94

Induction of labor with misoprostol for premature rupture of

membranes beyond thirty-six weeks gestation
Deborah A. Wing, MD, and Richard H. Paul, MD
Los Angeles, California
OBJECTIVE: Our purpose was to compare vaginally administered misoprostol (Cytotec) with intravenous
oxytocin for labor induction in women with premature rupture of membranes beyond 36 weeks gestation.
STUDY DESIGN: Two hundred subjects with rupture of membranes without labor were randomly assigned to
receive vaginally administered misoprostol or intravenous oxytocin. Twenty-five micrograms of misoprostol
(Cytotec) was placed in the posterior vaginal fornix. If cervical ripening (Bishop score of 8 or cervical dilata-
tion of 3 cm) or active labor did not occur, a single repeat dose of misoprostol was given 6 hours later.
Oxytocin was administered intravenously by a standardized incremental infusion protocol to a maximum
dose of 22 mU per minute.
RESULTS: Of the 197 subjects evaluated, 98 received misoprostol and 99 oxytocin. The average interval
from start of induction to vaginal delivery was about 1 hour longer in the misoprostol group (811.5 511.4
minutes) than in the oxytocin group (747.0 448.0 minutes) (P = .65, log transformed data). Oxytocin admin-
istration was necessary in 37 of 98 (37.8%) of misoprostol-treated subjects. Vaginal delivery occurred in 85
misoprostol-treated subjects (86.7%) and 82 (85.9%) oxytocin-treated subjects (relative risk 1.17, 95% confi-
dence interval 0.78 to 1.78, P = .45) with the remainder undergoing cesarean birth. There was no difference
in the incidence of tachysystole (six or more uterine contractions in a 10-minute window for two consecutive
10-minute periods) or hypertonus between the two groups. There was no significant difference in frequency
of abnormal fetal heart rate tracings between the two groups (29.6% in the misoprostol group and 28.9% in
the oxytocin group, P = .91). Chorioamnionitis was diagnosed in 28 (28.6%) misoprostol-treated subjects and
26 (26.3%) oxytocin-treated subjects (P = .72, relative risk 1.06, 95% confidence interval 0.78 to 1.45). No
significant differences were found in the incidence of fetal meconium (8.1% and 9.1%), 1- or 5-minute Apgar
scores <7 (11.0% and 10.2% of 1-minute Apgar scores, and 2.0% and 2.0% of 5-minute Apgar scores),
neonatal resuscitation (24.5% and 27.6%), or admission to the neonatal intensive care unit (25.5% and
32.3%) between the two groups.
CONCLUSIONS: Vaginal administration of misoprostol (Cytotec) is an effective alternative to oxytocin infu-
sion for labor induction in women with premature rupture of the membranes near term. The incidence of un-
toward effects is similar with use of the two agents. (Am J Obstet Gynecol 1998;179:94-9.)
Key words: Induction of labor, misoprostol, premature rupture of membranes
Spontaneous rupture of membranes occurs beyond 36
weeks gestation and before the onset of labor in approx-
imately 10% of pregnancies.
1
The management of this
condition is controversial. Traditionally, induction of
labor is undertaken to prevent chorioamnionitis and
neonatal sepsis. The incidence of both these problems is
increased when premature rupture of membranes is pre-
sent >24 hours before delivery than when delivery occurs
within 24 hours.
1, 2
Multiple studies have compared the
use of expectant management with active labor induc-
tion for treatment of this problem.
3-7
Expectant manage-
ment results in a lower incidence of cesarean deliveries
performed for failed labor inductions.
4, 5
However, this
benefit must be weighed against higher rates of maternal
and neonatal infection
6
and the possibility of cord pro-
lapse resulting from delayed time of delivery with expec-
tant management.
Prostaglandins have been shown to be effective agents
for cervical ripening and labor induction.
8
Several stud-
ies have demonstrated the safety and effectiveness of var-
ious preparations of prostaglandin E
2
(PGE
2
) when pre-
mature rupture of the membranes is present.
9-15
These
studies have shown that the use of intravenous oxytocin
and the incidence of cesarean delivery are less when
From the Department of Obstetrics and Gynecology, Womens and
Childrens Hospital, University of Southern California School of
Medicine.
Received for publication August 18, 1997; revised December 9, 1997;
accepted December 22, 1997.
Reprint requests: Deborah A. Wing, MD, Womens and Childrens
Hospital, University of Southern California School of Medicine,
Department of Obstetrics and Gynecology, 1240 N Mission Road, Los
Angeles, CA 90033.
Copyright 1998 by Mosby, Inc.
0002-9378/98 $5.00 + 0 6/1/88331
Volume 179, Number 1 Wing and Paul 95
Am J Obstet Gynecol
PGE
2
is used to induce labor than when it is not used.
We have previously shown that vaginal administration
of misoprostol (Cytotec), a synthetic prostaglandin E
1
analog, is as effective for prelabor induction cervical
ripening and the induction of labor as dinoprostone
(PGE
2
) is in different vehicles (Prepidil or Cervidil), the
only Food and Drug Administration (FDA)approved
drug for this purpose.
16-18
Because misoprostol appears
as efficacious as dinoprostone for preinduction cervical
ripening and the induction of labor, we believed it could
also be used safely and effectively in women who have
premature rupture of membranes. Others have reported
the use of misoprostol for cervical ripening and labor in-
duction in women with premature rupture of mem-
branes, but to our knowledge there is only one investiga-
tion in which premature rupture of membranes was the
sole indication for labor induction. Misoprostol was ad-
ministered orally in this study.
19
Thus the objective of this study was to compare vagi-
nally administered misoprostol with oxytocin infusion to
induce labor in women with premature rupture of the
membranes beyond 36 weeks gestation who had no evi-
dence of spontaneous labor.
Material and methods
From May 31, 1995, to Feb. 2, 1997, all women with
spontaneous rupture of membranes beyond 36 weeks
gestation at Womens and Childrens Hospital, Los
Angeles CountyUniversity of Southern California
Medical Center were evaluated for study participation.
The study was approved by the Los Angeles County
University of Southern California Investigational Review
Board. Women meeting study criteria were asked about
their willingness to participate in the trial, and if they
elected to do so, an informed consent was obtained.
Rupture of membranes was confirmed by a combina-
tion of two or more of the following: (1) visualization of
amniotic fluid in the vaginal vault with the use of a sterile
speculum, (2) pH >6.5 as indicated by colorimetric pH
change by Nitrazine paper (Bristol-Myers Squibb, Cherry
Hill, NJ), or (3) microscopic appearance of an arboriza-
tion pattern of the amniotic fluid after the fluid in the
vagina was placed on a glass slide and allowed to dry.
Inclusion criteria, in addition to confirmation of rup-
tured membranes, were (1) singleton gestation, (2) reac-
tive fetal heart rate (FHR) pattern, (3) cephalic presenta-
tion, and (4) presumed gestational age of 36 weeks as
determined by dates by last menstrual period, serial pre-
natal examinations, or prenatal ultrasonographic exami-
nation.
Subjects were excluded if any of the following were
present: (1) cervical dilatation in >3 cm, (2) uterine con-
tractions at a rate of >12 per hour, (3) an estimated fetal
weight >4500 gm or other evidence of cephalopelvic dis-
proportion, (4) an estimated fetal weight <1800 g as as-
sessed by ultrasonography, (5) placenta previa or unex-
plained vaginal bleeding, (6) active herpes simplex, (7)
previous cesarean delivery or history of uterine incision,
(8) evidence of chorioamnionitis as determined by tem-
perature 100.4F and the presence of uterine tender-
ness or foul-smelling amniotic fluid, (9) parity >5, (10)
any moderate or severe preexisting medical disease, such
as cardiovascular disease or chronic renal failure, and
(11) any contraindication for use of prostaglandins, such
as glaucoma or sickle cell disease.
The subjects were assigned by means of a computer-
ized random number generator to receive either miso-
prostol (Cytotec, GD Searle, Chicago) or oxytocin.
Group allocation was predetermined and placed in con-
secutively numbered and sealed opaque envelopes. Once
a subject was deemed eligible and gave informed consent
for study participation, she was assigned a sequential
study number. The primary investigator, who was respon-
sible for maintaining the envelopes and not directly in-
volved in patient care, was then contacted and would
open the next envelope for the purpose of treatment al-
location.
Over the 21-month study period a total of 214 subjects
were asked to participate, and 200 agreed. Of these, 101
were randomized to receive misoprostol and 99 to re-
ceive oxytocin. Three subjects were excluded from data
analysis because of deviation from study protocol. These
subjects received a total of three doses of misoprostol. No
women withdrew from the study protocol.
The initial Bishop score was determined by a senior
obstetrics-gynecology resident, and when possible sub-
jects were reexamined by the same individual. Repeat
Bishop scores were determined before each misoprostol
dose and just before oxytocin administration in miso-
prostol-treated subjects. A Bishop score of 13 was arbi-
trarily assigned for those subjects who had entered the
active phase of labor. Once a patient was in the active
phase of labor, routine intrapartum management oc-
curred without regard to the treatment allocation.
Induction with either misoprostol or oxytocin was
started a minimum of 6 hours after the spontaneous rup-
ture of membranes in the absence of uterine contrac-
tions. The mean time from rupture of membranes to ini-
tiation of induction was 890.6 1071.1 minutes in the
misoprostol treatment group and 843.1 981.7 minutes
in the oxytocin treatment group (P = .94, log-trans-
formed data).
Twenty-five micrograms (one fourth of a 100 g tablet)
of misoprostol was placed in the posterior vaginal fornix
by a senior house officer. If the subject did not demon-
strate adequate uterine contraction frequency (more
than three contractions in a 10-minute window of obser-
vation), the same dose was repeated one time in 6 hours
96 Wing and Paul July 1998
Am J Obstet Gynecol
for a maximum dose of 50 g. If the subject did not
demonstrate adequate uterine activity 6 hours after re-
ceiving the second dose of misoprostol, an oxytocin infu-
sion was initiated.
Oxytocin was administered by an infusion pump ac-
cording to a standard protocol. The infusion was initi-
ated with a dose of 1 mU/min with incremental increase
every 30 minutes to a maximum of 20 mU/min.
Continuous external fetal monitoring and external
tocodynamometry were used. FHR patterns were classi-
fied in the manner described by Kubli et al.
20
Abnormal
FHR patterns were defined as the presence of either fetal
tachycardia or bradycardia, late decelerations, or moder-
ate-to-severe variable FHR decelerations.
Evaluation of uterine activity monitoring was per-
formed to assess the frequency and duration of tachysys-
tole, hypertonus, and hyperstimulation syndrome.
21
Uterine hypertonus was defined as a single uterine con-
traction lasting 2 minutes, tachysystole as at least six
uterine contractions in 10 minutes for two consecutive
10-minute windows, and hyperstimulation as either hy-
pertonus or tachysystole associated with an abnormal
FHR pattern. Either intravenous or subcutaneous terbu-
taline 0.25 mg or intravenous magnesium sulfate was ad-
ministered to treat these contraction abnormalities.
The diagnosis of intraamniotic infection or chorioam-
nionitis was made if any of the following were present:
maternal temperature 100.4F, foul-smelling amniotic
fluid, fundal tenderness, or persistent elevation in FHR
baseline 160 beats/min. Chorioamnionitis was treat-
ed with antipyretics and appropriate antimicrobial
agents.
The primary outcome measure was the occurrence of
vaginal delivery within 24 hours from the start of induc-
tion, defined as a successful induction. Induction failure
was defined as failure to achieve cervical dilatation 4 cm
after a trial of oxytocin. Other outcome variables were
route of delivery, and time interval from start of induc-
tion to delivery.
Sample size calculations were based on the number of
subjects achieving a vaginal delivery within 24 hours after
initiating the induction attempt by use of the method de-
scribed by Meinert.
22
A 20% difference in the numbers
of subjects achieving a successful induction in the miso-
prostol treatment arm versus the oxytocin treatment arm
was assumed. It was assumed that 80% of misoprostol-
treated patients and 60% of oxytocin-treated patients
would achieve this outcome. On the basis of a type I error
of .05 and a type II error of .2, a sample size of 81 per
treatment arm was necessary. The test was two sided.
Statistical analysis was performed with use of the
2
,
Student t, Mann-Whitney U, and Fishers exact tests
where appropriate. All tests were 2-sided, with a .05 sig-
nificance. Differences in age, estimated gestational age,
total doses of the inductive agent required, total oxytocin
dose, time in tachysystole (log transformed), and time to
delivery (log transformed) were analyzed with t tests; dif-
ferences in gravidity, parity, route of delivery, presence of
complications, and need for oxytocin were analyzed with

2
tests or Fishers exact tests when appropriate. Apgar
and Bishop scores were analyzed with use of the Mann-
Whitney U test. Relative risk and corresponding 95%
confidence interval comparing misoprostol to oxytocin
treatments were also reported when necessary.
Results
The subjects were similar with respect to mean age,
gravidity, parity, height, weight, ethnicity, and estimated
gestational age at entry. Forty-one (41.8%) of the miso-
prostol subjects and 47 (48.0%) of the oxytocin subjects
were nulliparous (P = .35). The mean estimated gesta-
tional age for the misoprostol treatment group was 38.7
1.5 (SD) weeks and for the oxytocin treatment group
38.9 1.6 (SD) weeks (P = .46). The median preinduc-
tion Bishop score was 3 in the misoprostol group (range
0 to 10) and 4 in the oxytocin group (range 0 to 10) (P =
.57, Mann-Whitney U test).
A similar percentage of subjects in both treatment
groups had a treatment success. Seventy-five (75.8%) of
misoprostol-treated subjects and 73 (74.5%) of oxytocin-
treated women were delivered vaginally within 24 hours
of initiating induction (P = .87). There was no significant
difference in the mean time interval from start of induc-
tion to delivery between the two treatment groups. The
mean time from start of induction to delivery, regardless
of the route, was 900.8 558.1 minutes for the misopros-
Table I. Time intervals to delivery
Misoprostol (n = 98) Oxytocin (n = 99) Statistical significance
Initiation to delivery (min) 900.8 558.1 833.5 485.3 P = .99
*
Initiation to vaginal delivery (min) 811.5 511.4 747.0 448.0 P = .65
*
Vaginal delivery in 12 h 44 (44.4%) 49 (50%) P = .30
Vaginal delivery in 24 h 75 (75.8%) 73 (74.5%) P = .87
Data presented as mean SD or number and percent.
*
Based on log-transformed data.
Volume 179, Number 1 Wing and Paul 97
Am J Obstet Gynecol
tol-treated subjects and 833.5 485.3 minutes for the
oxytocin-treated subjects (P = .99, log-transformed data).
The mean time intervals from start of induction to vagi-
nal delivery were also similar. The mean time from start
of induction to vaginal delivery was 811.5 511.4 minutes
for misoprostol-treated women and 747.0 448.0 min-
utes for oxytocin-treated women (P = .65, log-trans-
formed data) (Table I).
Parity influenced the success of induction, regardless
of the treatment arm. In the misoprostol treatment
group 26 nulliparous (63%) and 49 multiparous (86%)
women were delivered vaginally within 24 hours after ini-
tiating induction, and in the oxytocin treatment group
29 nulliparous (60%) and 44 multiparous (86%) women
were delivered in this time period. Forty-one (41.8%) of
the misoprostol-treated subjects and 48 (48.4%) of the
oxytocin-treated subjects were nulliparous (P = .35). The
mean duration from induction to delivery in misopros-
tol-treated nulliparous women was 1116.3 546.1 min-
utes and in misoprostol-treated parous subjects it was
745.8 517.9 minutes, whereas the mean duration from
induction to delivery in oxytocin-treated nulliparous
women was 1080.1 489.3 minutes and in oxytocin-
treated multiparous women it was 601.3 350.90 min-
utes. These differences were not statistically different be-
tween the two treatment groups (nulliparous subjects P =
.87 and multiparous subjects P = .29, log-transformed
data).
The misoprostol-treated women required an average of
1.3 0.5 doses. Sixty-eight women received one dose of
misoprostol, and 30 received two doses. The average time
interval between doses was 469.7 182.2 minutes (range
330 to 1050 minutes). Thirty-seven (37.3%) women in
this group required oxytocin augmentation. The indica-
tions for oxytocin augmentation were failure to begin ac-
tive labor after two doses of misoprostol (14/37, 37.8%),
inadequate uterine activity in the active phase of labor
(13/37, 35.1%), and adequate cervical ripening after the
first dose of misoprostol (10/37, 27.0%).
Uterine tachysystole occurred in six subjects in each
treatment group. The time interval from the last dose of
misoprostol to the onset of tachysystole was 243.3 118.8
minutes and from initiation of oxytocin to onset of
tachysystole 417.0 209.6 minutes (P = .14). Hypertonus
was reported in only one misoprostol-treated subject.
There were no instances of uterine hyperstimulation.
Abnormal FHR tracings occurred in 29 (29.6%) and 28
(28.9%) of the misoprostol-treated and oxytocin-treated
women, respectively (P = .91) (Table II).
Evidence of intraamniotic infection occurred in simi-
lar frequencies in the two treatment groups. Twenty-eight
(28.6%) misoprostol-treated women and 26 (26.3%) oxy-
tocin-treated women had intraamniotic infection (P =
.71, relative risk 1.06, 95% confidence interval 0.78 to
1.45). Clinical suspicion of neonatal sepsis occurred in
21 (21.4%) infants born to misoprostol-treated women
and 27 (27.3%) infants of oxytocin-treated women (P =
.34, relative risk 0.85, 95% confidence interval 0.60 to
1.19). There were 2 cases of confirmed neonatal sepsis,
both born to mothers treated with oxytocin.
Eighty-five (85.9%) misoprostol-treated women were
delivered vaginally and 82 (83.7%) oxytocin-treated
women were delivered vaginally (relative risk 1.17, 95%
confidence interval 0.78 to 1.78). Of the 13 cesarean
births in women assigned to the misoprostol treatment
arm, 9 were for arrest disorders of labor and 4 were for
abnormal FHR tracings. Of the 17 cesarean deliveries in
the women treated with oxytocin, there were 10 for arrest
disorders, 4 for abnormal FHR tracings, and 3 for failed
inductions.
Neonatal outcomes were also similar between the two
treatment groups (Table III). The mean birth weights
did not differ between the two groups (3214 428 g in
the misoprostol-treated patients and 3250 480 g in
the oxytocin-treated patient (P = .59) The percentage of
infants requiring resuscitation at delivery, demonstrating
meconium passage, assigned Apgar scores <7 at 1 and 5
minutes, and requiring admission to the intensive care
Table II. Intrapartum complications
Misoprostol (n = 98) Oxytocin (n = 99) Statistical significance
Abnormal FHR patterns 29 (29.6%) 28 (28.9%) P = .91
Repetitive moderate-severe variable decelerations 17 10
Late decelerations 3 1
Prolonged decelerations 6 9
Other 0 1
Combinations 3 7
Meconium passage 8 (8.1%) 9 (9.1%) P = .82
Thin 5 9
Thick 3 0
Chorioamnionitis/intrauterine infection 28 (28.6%) 26 (26.3%) P = .71
Data presented as number and percent.
98 Wing and Paul July 1998
Am J Obstet Gynecol
unit were similar between the treatment groups.
Comment
There was no significant difference in the percentage
of subjects having success of induction, defined as vagi-
nal delivery within 24 hours after initiation of induction,
with use of vaginally administered misoprostol or oxy-
tocin infusion. There was also no significant difference in
the mean time intervals from start of induction to deliv-
ery in women with spontaneous rupture of membranes
beyond 36 weeks of gestation when treated with either
misoprostol or oxytocin. There was a trend toward a
higher number of failed inductions in the oxytocin treat-
ment group, because all three cesarean deliveries per-
formed for this indication occurred in oxytocin-treated
subjects. However, this difference was not statistically sig-
nificant.
We were unable to reduce the cesarean delivery rate in
women with premature rupture of membranes by admin-
istering misoprostol rather than oxytocin for labor in-
duction. Because the majority of cesarean sections in
misoprostol-treated women were performed for labor
dystocia, rather than failed induction, misoprostol ap-
pears to be effective for causing cervical dilatation and ef-
facement and inducing labor in patients with premature
rupture of membranes. We were also unable to reduce
the numbers of women receiving antimicrobial therapy
for the diagnosis of chorioamnionitis by administering
misoprostol rather than oxytocin. Intravaginal misopros-
tol administration may have contributed to the relatively
high frequency of chorioamnionitis in this treatment
arm.
We did not meet our assumptions for our power calcu-
lation, because the numbers of subjects achieving a suc-
cessful induction did not differ between the two groups.
However, it would appear that misoprostol can be used
with similar efficacy and safety in patients with premature
rupture of membranes beyond 36 weeks gestation.
The dosing regimen of misoprostol used in this investi-
gation was chosen on the basis of our past experience
with this medication for cervical ripening and labor in-
duction
18
and reflects a degree of conservatism in our ap-
proach to this subset of patients.
In our efforts to create the safest dosing regimen possi-
ble for misoprostol, we designed this protocol to reflect
the most conservative dosing regimen we had had expe-
rience with to date, that of misoprostol 25 g every 6
hours. It would seem from extrapolation from our most
recent investigation in which we compared giving miso-
prostol every 4 hours to a 24-hour exposure to the dino-
prostone vaginal insert Cervidil that a similar dosing fre-
quency could also be used safely in patients with
ruptured membranes.
23
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Misoprostol (n = 98) Oxytocin (n = 99) Statistical significance
Birth weight (g) 3214 428 3250 480 p = .59
Apgar score <7
1 min 11 (11.1%) 10 (10.2%) p = .84
5 min 2 (2.0%) 2 (2.0%) p = .99
*
Neonatal resuscitation 24 (24.5%) 27 (27.6%) p = .63
Admission to NICU 25 (25.5%) 32 (32.3%) p = .29
Days in NICU 9.2 6.4 7.7 3.3 p = .29
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*
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