Materials and Methods
A randomized controlled trial was undertaken at Mater Health Services Brisbane between March 2010 and August 2013. All women with live singleton pregnancies at or beyond 37 + 0 weeks gestation who were booked for IOL with the use of PGE 2 vaginal gel and with a modified Bishop’s score <7 were considered eligible for inclusion in the study. Exclusion criteria included multiple pregnancy, previous cesarean delivery or other uterine surgery, major fetal congenital abnormality or fetal death, any contraindications to vaginal birth (eg, active genital herpes, major placenta praevia), maternal age <18 years, or inability to consent for whatever reason. The trial protocol was registered (ACTRN:12613000370707), and ethics approval was granted from the Mater Health Services Human Research Ethics Committee (Ref 1315M).
After an initial dose of PGE 2 vaginal gel in the evening (2 mg for nulliparous women, 1 mg for multiparous women), women were reviewed at approximately 6:00 AM the next morning. Immediately before their cervical assessment, participants were assigned randomly into either the amniotomy group or repeat-PGE 2 group. Women in the amniotomy group underwent ARM regardless of modified Bishop’s score and received further doses (1 mg PGE 2 , at 6-hour intervals, to a maximum of 3 doses) only if ARM by an experienced clinician was not technically possible at each review. Women who were assigned randomly to the repeat-PGE 2 group continued to receive further doses (1 mg PGE 2 , at 6-hour intervals, to a maximum of 3 doses) until the modified Bishop’s score was ≥7, at which time an ARM was performed. In both groups, a Syntocinon infusion was commenced as soon as the membranes were ruptured. The infusion was commenced at a rate of 1 mU/min and was increased in increments of 4 mU/min every 30 minutes to a maximum rate of 32 mU/min, until 3-4 contractions every 10 minutes were achieved. Active management of the third stage was used. The trial protocol is summarized in Figure 1 .
The primary outcome measure was the length of time from commencement of IOL until birth. The commencement of IOL was defined as the time the first dose of PGE 2 was inserted. Secondary outcome measures included birth “in-hours,” mode of birth, use of epidural analgesia in labor, need for broad-spectrum antibiotics in labor, admission of baby to nursery, postpartum hemorrhage, uterine hyperstimulation with fetal heart rate changes, women’s experience and satisfaction with IOL, and duration of hospital admission. The concept of an “in-hours” birth was used as a measure of both the duration of induced labor and safety, recognizing the frequently reported association between evening/nighttime births and increased adverse perinatal outcomes. An “in-hours” birth was defined as a birth that occurred between 8:00 AM and 5:00 PM. Uterine hyperstimulation with fetal heart rate changes was defined as any event of excessive uterine activity (>5 contractions in 10 minutes) at which time PGE 2 vaginal gel was removed from the vagina or acute tocolysis was administered. A combination of visual inspection by clinicians and weighing of pads/linen was used to estimate postpartum blood loss. Need for broad-spectrum antibiotics in labor was recorded as a surrogate marker of chorioamnionitis. The outcomes of women’s experience and satisfaction with IOL are the subject of subsequent publication and are not reported here.
Randomization (1:1) into the 2 study arms was according to a computer-generated random allocation list. Sealed sequentially numbered opaque envelopes were prepared by Mater Medical Research Institute. At the time of the morning review after an initial dose of PGE 2 vaginal gel, the envelopes were opened by the midwife caring for the woman after confirming verbal consent. Given the nature of the intervention, it was not possible to blind either clinicians or women to their allocation.
Assuming a type-1 error of 0.05 and a power of 80%, a sample size of 125 women per group was calculated to detect a difference of 5 hours (20.5-15.5 hours) in the time from first dose of PGE 2 vaginal gel until birth. These assumptions were based on an unpublished clinical audit that measured a change in policy at Mater Health Services from the use of a multiple-dose PGE 2 vaginal gel protocol to an early amniotomy protocol that was associated with a 5- to 6-hour reduction in the time from IOL to birth. Statistical analyses of primary and secondary outcomes were performed according to the intention-to-treat principle but have also been presented as-per-protocol. The chi squared tests, Fisher exact test, independent samples t -tests, and Mann-Whitney U tests have been used to compare categorical, categorical (small cell numbers), normally distributed, and nonnormally distributed continuous outcomes, respectively, with the use of StataSE software (version 10.1; StataCorp, College Station, TX). Comparisons were deemed statistically significant at a probability level of .05.
Overall, a protocol violation was identified in 39% of cases, with more protocol violations occurring in the repeat-PGE 2 group than in the amniotomy group (65 vs 36). Many protocol violations represented a delay to undertake a review or delay to commence Syntocinon. In the absence of an agreed standard, “>4 hours delay” was chosen as the discriminator as to whether a protocol violation had occurred ( Table 1 ).
| Repeat PGE 2 group (n = 61 protocol violations) a | Amniotomy group (n = 35 protocol violations) |
|---|---|
| After initial PGE 2 dose, >4 hour delay to undertake first review (n = 29) | After initial PGE 2 dose, >4 hour delay to undertake first review (n = 25) |
| After subsequent doses of PGE 2 (if indicated), >4 hour delay to undertake next review (n = 11) | After subsequent doses of PGE 2 (if indicated), >4 hour delay to undertake next reviews (n = 4) |
| After ARM, >4 hour delay to commence Syntocinon (n = 10) | After ARM, >4 hour delay to commence Syntocinon (n = 2) |
| Performing ARM at 2nd or 3rd review when the modified Bishop’s score < 7 (n = 32) | Administering more PGE 2 vaginal gel at 2nd or 3rd review when the modified Bishop’s score ≥5 (n = 4) |
| Failure to perform ARM at any review when the modified Bishop’s score ≥7 (n = 0) | — |
Results
Between March 2010 and August 2013, there were 2057 women booked for PGE 2 vaginal gel IOL at Mater Health Services, Brisbane, Australia who were eligible for inclusion. Two hundred sixty-seven women were approached by the medical officer on the evening of their IOL, of whom 22 declined to participate. Sealed opaque envelopes were prepared, and 250 of the envelopes were opened. However, data were available for only 245 eligible women; it is not known the reason that these 5 additional envelopes were opened, which was not recognized until recruitment was ceased. Of the 245 women who were assigned randomly, 124 were allocated to the repeat-PGE 2 group and 121 to the amniotomy group. Outcome data were available for all 245 participants. The flow of participants is presented in the Consolidated Standards of Reporting Trials diagram ( Figure 2 ).
The baseline characteristics of women who were assigned randomly to the repeat-PGE 2 group and amniotomy group did not differ with respect to age, body mass index, gestation at IOL, ethnicity, indication for IOL, or modified Bishop’s score at the commencement of IOL, either overall or in the subgroup of those treated as-per-protocol. Most women were white with a mean booking body mass index in the overweight range. PGE 2 IOL was performed most commonly because the woman was postterm, and >80% of IOLs were performed for an identifiable clinical indication. In addition, the baseline characteristics of the 2147 eligible women who were not approached were analyzed and confirmed to be similar to the study participants ( Table 2 ).
| Baseline characteristic | Intention-to-treat, n (%) | As-per-protocol, n (%) | Eligible for recruitment, n (%) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Amniotomy group (n = 121) | Repeat- PGE 2 group (n = 124) | P value | Amniotomy group (n = 86) | Repeat- PGE 2 group (n = 63) | P value | Recruited (n = 245) | Not recruited (n = 1812) | P value | |
| Age, y a | 29.3 ± 5.2 | 29.8 ± 4.8 | .39 | 28.8 ± 5.0 | 29.2 ± 4.4 | .67 | 29.5 ± 4.9 | 29.7 ± 5.80 | .48 |
| Body mass index, kg/m 2 a | 26.6 ± 5.9 | 26.9 ± 6.2 | .89 b | 26.8 ± 6.5 | 26.3 ± 5.9 | .71 b | 26.7 ± 6.3 | 26.0 ± 7.0 | .18 b |
| Nulliparity, n (%) | 92 (76.0) | 93 (75.0) | .15 | 61 (70.9) | 47 (74.6) | .25 | 185 (75.5) | 1268 (70.0) | .09 |
| Gestation, wk a | 40.1 ± 1.5 | 40.3 ± 1.4 | .29 b | 40.1 ± 1.5 | 40.5 ± 1.4 | .06 b | 40.1 ± 1.4 | 39.9 ± 1.4 | .31 b |
| Modified Bishop’s score a | 3.6 ± 1.3 | 3.6 ± 1.4 | .98 | 3.5 ± 1.4 | 3.7 ± 1.4 | .24 | 3.6 ± 1.5 | 3.5 ± 1.5 | .56 |
| Ethnicity, n (%) | .85 | .31 | .22 | ||||||
| White | 93 (76.8) | 86 (69.4) | 69 (80.2) | 43 (68.3) | 179 (73.1) | 1168 (64.5) | |||
| Asian | 10 (8.3) | 14 (11.3) | 6 (7.0) | 9 (14.3) | 24 (9.8) | 344 (19.0) | |||
| Aboriginal and/or Torres Strait Islander | 2 (1.7) | 3 (2.4) | 2 (2.3) | 1 (1.6) | 5 (2.0) | 41 (2.3) | |||
| Pacific Islander/Maori | 4 (3.3) | 4 (3.2) | 1 (1.2) | 0 | 8 (3.3) | 48 (2.7) | |||
| Other | 12 (9.9) | 17 (13.7) | 8 (9.3) | 10 (15.8) | 29 (11.9) | 211 (11.6) | |||
| Indication for induction of labor, n (%) | .76 | .55 | .12 | ||||||
| Postterm | 64 (52.9) | 68 (54.8) | 43 (50.0) | 39 (61.9) | 132 (53.9) | 853 (47.1) | |||
| Diabetes mellitus | 20 (17.0) | 20 (16.1) | 16 (18.6) | 9 (14.3) | 40 (16.3) | 215 (11.9) | |||
| Hypertension | 6 (5.0) | 10 (8.1) | 4 (4.7) | 4 (6.3) | 16 (6.5) | 198 (10.9) | |||
| Isoimmunization | 0 | 1 (0.8) | 0 | 1 (1.6) | 1 (0.4) | 7 (0.4) | |||
| Suspected small for gestational age/fetal growth restriction | 4 (3.3) | 1 (0.8) | 5 (5.8) | 1 (1.6) | 5 (2.0) | 67 (3.7) | |||
| Cholestasis | 5 (4.1) | 5 (4.0) | 4 (4.7) | 3 (4.8) | 10 (4.1) | 63 (3.4) | |||
| Antepartum hemorrhage | 0 | 0 | 0 | 0 | 0 | 11 (0.6) | |||
| Social | 3 (2.5) | 2 (1.6) | 3 (3.5) | 2 (3.2) | 5 (2.0) | 167 (9.2) | |||
| Other | 19 (15.7) | 17 (13.7) | 12 (14.0) | 4 (6.4) | 36 (14.7) | 232 (12.8) | |||
a Data are given as mean ± standard deviation
The morning after an initial dose of PGE 2 vaginal gel, 10.0% of those women who had been assigned randomly to the amniotomy group and 12.8% of those who were assigned randomly to the repeat-PGE 2 group had a favorable cervix (modified Bishop’s score, ≥7). Of the women who were assigned randomly to the amniotomy group, most (80.8%) received just a single dose of PGE 2 vaginal gel; 15.0% received 2 doses; 4.2% received 3 doses, and 89% were administered a Syntocinon infusion. Of the women assigned randomly to the repeat-PGE 2 group, only 36.7% received a single dose of PGE 2 vaginal gel; 47.5% received 2 doses; 15.8% received 3 doses, and a similar proportion (87%) were administered a Syntocinon infusion.
The primary outcome is presented in Table 3 . Overall, the time for IOL-to-birth was >5 hours shorter in women randomized to the amniotomy group (24.8 vs 30.0 hours; mean difference, 5.2 hours [95% confidence interval, –2.5 to –7.8]). This result was also significant in the subgroup of those treated as-per-protocol. In an examination of the time intervals that comprise the overall IOL-to-birth time, there was a trend toward a 1-hour shorter interval from ARM until birth in women who received repeat doses of PGE 2 . However, a 1-hour shorter interval from first dose PGE 2 to next review and a 5- to 6-hour shorter interval between the first dose of PGE 2 and rupture of membranes contributed to the overall finding of a shorter IOL-to-birth time in women who were assigned randomly to the amniotomy group. Despite a shorter duration of IOL and fewer women remaining undelivered after 24 hours in the amniotomy group, the likelihood of an in-hours birth was no different between the groups. In addition, the shorter IOL-to-birth time in the amniotomy group did not eventuate in a shorter overall length of hospital stay compared with women in the repeat-PGE 2 group.
| Time intervals | Intention-to-treat, mean (SD) | As-per-protocol, mean (SD) | ||||||
|---|---|---|---|---|---|---|---|---|
| Amniotomy group (n = 121) | Repeat-PGE 2 group (n = 124) | Mean difference (95% confidence interval) | P value | Amniotomy group (n = 86) | Repeat-PGE 2 group (n = 63) | Mean difference (95% confidence interval) | P value | |
| Between 1st dose PGE 2 and birth, hr | 24.8 (8.3) | 30.0 (12.0) | 5.2 (2.5–7.8) | < .01 a | 22.9 (8.3) | 26.8 (10.8) | 3.9 (0.7–7.1) | .02 a |
| Between 1st dose PGE 2 and next review | 12.4 (3.6) | 13.7 (5.0) | 1.4 (0.3–2.5) | — | 11.0 (2.0) | 12.0 (3.1) | 0.9 (0.1–1.7) | — |
| Between 1st dose PGE 2 and ARM | 14.2 (5.3) | 20.6 (9.6) | 6.4 (4.4–8.4) | — | 12.4 (4.5) | 17.8 (8.2) | 5.3 (3.2–7.5) | — |
| Between review after 1st dose and birth | 12.3 (7.2) | 16.4 (10.1) | 4.1 (1.9–6.3) | — | 11.6 (7.3) | 17.0 (11.5) | 5.4 (2.3–8.4) | — |
| Between ARM and birth | 9.9 (4.9) | 8.7 (5.2) | –1.3 (–2.6 to 0.1) | — | 9.7 (4.8) | 8.0 (4.8) | –1.6 (–3.4 to 0.2) | — |
| Between 1st dose PGE 2 and discharge home, hr | 100.6 (32.4) | 103.2 (32.6) | –2.6 (–10.9 to –5.6) | .53 | 95.7 (33.4) | 94.6 (30.1) | 1.1 (–9.7 to 11.7) | .85 |
| Delivery not achieved within 24 hr | 57 (47.1) | 84 (67.7) | 0.70 (0.56–0.87) b | < .01 a | 29 (33.7) | 33 (53.3) | 0.64 (0.44–0.94) | .02 a |
| In-hours birth (8:00 AM-5:00 PM) | 51 (42.2) | 46 (37.1) | 1.13 (0.83–1.55) b | .42 | 41 (47.7) | 30 (47.6) | 1.00 (0.71–1.41) | .99 |
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