the clinician than evaluating onl y one indication (i.e, po stdate pregnancy). Finall y, in evaluating temporal data we purposely deleted the failed inductions and cesarean patients. The three patients with failed inductions who were deli vered 3 to 10 days later could not plausibly be included in the an alysis of temporal data. If all cesarean section patients were included in the data for the induction to regular labor interval, the conclusions would remain the same, with the experimental group attaining labor in a shorter time int erval. The inclusion of cesarean section patients in the induction to delivery analysis was no t calculated because it would not provide
Traditional protocol (n = 68)
Experimental protocol (n = 70)
4 1 (60.3%) 27 (39.7%)
44 (62.9%) 26 (37.1%)
0.76
10 (14.7%) 30 (44.1%) 28 (41.2%)
15 (2 1.4%) 28 (40.0%) 27 (38.6%)
0.59
P Value
meaningful information to the clinician . The timing of the cesarean delivery was not based on cervical status at the time of the operative procedure and would therefore not be refl ective of th e actual stage of labor or progression. Five of our findings are of particular interest. First, patients in the experimental protocol reached a predetermined milestone of uterine activit y 1 hour 25 min utes faster than patients in the traditional protocol (P = 0.03). It is quite common for patients to require >8 mU /min oxytocin for induction . Hauth et al. " demonstra ted that 82% of patients required ~10 mU/min oxytocin to achieve adequate labor. Indeed, in this study the dosage of ox ytocin at the time of adequate labor approached 9 m U / min in both groups. Second, although the expe rimental group had an induction-deliver y interval of I hour 6 minutes (1.1 hours) shorter than that of the tr aditional group (slower increase) , this difference did not rea ch statistical significance. A parallel and perhaps eq ually important finding is that there is so much variation in the length of labor in both groups in thi s stud y that demonstrating a difference would require a randomized trial larger in size than mo st that have been reported in thi s field of investigation. Indeed , this trial is larger than most, but because of the large standard deviation of the induction-delivery interval, this gr oup of 138 patients would only be able to detect a difference of 2.5 hours in the induction-deliver y interval, with a power of 80 %. Without a difference in hyperstimulation risk and with only a small difference in absolute oxytocin dosage between protocols, the more rapid onset of uterine activity in the experimental group tilts thes e data in favor of that protocol, pending a more definitive answer to this question . It seems plausible to us that on ce adequate labor is established, so long as hyperstimulation and other problems do not ocur, it doesn't matter which pr otocol is used . Third , safety issues are primaril y related to hyperstimulation, which was equivalent with these protocols in our hands. Although our rates of hyperstimulation have precedent," our definition was particularly strict because of our de sire to determine if one protocol was harder to control than the other. Also, although there
Comparison of two oxytocin induction protocols 379
Volume 167 Number 2
Table VII. Oxytocin management
Maximum oxytocin dosage for patient (mD/min, mean ± SD) Dosage of oxytocin at time of adequate labor* (ml.l/rnin, mean ± SD) Oxytocin management modified for uterine hyperstimulation or FHR changes (No.) No changes Decreased Discontinued temporarily
Traditional protocol (n = 68)
Experimental protocol (n = 70)
P Value
11.34 ± 5.88
13.39 ± 7.10
0.07
8.33 ± 5.19
8.90 ± 6.70
0.60
37 (51.6%) 11 (17.7%) 20 (30.7%)
29 (40.6%) 12 (17.4%) 29 (42.0%)
0.27
*Thirteen women did not achieve adequate labor and were not included in this calculation.
Table VIII. Labor patterns for vaginal deliveries
Induction to establishment of regular labor pattern (hr, mean ± SD) Induction to delivery (hr, mean ± SD) Rupture of membranes to delivery (hr, mean ± SD) Epidural anesthesia to delivery (hr, mean ± SD)
was an increase in the maximum oxytocin dose in the experimental group, we do not believe this very small increase is clinically significant. Fourth, FHR alterations versus normal heart rate patterns were noted to have occurred more frequently in the experimental group, although this was not statistically significant. This can be concerning. Variable decelerations occurred frequently and more often in the experimental group. Late decelerations occurred infrequently in both groups, although there was a small increased incidence in the experimental group. In analyzing these results, we found that the two groups did not differ in the incidence of uterine hyperstimulation resulting in FHR alterations (Table V). The data do not support that the variable or late decelerations were related to hyperstimulation and thus the oxytocin protocol. Therefore it is not clear that the safety of induction was altered by the oxytocin protocol. Of importance, the perinatal outcome was similar between the two groups. Nonetheless, the alteration in FHR, if affiliated with the oxytocin protocol, may outweigh any benefits an early labor pattern may bring. Finally, there were more operative vaginal deliveries in the experimental group. This was initially a surprise finding. Akoury et al.," however, have also suggested a higher incidence of operative vaginal deliveries in an aggressive oxytocin protocol. On review of our fetal monitor strips, none of these patients had operative vaginal deliveries secondary to hyperstirnulation-related FHR changes. An explanation for this finding, if not related to hyperstimulation or to chance, is not
Traditional protocol (n = 53)
Experimental protocol (n = 53)
P Value
4.85 ± 4.22
3.43 ± 2.15
0.03
10.04 ± 5.50 11.59 ± 9.01
8.98 ± 5.60 11.36 ± 8.32
0.33 0.89
5.69 ± 4.00
6.80 ± 5.68
0.38
straightforward. Possibly an intrinsic factor pertaining to the oxytocin protocol allows for more episodes of second-stage cord compression and thus more operative vaginal deliveries. This factor could be of concern, and obviously more study is required before a full explanation is found. Several recent additions to the oxytocin literature have advanced our knowledge and understanding of this drug, which is so uniquely identified with obstetric practice. Mercer et al." reported a randomized trial of 123 patients in two study arms, both of which used dosage increments similar to our experimental group. A longer time interval group (2':60 minutes) has less hyperstimulation and fewer cesarean sections for fetal distress than did a 20-minute time increment group. Their data suggest that longer time intervals produce less hyperstimulation, consistent with Seitchik's and Castillo's" finding that a longer time interval between dose increases was associated with less hyperstimulation. Unlike Mercer et aI., we found no difference in hyperstimulation between our study arms, perhaps because of a longer time interval in both of our groups. Interestingly, Mercer et al. had induction-to-delivery standard deviations even larger than ours. Their standard deviations for this interval of 8 hours (SEM 1.1 with 53 patients) and 7.8 hours (SEM 1.2 with 43 patients) were similar to ours. Blakemore et al.' randomized 52 patients into 15minute and 60-minute arms with mixed types of dosage increases. The hourly group received less oxytocin, but
380
Muller, Stubbs, and Laurent
overall effectiveness of the regimens was uncertain, with standard deviations of 7.85 and 7.4 hours in the two groups and a power of 0.8 to detect a 55% difference in the length of labor. In conclusion, several authors have supported the concept that slow rate of increase of oxytocin administration may be advantageous in the induction oflabor. Our study demonstrates that larger increments in association with slow intervals may improve efficacy by obtaining labor sooner without altering incidence of hyperstimulation or perinatal outcome. However, the difference in FHR changes and operative vaginal deliveries suggest caution in concluding that the large incremental protocol is clinically preferable until more data are available.
REFERENCES 1. Theobald GW,Graham A, CampbellJ, Gange PD, Driscoll WJ. The use of posterior pituitary extract in physiologic amounts in obstetrics: a preliminary report. BMJ 1948;2:123-7. 2. Seitchik J, Amico J, Robinson AG, Castillo M. Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. AMJ OBSTET GYNECOL 1984;150:225-8. 3. Foster TC, Jacobson JD, Valenzuela GJ. Oxytocin augmentation of labor: a comparison of 15- and 30-minute dose increment intervals. Obstet Gynecol 1988;71-147-9. 4. Blakemore KJ, Qin NG, Petrie RH, Paine LL. A prospective comparison of hourly and quarter-hourly oxytocin dose increase intervals for the induction oflabor at term. Obstet Gynecol 1990;75:757-61. 5. Mercer B, Pilgrim P, Sibai B. Labor induction with continous low-doseoxytocin infusion: a randomized trial. Obstet Gynecol 1991;77:659-63. 6. American College of Obstetricians and Gynecologists. Induction and augmentation of labor. Washington: American College of Obstetricians and Gynecologists, 1987; Technical Bulletin no 1l0. 7. BlancoJD, Finley BE. Induction and stimulation of labor. In: Pauerstein CJ, ed. Clinical obstetrics. New York:John Wiley, 1987:495-501. 8. O'Driscoll K, Meagher D. Diagnosis of labor. In: O'Driscoli K, Meagher D, eds. Activemanagement oflabor. Philadelphia: WB Saunders, 1980:23-30. 9. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266-8. 10. FleissJL. Appendix: sample size determination. In: Fleiss JL, ed. The design and analysis of clinical experiments. New York: John Wiley, 1986:369-71. 11. American College of Obstetricians and Gynecologists. Induction and augmentation of labor. Washington: American College of Obstetricians and Gynecologists, 1991; Technical Bulletin no 157. 12. SeitchikJ. The management of functional dystocia in the first stage of labor. Clin Obstet Gynecol 1987;30:42-9. 13. Hauth JL, Hankins GD, Gilstrap LC, Strickland DM, Vance P. Uterine contraction pressures with oxytocin induction/augmentation. Obstet Gynecol 1986;68:305-9. 14. Seitchik J, Castillo M. Oxytocin augmentation of dysfunctional labor. 1. Clinical data. AM J OBSTET GYNECOL 1982;144:899-905. 15. Akoury HA, MacDonald FJ, Brodie G, Laddick MB, Chaudhry NM, Frize M. Oxytocin augmentation of labor and perinatal outcome in nulliparas. Obstet Gynecol 1991;78:227-30.
August 1992 Am J Obstet Gynecol
Editors' note: This manuscript was revised after these discussions were presented.
Discussion DR. TERRY B. LEVENSON, Conway, South Carolina. In 1906 Dale demonstrated that myometrial tissue would contract when exposed to posterior pituitary extracts in vitro. By 1913 Watson had begun to use such extracts for the induction of labor. Complications such as uterine rupture and its attendant morbidity and mortality discouraged this practice until Theobald et al. described the administration of drip oxytocin in 1948. In 1949 DuVigneaud demonstrated the structure of the octapeptide oxytocin, work for which he was later awarded the Nobel Prize in Chemistry. Synthetic production of oxytocin soon followed.' Possession of this powerful mediator of uterine contractility begs the question what is the safest and most effective way to use it? To this end a number of studies have been done to demonstrate that this medication can be used in variety of clinical stiuations, but comparative studies of various protocols have been few. The article presented by Muller et al. compares the effectiveness of two protocols for administering oxytocin to induce labor. The control and experimental groups in their study were remarkably similar in terms of patient demographics and indications for induction of labor. Bishop scores, cervical dilatation at the onset of induction, and use of prostaglandin gels and epidural anesthesia were likewise very similar. The control group was given oxytocin at 1 to 2 m U I min, and the infusion was increased by 1 to 2 m U I min at 30-minute intervals until adequate labor occurred. The experimental group received the same starting dose, but infusion rates were doubled every 40 minutes until a rate of 8 mU Imin was reached, and then increases were made in smaller increments to advoid hyperstimulation of the uterus. Maximum doses of oxytocin tended to be higher in the experimental group, but this difference was not statistically significant. Dosages infused at the time adequate labor was achieved were similar in both arms of the study. Hyperstimulation occurred in both groups with equal frequency but did not lead to untoward outcomes. Management difficulties were similar in both groups in that decreasing the infusion rate or discontinuing the infusion temporarily was required as often in the experimental group as in the control group. Abnormal FHR patterns were seen more often in the experimental group. This was believed to be due to a higher incidence of variable decelerations in this group. Careful analysis failed to show a relationship between hyperstimulation and these decelerations, indicating this effect was not due to the ocytocin infusion protocol. Cesarean section delivery occurred with equal frequency in both groups. Fetal distress was the indication
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in only two of 62 patients in the control group and three of 69 in the experimental group. Dystocia was the most common indication, occurring with equal fre. quency in both groups. More assisted vaginal deliveries occurred m the experimental group than the control group, most of which were for FHR changes in the second stage of labor. These were not believed to be due to uterine hyperstimulation. Obstetric outcomes were uniformly good in both groups, and no infants delivered had 5-minute Apgar scores
Key words: Ox ytocin , labor Since Theobald et al. I first de scribed the use of continuous intravenous oxytocin in 1948, multiple protocols have been advocated by various authors for the use of oxytocin in the induction of labor. These oxytocin induction protocols var y in the initial dose, the time interval between dose increases, and the size of the dose increase. Seitchik et al." demonstrated in vivo that oxytocin concentrations reach steady state after 30 to 40 minutes. This finding has led to the formation of oxytocin induction protocols with int erval increases of ~30 minute s," including the protocol listed by The American College of Obstetricians and Gynecologists (ACOG) Technical Bulletin No. 110." The Uni versity of Texas Health Science Center in San Antonio presented a similar time interval between increases of continuous ox ytocin, but it varied from the ACOG protocol by its larger rate increments." The question arises as to whether the se lar ger rate increments, which obtain higher ox ytocin dosages sooner, may shorten the time from in-
Fromthe Department of Obstetrics and Gynecology, CarolinasMedical Center. Presented as Invited Guestat the Fifty{ourth Annual Meeting of The South Atlantic Association of Obstetricians and Gynecologists, Palm Beach, Florida, January 26-29, 1992. Reprint requests: Thomas M. Stubbs, MD, Department of Obstetrics and Gynecology, Carolinas Medical Center, P.O. Box 32861, Charlotte, NC 28232. 6/6/38061
duction to labor and delivery without increasing the risk to the fetus . The purpose of our study was to compare two oxytocin induction protocols: the one listed by ACOG and one similar to that presented by the University of Texas Health Science Center in San Antonio. Safety and efficacy were assessed for each protocol by comparing hyperstimulation, fetal distress, time from induction to labor, and time from induction to delivery. Material and methods This randomized, prospective study was performed at the Carolinas Medical Center after the approval of the Institutional Review Board of the medical center. A total of 151 patients with indication for induction of labor consented to participate in the study and were randomized to one of the two induction protocols described below. Randomization was performed only after the patient agreed to be in this clinical trial and was by computer-generated random assignment with sealed, opaque envelopes. Clinical management was by house officers with immediate inhouse consultation available at all times . Inclusion criteria were a gestational age of 37 to 42 weeks, cephalic presentation, an adequate pelvis by clinical pelvimetry, no more than one prior lower segment cesarean section, and premature rupture of membranes with patient not in labor. Patients not in labor who received prostaglandin gels for cervical ripening
373
374 Muller, Stubbs, and Laurent
were randomized after receiving the gels. Labor was defined as regular contractions with evidence of cervical change (dilatation or effacement)." Excluded from the study were women with an abnormal presentation, abruptio placentae, placenta previa, previous vertical cesarean section, unknown uterine scar, previous myotomy, twins, polyhydramnios, active genital herpes, magnesium sulfate therapy, estimated fetal weight ~4500 gm , nonreassuring fetal testing results, and regular uterine contractions (patients already contracting were considered augmentation of labor). A total of 76 patients were randomized to the traditional protocol, which was modeled after ACOG Technical Bulletin No. 1106 and which is currently used at our center. This will be referred to as the traditional protocol. Oxytocin was started at I to 2 m U / min and was gradually increased in dose increments of 1 to 2 mU /min at 30-minute intervals as needed. The rate was increased as needed according to the judgment of the nurses and physicians at the bedside. A total of 75 patients were randomized to the experimental protocol , a protocol similar to that described by Blanco and Finley.' This will be referred to as the experimental protocol. Oxytocin was started at 1 to 2 m U / min, and each new oxytocin rate was doubled from the preexisting rate (for example, 1,2,4,8,16 mU /min). An interval of 40 minutes between increases was used. After a level of 8 mU/min was reached, less than doubling the rate was acceptable if progression to hyperstimulation was feared (for example, 8, 10, 12 mU/min). For both protocols 20 IU of synthetic oxytocin (Lyphomed, Fujisawa USA , Deerfield, 111.) was mixed in 1 L 5% dextrose in lactated Ringers' solution and delivered by a secondary intravenous line . Oxytocin infusion rate was controlled by continuous electronic infusion pump. Continuous electronic fetal heart rate (FHR) and contraction monitoring were performed in all patients. Amniotomy was performed and an intrauterine pressure catheter was placed by the supervising physician when clinically indicated. Oxytocin was decreased for hyperstimulation, defined as five or more contractions in 10 minutes, contraction duration > 90 seconds , or baseline uterine tone of 25 mm Hg. Ox ytocin was temporarily discontinued for nonreassuring fetal heart rate changes, which included severe variable decelerations, re current late decelerations, prolonged decelerations, or loss of beat-to-beat variability. After 8 to 10 hours of ox ytocin, if the membranes were intact and the cervix was still unfavorable, ox ytocin was discontinued and the patient was scheduled for a second or third day of induction to be performed the following day. A Bishop score was documented at the beginning of each induction day." Epidural anesthesia was not withheld from patients participating in this study. The same group of house
August 1992 Am J Obstet Gynecol
officers used the same continuous-infusion , lumbar epi dural technique for patients in both protocols. Assisted vaginal deliveries were done onl y for clinical indication. Patient demographics, such as age, race, gravidity, parity, and gestational age and clinical criteria (indication for induction, Bishop score, membrane status, cervical dilatation, prostaglandin gels application) were obtained from each patient on admission to the study. Obstetric outcome (number of days for induction , method of delivery, complications associated with delivery) and neonatal outcome (Apgar scores and cord pH) were recorded at completion of induction. Type and frequency of hyperstimulation episodes and FHR patterns were noted by reviewing each fetal monitor strip. Temporal data on each patient included onset of induction to time of delivery and to time oflabor. Labor was defined as > 150 Montevideo units as measured by an intrauterine pressure catheter. When technical consideration prevented the use of an intrauterine pressure catheter, labor was defined as three palpably strong contractions each lasting 60 seconds during a 10-minute interval. Timing of rupture of membranes and placement of epidural anesthesia were recorded. For analysis the timing of epidural placement was categorized according to placement before or after a regular labor pattern was established. If patients required more than 1 da y of induction , then time to labor and time to delivery were calculated with data from the last da y of induction onl y. Sample size determination was based on the detection of a 2-hour difference in total length of labor between the two groups. Assuming a standard deviation of 4 hours in total length of labor, an 80% power, and an alpha level of 0.05, a total of 63 women in each group was needed." A 10% failure rate was assumed, which necessitated increasing the enrollment to a minimum of 70 women in each group for a total sample size of 140. Two-tailed t tests were used to determine significant differences between the two treatment groups for all continuous variables. Significant associations between categoric variables was determined with X2 analysis. Once significant univariate associations were determined, then stepwise multiple regression was used to examine temporal outcomes multivariately. Stepwise logistic regression was used to examine the outcomes of h yperstimulation and abnormal FHR patterns. Throughout all analysis a p value of 0.05 was used for the level of significance. Results
A total of 151 patients were randomized according to the protocol, but there were 13 patients who had to be deleted from the study because of patient withdrawal, placement on regimen of intravenous magne-
Comparison of two oxytocin induction protocols 375
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Table I. Patient demographics comparing ox ytocin induction groups Traditional protocol (n
= 68)
Experimental protocol (n
= 70)
Table II. Indications for oxytocin induction Traditional protocol
Age (yr,
22.3 :!: 5.3
22.7 :!: 5.7
0.72
Gestational age (wk, mean:!: SO) Race (No.) Nonwhite White Parity (No.) Primigravid Multiparous Previous cesarean section (No.) Yes No
40.6 :!: 1.5
40.5:!: 1.6
0.89
43 (63.2%) 25 (36.8%)
37 (52.9%) 33 (47.1%)
0.24
45 (66.2%) 23 (33.8%)
46 (65.7%) 24 (34.3%)
0.95
4 (5.9%) 64 (94.1%)
4 (5.7%) 66 (94.3%)
0.56
me an x SO)
(n
P Value
siu m sulfate for worsening preeclampsia, or failure to meet the inclusion criteria. Of the deleted individuals eight had been assigned to the traditional protocol and five to the experimental protocol. A total of 138 patients met the inclusion criteria for the stud y, with 68 assigned to the traditional protocol a nd 70 assigned to the ex perimental protocol. Patient demographics shown in T able I indicate that there were no significan t differences between the two study groups with respect to age , estimated gestational age, race, parity, or vagina l birth after cesarean delivery. The indications for induction of labo r are listed in Table II. The most frequent indications in both groups were postdates and premature rupture of membranes, whereas gestational diabetes was more freque nt in the traditional protoco l group compared with the ex perimental grou p. The clinica l characteristics presented in T able III demonstrate no significant differences between the two gr oups with relation to the Bish op score at the time of enrollment in the study, the Bishop score at the time of induction on the da y of deli ver y, th e cervical dilatation at onset of induction , or the status of the membr anes on entry to the study. The use of epidural an esthesia , prostaglandin gels for cervical ripening, and intrauterine pressure cathete rs was similar between the two gro u ps. The ob stetric outcomes outlined in Table IV show that the groups were similar in terms of mean infant birth weight, cord pH, and Apga r scor es. There were no 5-minu te Apgar scores < 8 in either of the two gr oups. Seventy-five percent of the patients in each gro up delivered on the first da y o f induction, with the rem ainder delivered on the second and third days of induction. The number of second- and third-day inductions were similar between the two protocol groups (Table IV). Exam ination of the I-day inductions as
I
(n
= 70)
I
%
No.
25 23
36.8 33.8
30 20
42.9 28.6
4
5.9
7
10.0
No.
Postdate pregnancy Premature rupture of membranes Maternal medical indications Intr auterine growth retardation Impending macrosomia Gestational diabetes Oligohydramnios
= 68)
Experimental protocol
1.5 2
13
o
2.9
19.1
o
%
1.4
o 9 3
o
12.9
4.3
co mpared with the 2- and 3-day inductions indicated that the I-day inductions achieved adequate labor and delivery sooner, and required significantly less oxytocin. There was no difference, however , in FHR changes or cases of hyperstimulation (not shown). There was a significant difference between the two study groups in the method of delivery (Table IV ). Although the cesarean section rates were similar with th e two protocols, there was an increased incidence of assisted vaginal deliveries in the experimental group. In re viewing the labor data on the 24 patients who had assisted vaginal deli veries, 11 patients (one in the traditional group and 10 in the experimental group) underwent assisted deliveries for second stage FHR changes (i.e., severe variables or persistent bradycardia). There were 11 patients (four in the traditional group and seve n in the experimental group) who underwent assisted deliveries for maternal exhaustion and two patients in th e traditional group who ha d assisted deliveries for persistent occipitoposterior presentation. Neonatal outcome was not signifi cantly different between the two protocols in the assisted and spontaneous vaginal deliveries with respect to cord pH , birth weight or 5-minute Apgar scores (not shown). The most frequent ind ication for cesarean section in both groups was secondary arrest of dilatation or arrest of desc ent, although feta l distress occurred in five patients and face presentations in five patients (Table IV) . Complications were similar between the protocols, and there were a total of five patients who had failed inductions in the study. Three of these patients delivered vaginally 7 to 10 days later (two in the traditional protocol and one in the experimental protocol), and the remaining two required cesarean sections at the time of the failed induction (one in each protocol). Mild shoulder dystocia occu rred in four patients, with three of the four occurring in the experimental group. There were no adverse neonatal outcomes from these four de liveries. Meconium staining and nuchal
376 Muller, Stubbs, and Laurent
August 1992 Am J Obstet Gynecol
Table III. Clinical characteristics of oxytocin induction groups
Status of membranes at onset of induction (No.) Intact Ruptured Cervical dilatation at onset of induction (em, mean :t SD) Prostaglandin gels used before induction (No.) Yes No Bishop score at onset of induction (mean :t SD) Bishop score on day of delivery (mean :t SD) Intrauterine pressure catheter (No.) Yes No Epidural anes thesia (No.) Yes No
cord were the most frequent complicating events; these occurred equally in the two groups. According to the stringent definition of uterine hyperstimulation used in this study, there were 38 (60.3%) women in the traditional protocol and 43 (62.9%) in the experimental protocol who were classified as having hyperstimulation (Table V). The types of hyperstimulation are shown in Table VI, with five or more con tractions occurring in IO minutes being the most frequent hyperstimulation pattern. A description of FHR patterns is included in Table VI, with the most commonly occurring FHR change being variable deceleration. Normal FHR patterns throughout labor induction were seen in 41.2% ofthe women in the traditional protocol group and in 27 .1 % of the experimental group, with a tre nd toward significance (p = 0.08) (not shown). Although the incidence of uterine hyperstimulation was greater than expected, it was associated with changes in FHR patterns in only 10 of the 40 patients in the traditional group and 15 of the 43 patients in the experimental group (Table V). Table VII shows that the mean maximum dose of oxytocin in the two groups differed but was not statistically significant (p = 0 .07). The oxytocin dose at the time labor was attained was similar in the two protocols. The number of patients who had the oxytocin dosage modified by either decreasing or temporarily discontinuing the infusion due to perceived hyperstimulation or FHR changes did not significantly differ according to oxytocin protocol. If the oxytocin was discontinued temporarily, the average length of time it was off was 1.8 hours -in the traditional protocol group and 1.7 hours in the experimental group (not shown). If the oxytocin was temporarily turned off, the mean number of times this occurred during the induction was 1.9 times in each group. The temporal in tervals of labor are presented in
Traditional protocol (n = 68)
Experimental protocol (n = 70)
42 (66.8%) 26 (38.2%) 1.8 :t I.l
44 (62.9 %) 26 (37.1%) I. 7 :t I.l
38 (55.9%) 30 (44.1%) 5.4 :t 2.3 5.5 :t 2.3
41 (58.6%) 29 (41.4 %) 5.1 :t 2.2 5.3 :t 2.1
54 (79.4%) 14 (20.6 %)
59 (84.3%) II (15.7 %)
0.46
43 (63.2%) 25 (36.8%)
40(57.1 %) 30 (42.9%)
0.47
P Value 0.90 0.64
0.75 0.40 0.61
Table VIII. These data are only from patients who were delivered vaginall y. Excluded were patients who were delivered by cesarean section (13 in the traditional protocol group and 16 in the experimental protocol group) and those three patients with failed inductions who were delivered vaginall y at a later date. This part of the analysis used a total of 106 patients with 53 women in each group. The time from induction to labor was significantly different between the two groups (p = 0.03). However, the time from onset of induction to delivery time was not significantly different (p = 0.33). There was not a significant difference between the two groups in comparing the timing of epidural anesthesia or rupture of membranes with time of delivery. On examination of potential confounders it was de termined that the time required to establish a regular labor pattern was significantly decreased for women with ruptured membranes but was not significantly affected by epidural anesthesia, the timing of epidural placement, parity, use of prostaglandin gels, or Bishop score. The total length of labor from induction to de livery was significantly decreased for women who were multiparous, had ruptured membranes, did not have epidural anesthesia, or did not have prostaglandin gels placed (not shown) . Bishop scores at time of induction and use of epidural anesthesia did not affect the total length of labor. In the multivariate analysis higher oxytocin dosages at the time of labor, ruptured membranes, timing of the epidural placement, and being assigned to the experimental protocol were all associated with a significantly reduced time for establishment of a regular labor pattern. The total oxytocin dose for the study, use of epidural anesthesia, use of prostaglandin gels, presence of hyperstimulation, and parity were not significantly associated with th e time required to achieve a regu lar
Comparison of two oxytocin induction protocols 377
Volume 167 Number 2
Table IV. Obstetric outcome of oxytocin induction groups
Birth weight (gm, mean ± SD) Cord pH (mean ± SD) Arterial (No.) Venous (No.) Source unknown (No.) Not obtained (No.) 5 min Apgar score Days of induction (No.) I
2 3
Delivery method (No.) Vaginal Assisted vaginal Cesarean section Indication for cesarean section (No.) Dystocia Fetal distress Failed induction Face presentation Complications of delivery* (No.) Shoulder dystocia Meconium staining Nuchal cord Othert No complications
Traditional protocol (n = 68)
Experimental protocol (n = 70)
3386 ± 566 7.27 ± 0.07 56 6
0.96 0.39
8.9 ± 0.37
3391 ± 531 7.26 ± 0.07 57 5 I 7 8.8 ± 0.41
51 (75.0%) 6 (8.8%) 11 (16.2%)
53 (75.7%) 9 (12.9%) 8 (11.4%)
0.58
48 (70.6%) 7 (10.3%) 13(19.1%)
37 (52.9%) 17 (24.3%) 16 (22.8%)
0.05
6 (46.1%) 2 (15.4%) 1 (7.7%) 4 (30.8%)
II (73.3%) 3 (13.3%) 1(6.7%) 1(6.7%)
0.36
I 6 9
3 8 10 9 40
2
4
II
42
p Value
0.42
*More than one complication may be reported for some patients. tIncludes pregnancy-induced hypertension (n = 6), postpartum hemorrhage (n = I), malpresentation (n = 4), suspected chorioamnionitits (n = 6), uterine inversion (n = I), precipitate delivery (n = I), anxiety (n = I). labor pattern. The only variables that contributed significantly toward the reduction in total length of labor were higher total oxytocin doses for the study, ruptured membranes, and parity. Epidural placement and use of prostaglandin gel did not significantly affect the total length of labor in the adjusted analysis. Multiple logistic regression was used to adjust for potential confounders while assessing the relationship between oxytocin protocols and the outcomes of hyperstimulation and FHR patterns. In a stepwise procedure the likelihood ratio test indicated that none of the independent variables contributed significantly to the incidence of hyperstimulation. The placement of an epidural anesthetic was the only variable that contributed significantly to FHR changes.
Comment The yearly oxytocin induction rate of 5.3% (239/4552) in this center suggests that each year approximately 200,000 American women undergo oxytocin induction of labor. An additional large number of patients undergoes oxytocin augmentation of labor each year. Considering the large number of patients involved, surprisingly few papers have reported clinical trials comparing the several options in technique. Part of the explanation may be that several of the options have proved acceptably safe and effective during ex-
tensive clinical usage in particular centers. Nonetheless, in our view there is no reason why these protocols should necessarily be equivalent in any way, and a multiplicity of techniques suggests a need for comparisons to determine which is best. Considering the relative paucity of data comparing several widely used protocols, in our opinion the recent revision of ACOG Technical Bulletin No.157 1 1 (1991, revised from no.llO,1987) appropriately expanded its list of proffered techniques. Even so, that Technical Bulletin does not list all protocols that have seen extensive and satisfactory clinical application. Among the various options in oxytocin induction administration, the time interval between increases can be varied, and also the rate at which the dosage is increased can be varied independently of whatever time interval is chosen. Several recent reports have compared shorter versus longer time intervals between dosage increases." In contrast, we have sought to compare slower versus faster rates of dosage increase for labor induction, with the time intervals approximately the same. Both of our study arms had "longer" intervals between doses, as suggested by Seitchik," because of the time necessary for a given dose to reach its maximum effect. We are unaware of any previous randomized trials making such a comparison. There are several points to be made concerning the
378 Muller, Stubbs, and Laurent
August 1992 Am J Obstet Gyne col
Table V. Uterine hyperstimul ation and FHR patterns of oxytocin induction groups
Presence of uterine hyperstimulation (No.) Yes No Uterine hyperstimulation resulted in FHR alterations (N o.) Yes No No hyperstimulation occurred
Table VI. Contraction and FHR patterns of oxytocin induction groups
Contraction pattern (No.)* Normal ~5 cont ractions per 10 min Prolonged contractions Baseline ~ 25 min Coupling Other FHR pattern (No.j] Normal Variable Late de celerations Prolonged decelerations Decreased variability Other
Traditional protocol (n = 68)
Experimental protocol (n = 70)
27 29
26 32
10 3 8 0
II
28 29 3 14 10 2
19 34 7 14 10 4
8 8
It
*More than one contraction pattern may be reported for some patients. t One patient experienced dysfun ctional labor with no hyper stimulation. :l:More than one FHR pattern may be reported for some patients.
methods. First, the randomization worked quite well, with patient demographics and clinical characteristics similar between the two groups. Second, this study concern ed induction of labor, and all patients with indications for induction were evaluated for inclusion into the study. Because there are a multitude of indications, we felt this would be more clinically valuable to the clinician than evaluating onl y one indication (i.e, po stdate pregnancy). Finall y, in evaluating temporal data we purposely deleted the failed inductions and cesarean patients. The three patients with failed inductions who were deli vered 3 to 10 days later could not plausibly be included in the an alysis of temporal data. If all cesarean section patients were included in the data for the induction to regular labor interval, the conclusions would remain the same, with the experimental group attaining labor in a shorter time int erval. The inclusion of cesarean section patients in the induction to delivery analysis was no t calculated because it would not provide
Traditional protocol (n = 68)
Experimental protocol (n = 70)
4 1 (60.3%) 27 (39.7%)
44 (62.9%) 26 (37.1%)
0.76
10 (14.7%) 30 (44.1%) 28 (41.2%)
15 (2 1.4%) 28 (40.0%) 27 (38.6%)
0.59
P Value
meaningful information to the clinician . The timing of the cesarean delivery was not based on cervical status at the time of the operative procedure and would therefore not be refl ective of th e actual stage of labor or progression. Five of our findings are of particular interest. First, patients in the experimental protocol reached a predetermined milestone of uterine activit y 1 hour 25 min utes faster than patients in the traditional protocol (P = 0.03). It is quite common for patients to require >8 mU /min oxytocin for induction . Hauth et al. " demonstra ted that 82% of patients required ~10 mU/min oxytocin to achieve adequate labor. Indeed, in this study the dosage of ox ytocin at the time of adequate labor approached 9 m U / min in both groups. Second, although the expe rimental group had an induction-deliver y interval of I hour 6 minutes (1.1 hours) shorter than that of the tr aditional group (slower increase) , this difference did not rea ch statistical significance. A parallel and perhaps eq ually important finding is that there is so much variation in the length of labor in both groups in thi s stud y that demonstrating a difference would require a randomized trial larger in size than mo st that have been reported in thi s field of investigation. Indeed , this trial is larger than most, but because of the large standard deviation of the induction-delivery interval, this gr oup of 138 patients would only be able to detect a difference of 2.5 hours in the induction-deliver y interval, with a power of 80 %. Without a difference in hyperstimulation risk and with only a small difference in absolute oxytocin dosage between protocols, the more rapid onset of uterine activity in the experimental group tilts thes e data in favor of that protocol, pending a more definitive answer to this question . It seems plausible to us that on ce adequate labor is established, so long as hyperstimulation and other problems do not ocur, it doesn't matter which pr otocol is used . Third , safety issues are primaril y related to hyperstimulation, which was equivalent with these protocols in our hands. Although our rates of hyperstimulation have precedent," our definition was particularly strict because of our de sire to determine if one protocol was harder to control than the other. Also, although there
Comparison of two oxytocin induction protocols 379
Volume 167 Number 2
Table VII. Oxytocin management
Maximum oxytocin dosage for patient (mD/min, mean ± SD) Dosage of oxytocin at time of adequate labor* (ml.l/rnin, mean ± SD) Oxytocin management modified for uterine hyperstimulation or FHR changes (No.) No changes Decreased Discontinued temporarily
Traditional protocol (n = 68)
Experimental protocol (n = 70)
P Value
11.34 ± 5.88
13.39 ± 7.10
0.07
8.33 ± 5.19
8.90 ± 6.70
0.60
37 (51.6%) 11 (17.7%) 20 (30.7%)
29 (40.6%) 12 (17.4%) 29 (42.0%)
0.27
*Thirteen women did not achieve adequate labor and were not included in this calculation.
Table VIII. Labor patterns for vaginal deliveries
Induction to establishment of regular labor pattern (hr, mean ± SD) Induction to delivery (hr, mean ± SD) Rupture of membranes to delivery (hr, mean ± SD) Epidural anesthesia to delivery (hr, mean ± SD)
was an increase in the maximum oxytocin dose in the experimental group, we do not believe this very small increase is clinically significant. Fourth, FHR alterations versus normal heart rate patterns were noted to have occurred more frequently in the experimental group, although this was not statistically significant. This can be concerning. Variable decelerations occurred frequently and more often in the experimental group. Late decelerations occurred infrequently in both groups, although there was a small increased incidence in the experimental group. In analyzing these results, we found that the two groups did not differ in the incidence of uterine hyperstimulation resulting in FHR alterations (Table V). The data do not support that the variable or late decelerations were related to hyperstimulation and thus the oxytocin protocol. Therefore it is not clear that the safety of induction was altered by the oxytocin protocol. Of importance, the perinatal outcome was similar between the two groups. Nonetheless, the alteration in FHR, if affiliated with the oxytocin protocol, may outweigh any benefits an early labor pattern may bring. Finally, there were more operative vaginal deliveries in the experimental group. This was initially a surprise finding. Akoury et al.," however, have also suggested a higher incidence of operative vaginal deliveries in an aggressive oxytocin protocol. On review of our fetal monitor strips, none of these patients had operative vaginal deliveries secondary to hyperstirnulation-related FHR changes. An explanation for this finding, if not related to hyperstimulation or to chance, is not
Traditional protocol (n = 53)
Experimental protocol (n = 53)
P Value
4.85 ± 4.22
3.43 ± 2.15
0.03
10.04 ± 5.50 11.59 ± 9.01
8.98 ± 5.60 11.36 ± 8.32
0.33 0.89
5.69 ± 4.00
6.80 ± 5.68
0.38
straightforward. Possibly an intrinsic factor pertaining to the oxytocin protocol allows for more episodes of second-stage cord compression and thus more operative vaginal deliveries. This factor could be of concern, and obviously more study is required before a full explanation is found. Several recent additions to the oxytocin literature have advanced our knowledge and understanding of this drug, which is so uniquely identified with obstetric practice. Mercer et al." reported a randomized trial of 123 patients in two study arms, both of which used dosage increments similar to our experimental group. A longer time interval group (2':60 minutes) has less hyperstimulation and fewer cesarean sections for fetal distress than did a 20-minute time increment group. Their data suggest that longer time intervals produce less hyperstimulation, consistent with Seitchik's and Castillo's" finding that a longer time interval between dose increases was associated with less hyperstimulation. Unlike Mercer et aI., we found no difference in hyperstimulation between our study arms, perhaps because of a longer time interval in both of our groups. Interestingly, Mercer et al. had induction-to-delivery standard deviations even larger than ours. Their standard deviations for this interval of 8 hours (SEM 1.1 with 53 patients) and 7.8 hours (SEM 1.2 with 43 patients) were similar to ours. Blakemore et al.' randomized 52 patients into 15minute and 60-minute arms with mixed types of dosage increases. The hourly group received less oxytocin, but
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Muller, Stubbs, and Laurent
overall effectiveness of the regimens was uncertain, with standard deviations of 7.85 and 7.4 hours in the two groups and a power of 0.8 to detect a 55% difference in the length of labor. In conclusion, several authors have supported the concept that slow rate of increase of oxytocin administration may be advantageous in the induction oflabor. Our study demonstrates that larger increments in association with slow intervals may improve efficacy by obtaining labor sooner without altering incidence of hyperstimulation or perinatal outcome. However, the difference in FHR changes and operative vaginal deliveries suggest caution in concluding that the large incremental protocol is clinically preferable until more data are available.
REFERENCES 1. Theobald GW,Graham A, CampbellJ, Gange PD, Driscoll WJ. The use of posterior pituitary extract in physiologic amounts in obstetrics: a preliminary report. BMJ 1948;2:123-7. 2. Seitchik J, Amico J, Robinson AG, Castillo M. Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics. AMJ OBSTET GYNECOL 1984;150:225-8. 3. Foster TC, Jacobson JD, Valenzuela GJ. Oxytocin augmentation of labor: a comparison of 15- and 30-minute dose increment intervals. Obstet Gynecol 1988;71-147-9. 4. Blakemore KJ, Qin NG, Petrie RH, Paine LL. A prospective comparison of hourly and quarter-hourly oxytocin dose increase intervals for the induction oflabor at term. Obstet Gynecol 1990;75:757-61. 5. Mercer B, Pilgrim P, Sibai B. Labor induction with continous low-doseoxytocin infusion: a randomized trial. Obstet Gynecol 1991;77:659-63. 6. American College of Obstetricians and Gynecologists. Induction and augmentation of labor. Washington: American College of Obstetricians and Gynecologists, 1987; Technical Bulletin no 1l0. 7. BlancoJD, Finley BE. Induction and stimulation of labor. In: Pauerstein CJ, ed. Clinical obstetrics. New York:John Wiley, 1987:495-501. 8. O'Driscoll K, Meagher D. Diagnosis of labor. In: O'Driscoli K, Meagher D, eds. Activemanagement oflabor. Philadelphia: WB Saunders, 1980:23-30. 9. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266-8. 10. FleissJL. Appendix: sample size determination. In: Fleiss JL, ed. The design and analysis of clinical experiments. New York: John Wiley, 1986:369-71. 11. American College of Obstetricians and Gynecologists. Induction and augmentation of labor. Washington: American College of Obstetricians and Gynecologists, 1991; Technical Bulletin no 157. 12. SeitchikJ. The management of functional dystocia in the first stage of labor. Clin Obstet Gynecol 1987;30:42-9. 13. Hauth JL, Hankins GD, Gilstrap LC, Strickland DM, Vance P. Uterine contraction pressures with oxytocin induction/augmentation. Obstet Gynecol 1986;68:305-9. 14. Seitchik J, Castillo M. Oxytocin augmentation of dysfunctional labor. 1. Clinical data. AM J OBSTET GYNECOL 1982;144:899-905. 15. Akoury HA, MacDonald FJ, Brodie G, Laddick MB, Chaudhry NM, Frize M. Oxytocin augmentation of labor and perinatal outcome in nulliparas. Obstet Gynecol 1991;78:227-30.
August 1992 Am J Obstet Gynecol
Editors' note: This manuscript was revised after these discussions were presented.
Discussion DR. TERRY B. LEVENSON, Conway, South Carolina. In 1906 Dale demonstrated that myometrial tissue would contract when exposed to posterior pituitary extracts in vitro. By 1913 Watson had begun to use such extracts for the induction of labor. Complications such as uterine rupture and its attendant morbidity and mortality discouraged this practice until Theobald et al. described the administration of drip oxytocin in 1948. In 1949 DuVigneaud demonstrated the structure of the octapeptide oxytocin, work for which he was later awarded the Nobel Prize in Chemistry. Synthetic production of oxytocin soon followed.' Possession of this powerful mediator of uterine contractility begs the question what is the safest and most effective way to use it? To this end a number of studies have been done to demonstrate that this medication can be used in variety of clinical stiuations, but comparative studies of various protocols have been few. The article presented by Muller et al. compares the effectiveness of two protocols for administering oxytocin to induce labor. The control and experimental groups in their study were remarkably similar in terms of patient demographics and indications for induction of labor. Bishop scores, cervical dilatation at the onset of induction, and use of prostaglandin gels and epidural anesthesia were likewise very similar. The control group was given oxytocin at 1 to 2 m U I min, and the infusion was increased by 1 to 2 m U I min at 30-minute intervals until adequate labor occurred. The experimental group received the same starting dose, but infusion rates were doubled every 40 minutes until a rate of 8 mU Imin was reached, and then increases were made in smaller increments to advoid hyperstimulation of the uterus. Maximum doses of oxytocin tended to be higher in the experimental group, but this difference was not statistically significant. Dosages infused at the time adequate labor was achieved were similar in both arms of the study. Hyperstimulation occurred in both groups with equal frequency but did not lead to untoward outcomes. Management difficulties were similar in both groups in that decreasing the infusion rate or discontinuing the infusion temporarily was required as often in the experimental group as in the control group. Abnormal FHR patterns were seen more often in the experimental group. This was believed to be due to a higher incidence of variable decelerations in this group. Careful analysis failed to show a relationship between hyperstimulation and these decelerations, indicating this effect was not due to the ocytocin infusion protocol. Cesarean section delivery occurred with equal frequency in both groups. Fetal distress was the indication
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in only two of 62 patients in the control group and three of 69 in the experimental group. Dystocia was the most common indication, occurring with equal fre. quency in both groups. More assisted vaginal deliveries occurred m the experimental group than the control group, most of which were for FHR changes in the second stage of labor. These were not believed to be due to uterine hyperstimulation. Obstetric outcomes were uniformly good in both groups, and no infants delivered had 5-minute Apgar scores
