Current obstetric management of preterm rupture of membranes (PROM) at term includes immediate delivery.1 Management of preterm PROM is controversial, but several studies suggest intentional delivery is a reasonable option after 30 weeks,2 34 weeks,3,4 or 32 weeks of gestation with mature amniotic fluid lung studies.5 Local application of prostaglandin (PG) E2 has been shown to be an effective method of cervical ripening in preterm6,7 and term patients with PROM.8–11 Misoprostol also has been shown to be effective compared with oxytocin in patients with PROM who are at or near term.12–15 However, misoprostol has not been compared with PGE2 in studies designed exclusively for women with PROM. We compared local application of PGE2 gel with intravaginal misoprostol in women with PROM at or after 34 weeks of gestation who had an unripe cervix and were undergoing intentional labor induction.
MATERIALS AND METHODS
All women with spontaneous rupture of membranes at or beyond 34 weeks gestation who attended the Arnold Palmer Hospital for Children and Women from January 1, 1995, through December 31, 2000, were considered candidates for this study. Approval was obtained from the Orlando Regional Healthcare System Investigational Review Board. Women who met study criteria were counseled and gave informed consent to participate. Ruptured membranes were diagnosed when amniotic fluid drained from the cervical os during sterile speculum examination or if a pool of fluid in the posterior fornix had a positive result to both fern and phenaphthazine (nitrazine tests). Inclusion criteria were singleton gestations; absence of nonreassuring fetal heart rate patterns; cephalic presentation; gestational age of at least 34 weeks, as determined by date of last menstrual period, serial prenatal examination, or prenatal ultrasono-graphic examination; no evidence of labor, cervical dilatation less than 3 cm and effacement of no more than 80%, no contraindication to labor or vaginal delivery; and spontaneous rupture of membranes. Patients were excluded if they had estimated fetal weight over 4500 g; evidence of intrauterine infection; or any contraindication to use PG, such as severe cardiovascular disease, renal failure, glaucoma, or sickle cell disease. Patients with one previous low transverse cesarean delivery were not excluded.
Women were assigned to receive misoprostol or PGE2 gel by using a computer-generated random number table. Group allocations were placed in consecutively numbered sealed opaque envelopes. The envelopes were generated in lots of 50 with equal numbers of assignments to PGE2 or misoprostol; all envelopes were used before the next lot was started. Women assigned to the misoprostol group received 50 μg (half of a 100-μg tablet) of misoprostol (Cytotec; GD Searle and Company, Chicago, IL) intravaginally in the posterior fornix. The dose was repeated in 6 hours if the patient was not in labor (at least three contractions in 10 minutes, with cervical change.) The maximum total dose of misoprostol was 100 μg, or two doses. Women assigned to the PGE2 group received application of 2.5 mg of PGE2 gel in the vagina every 6 hours. The preparation and protocol for the PGE2 has been described elsewhere.16 If the patient was not in labor by 12 hours after the first dose of medication, an oxytocin induction was started.17
The initial determination of cervical dilatation and effacement was made by the obstetrics-gynecology resident on admission. The fetal heart rate was monitored by using continuous electronic fetal monitoring in all participants. We reviewed each fetal heart rate monitoring strip after delivery to assess the frequency and duration of tachysystole and hyperstimulation. Tachysystole was defined as at least six contractions in 10 minutes for two consecutive 10-minute periods. Hyperstimulation was defined as the presence of tachysystole associated with fetal tachycardia, late decelerations, or loss of beat-to-beat variability. Recognized episodes of hyperstimulation were managed with change in maternal position, oxygen administration, and 250 μg of terbutaline given subcutaneously. The occurrence of chorioamnionitis (maternal fever usually associated with maternal and fetal tachycardia, uterine tenderness, and peripheral leukocytosis) and postpartum endometritis (presence of maternal fever and uterine tenderness, leukocytosis, and foul-smelling lochia) was evaluated in all patients. Sepsis in the neonate was defined as at least one positive blood culture believed not to be a contaminant. The physicians who managed labor were not blinded to study group allocation.
Power analysis was based on detection of a 30% improvement in delivery within 12 hours, from 35%10 to 65% in the misoprostol group. Assuming an α value of .05 and 80% power, 40 patients in each group were required. Characteristics and outcome variables were analyzed by using the Student t-test, Mann Whitney U test, or χ2 analysis. P < .05 indicated statistical significance. Statistical and power analysis were performed by using computer software package SPSS (Chicago, IL). Statistical analysis was done on an intention-to-treat basis.
Fifty-four of the 109 women enrolled were allocated to receive misoprostol, and 55 received PGE2 gel. The distribution of patient age, parity, gestational age, maternal weight, previous cesarean delivery, time from PROM to randomization, and proportion of patients with an unfavorable cervix were similar in the misoprostol and PGE2 groups (Table 1). Twenty-four (44%) and 19 (35%) of patients in the misoprostol and PGE2 groups, respectively, were at more than 37 weeks of gestation (P = .29). Tachysystole during ripening occurred in 11 (20%) patients in the misoprostol and 3 (6%) in the PGE2 groups (P = .02, χ2 test). Hyperstimulation occurred in 5 (9%) women in the misoprostol and to women in the PGE2 group (P = .02, χ2 test).
Table 2 compares outcome variables and mode of delivery in the two study groups. None of the cesarean sections were performed during the ripening period for hyperstimulation. The mean time from start of induction to delivery was significantly shorter in the misoprostol group. A significantly lower maximum rate of oxytocin was administered to women in the misoprostol group. The indications for cesarean delivery were similar between the misoprostol and PGE2 groups; the most common reasons were nonreassuring fetal surveillance (5 [9%] patients vs with 6 [11%] patients, respectively; P = .53, χ2) and arrest of labor (4 [7%] patients vs 6 [11%] patients; P = .77, χ2). Table 3 shows the cumulative number of patients delivered from first insertion. Profiles of intrapartum complications and adverse maternal or perinatal outcomes were similar in both study groups (Table 4).
Intravaginal application of PGE2 and misoprostol for cervical ripening and labor induction in patients with PROM at and near term have been studied and found to be of benefit.10,14,15 Until now, misoprostol had not been tested against PGE2 in a study designed exclusively for patients with PROM. Several previous studies, however, included PROM patients. Intravaginal misoprostol at starting doses of 25 μg,18 50 μg,19,20 and 100 μg21 was compared with PGE2 in term pregnancies and was found in each study to be superior to PGE2. The percentage of patients with PROM in the studies varied from 1%18 to 36%.19 Our study also suggests that intravaginal misoprostol is superior to PGE2 in patients with PROM after 34 weeks of gestation.
Intentional delivery before term and without evidence of lung maturity in patients with PROM remains controversial. Recent data indicate that expectant management of patients with PROM after 34 weeks of gestation results in a significantly higher frequency of chorioamnionitis and neonatal sepsis.1,4,22 We observed an incidence of positive neonatal blood cultures of 9% in the misoprostol group and 7% in the PGE2. These rates are similar to those in the study of Mercer et al,5 who reported a confirmed neonatal sepsis incidence of 6.8% in women with PROM at 32–36 weeks of gestation who had immediate induction. They used oxytocin as the inducing agent, and the time from start to delivery was 14 hours compared with 16 hours in our study.
The incidence of tachysystole of 20% in our study probably reflects the intravaginal misoprostol dose of 50 μg. The dosing regimen of misoprostol was chosen on the basis of our experience16 with use of this medication for cervical ripening and labor induction. More recent investigations15 suggest that use of 25 μg of intravaginal misoprostol every 6 hours has a tachysystole rate of 6% and may be the optimal dose in patients with PROM. Although there is a trend toward longer hospitalizations in neonates of the misoprostol group, our numbers are insufficient to detect potentially important adverse events.
Bias may have been introduced because our study design did not require masking of the investigator. However, the use of randomization at study enrollment and strict study and labor and delivery protocols should have minimized selection or measurement bias.
When the study protocol was initially developed, PG application for cervical ripening in pregnant women with a previous low transverse cesarean delivery was thought to be safe.23 Current opinion now questions the safety of both PG24 and misoprostol25 use in pregnant women with a previous cesarean delivery.
In conclusion, in women with PROM after 34 weeks of gestation, intravaginal misoprostol shortened the time to delivery compared with PGE2 gel.
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