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Premature rupture of membranes in nulliparas at term with unfavorable cervices: a double-blind randomized trial of prostaglandin and placebo
Premature Rupture of Membranes in Nulliparas at Term With Unfavorable Cervices: A DoubleBlind Randomized Trial of Prostaglandin and Placebo S. CHUA, MRCOG, S. ARULKUMARAN, FRCOG, C. YAP, MBBS, N. SELAMAT, BSc, AND S. S. RATNAM, FRCOG Objective: To determine whether the use of a prostaglandin (PG) E2 3-mg pessary followed by a delay of 12 hours before stimulation of labor with oxytocin improves obstetric outcome compared with the use of a placebo pessary. Methods: One hundred fifty-five nulliparas at term with poor cervical scores (modified Bishop score below 6 of 10) and premature rupture of membranes (PROM) were recruited for this double-blind, placebo-controlled randomized trial. On admission to the study, either a PGE 2 pessary or an identical-appearing placebo pessary was inserted into the posterior fornix. If labor did not start in the next 12 hours or if symptoms and signs of infection were evident, labor was induced with oxytocin infusion. Assignment was unblinded at the end of the study, and details of the labor and maternal and neonatal outcome in women who received a PG pessary were compared with those who received a placebo pessary. Results: Women receiving a PG pessary were significantly less likely to require stimulation of labor at the end of 12 hours than were those given a placebo pessary (37 versus 58%, P = .002). The mean time between admission to study and delivery was significantly shorter in the PG group compared with the placebo group (15 versus 19 hours, P = .01). The rate of cesarean delivery was not statistically different in the two groups (13.9% with PG versus 15.8% with placebo). Conclusion: In nulliparas with poor cervical scores who present with PROM at term and no evidence of infection or obstetric complications, use of a PGE 2 pessary resulted in more women establishing labor earlier, with a resultant reduction in the admission-to-delivery interval, compared with the use of a placebo pessary. The cesarean delivery rates in the two groups were similar, and there were no significant differences in neonatal outcome. (Obstet Gynecol 1995;86: 550-4)
From the Department of Obstetrics and Gynaecology, National University Hospital, Singapore.
550 0029-7844/95/$9.50 SSDI 0029-7844(95)00214-C
N u l l i p a r o u s w o m e n at term with p r e m a t u r e r u p t u r e of m e m b r a n e s (PROM), especially those with poor cervical scores, have a high cesarean delivery rate w h e n labor is i n d u c e d with oxytocin i n f u s i o n on admission. 1-6 With an o v e r n i g h t conservative policy, those w h o establish s p o n t a n e o u s labor fare well, b u t a substantial p r o p o r t i o n of those w h o require s t i m u l a t i o n of labor the next m o r n i n g will be delivered by cesarean for dystocia. 7 A c o m p a r a t i v e s t u d y s of i m m e d i a t e oxytocin stimulation, as opposed to oxytocin s t i m u l a t i o n after o v e r n i g h t conservative m a n a g e m e n t , did not find a reduction in the cesarean delivery rate. C o n s e r v a t i v e m a n a g e m e n t has been reported to reduce the cesarean rate over that with i m m e d i a t e oxytocin induction. 4 However, traditional teaching a n d reports from large retrospective series 9-~3 p o i n t to an increased possibility of m a t e r n a l a n d neonatal infectious m o r b i d i t y with u n l i m i t e d conservative m a n a g e m e n t in term p r e g n a n cies, Some authors I4-~7 claimed that the use of prostaglandins (PG) results in a better obstetric outcome, whilst others ~s found that the use of two 3-rag PGE2 pessaries 4 hours apart, followed by oxytocin infusion, if necessary, did not confer benefit over the use of i n t r a v e n o u s (IV) oxytocin started a few hours after PROM. The m a i n difference b e t w e e n the s t u d y designs of those w h o have claimed success with PGE 2 a n d those who were u n s u c cessful was the period of latency after the use of PG before oxytocin infusion. Therefore, we c o n d u c t e d a d o u b l e - b l i n d placebo-controlled r a n d o m i z e d trial in n u l l i p a r a s at term with poor cervical scores a n d with PROM. In one s t u d y arm, we used a PGE2 3-mg pessary, and, in the other, a n identical-looking placebo pessary followed 12 hours later by s t i m u l a t i o n with
Obstetrics & Gynecology
oxytocin to determine whether the use of PG improves obstetric outcome.
Table 1. Maternal Characteristics
Materials and Methods
Mean (-+-SD) maternal age (y) Mean (+SD) gestational age (wk) Median interval PROM and a d m i s s i o n to s t u d y (h) Median cervical score
Nulliparous women who presented to the National University Hospital labor ward after 36 weeks' gestation and who had PROM more than 2 hours earlier and poor cervical scores, were considered for the study. Eighty percent of the women were from middle and high socioeconomic groups, whilst the others were from lower-income groups. We recruited 155 women for the study. To halve the cesarean delivery rate found in our earlier study is by lengthening the time between PG insertion and stimulation to 12 hours and, considering alpha 0.05 and power 0.9, we estimated that the sample size required to detect this increase would be 152. A sterile speculum examination was performed to confirm obvious leakage of amniotic fluid (AF). Cases in which there was doubt about the diagnosis of PROM and women with antenatal medical or obstetric complications (such as multiple pregnancy, malpresentation, meconium-stained AF, or evidence of intrauterine infection) were excluded from the study. A cardiotocograph was performed to assess fetal well-being and to confirm the absence of contractions. Women with no contractions in 10 minutes (any contractions being painless) were recruited for the study after informed consent was obtained, as approved by the department ethics committee. A digital examination was performed to assess the cervical score and to exclude occult cord prolapse. Cervical scoring was based on a modified Bishop score, with a rating of 0-2 given for each of the cervical characteristics of position, length, consistency, and dilation, in addition to station of the head. A poor cervical score was assessed as one below 6 of a possible 10 points. A PGE2 (Prostin; Upjohn, Crawley, UK) 3-mg pessary and an identical-looking placebo pessary prepared by the National University Hospital pharmacy were placed in dark bottles. The bottles were randomly numbered by computer-generated lists, and the master list was not revealed to the clinical investigators until the study was completed. On admission to the study, each subject was allocated a numbered bottle in consecutive sequence. The pessary was inserted into the posterior fornix, and the women were monitored in the delivery suite for an additional 2 hours. If the cardiotocographic tracing was normal and the woman was not in labor, she was sent to the antenatal ward to ambulate. If labor did not start in the next 12 hours or if symptoms and signs of infection were evident, she was brought to
VOL. 86, NO. 4, P A R T 1, O C T O B E R 1995
Prostaglandin 01 = 79)
Placebo (n = 76)
28 (5.1) 39 (1.3) 3 [2-131
28 (4.8) 39 (1.3) 3 [2-13]
3 [1-5] '
3 [1-5]
SD = s t a n d a r d deviation; PROM = p r e m a t u r e rupture of m e m branes. Data are presented as m e a n (-+SD) or m e d i a n [range between fifth and 95th percentiles].
the delivery suite for stimulation of labor with oxytocin infusion. Details of labor and maternal and neonatal outcome data were collected on a coding sheet. When rupture of membranes occurred more than 12 hours earlier, tile women were given prophylactic IV ampicillin (if they were not allergic) in labor. If delivery occurred more than 24 hours after PROM, the neonate was treated prophylactically with intramuscular ampicillin and gentamycin after taking ear, nose, and umbilical swabs for sepsis, and blood for culture and white cell count. At the end of the study, the randomization was unblinded and the details of labor and maternal and neonatal outcome of women who received PG pessaries were compared with those of women who received placebo pessaries. Statistical significance was calculated using X2, Fisher exact, and Wilcoxon rank-sum tests.
Results During the 3-year study period between January 1992 and December 1994, 155 women were randomly allocated to one of two treatment arms. There were no significant differences between the two groups in mean maternal age and mean gestational age at time of rupture of membranes. The median cervical scores and interval between rupture of membranes and admission to the study were similar in the two groups (Table 1). Women in whom a PG pessary was inserted were significantly less likely to require stimulation of labor at the end of 12 hours compared with those given a placebo pessary (29 of 79 [37%] in the PG group versus 44 of 76 [58%] in the placebo group, P = .002). If oxytocin was necessary at any time in labor, the mean maximum doses of oxytocin used in the two groups of w o m e n (9 m U / m i n u t e in the PG group and 12 m U / m i n u t e in the placebo group) were not significantly different (P = .09). As indicated in Table 2, women who had PG pessaries inserted on admission had a shorter interval between admission to the study and the onset of labor. Consequently, the latent period from rupture of mem-
Chua et a l
PROM and Nulliparas
551
T a b l e 2. Interval From Rupture of Membranes to Delivery
Prostaglandin Placebo (11 = 79) (11 = 76) Median interval from admission* to labor onset (h) Median interval from PROM to labor onset (h) Median length of labor (h) Median interval from ROIVlto delivery (h) Median interval from admission* to delivery (h)
8 12-161
12 11-931 <.001 15 [5-941
.009
7 [2-131 19 [8-381
7 [2-141 23 [9-441
.6 .05
15 [6-291
19 [6-991
.01
PROM = premature rupture of membranes; ROM = rupture of membranes. Data are presented as median [range between fifth and 95th percentiles]. *Admission to the study at time of randomization.
branes to onset of labor was significantly shorter in the PG g r o u p (P = .009). The lengths of labor of the two g r o u p s were not significantly different. The interval from r u p t u r e of m e m b r a n e s to delivery tended to be shorter in the PG group, b u t this difference did not reach statistical significance (P = .054). However, the m e d i a n interval b e t w e e n a d m i s s i o n to the s t u d y and delivery was significantly shorter in the PG g r o u p compared with those who received placebo (P = .01). There were no instances of h y p e r s t i m u l a t i o n in either
group,. There was no statistically significant difference in the rates of maternal a n d neonatal infection in the PG and placebo g r o u p s (Table 3). A l t h o u g h fewer mothers a n d neonates in the PG g r o u p received antibiotics c o m p a r e d with the placebo group, the difference did not reach statistical significance. Two w o m e n in the PG g r o u p and one in the placebo g r o u p were g i v e n IV ampicillin because of maternal pyrexia. The other w o m e n (56 of 77 in the PG g r o u p and 64 of 75 in the placebo group) received antibiotics prophylactically. Two neonates, one in each group, were given antibiotics for 7 days because of a positive blood culture. Twenty-five of 78 in
T a b l e 3. Maternal and Neonatal Infection
Maternal pyrexia (n) Prophylactic antibiotics to mother (n) Symptoms and signs of infection in neonate (11) Positive blood culture in neonate (n) Prophylactic antibiotics to neonate 01)
552
Chua et al
Placebo (n = 76)
P
2 58
1 65
1.0 .063
1
3
.361
1
1
26
35
PROM and Nulliparas
Prostaglandin Placebo 01 = 79) (n = 76)
P
12 I4-291
Prostaglandin (11 = 79)
Table 4. Indices of Maternal and Neonatal Outcorne in the Two Groups
1.0 .094
Cesarean delivery (11) Neonates with Apgar score <5 at 1 min Neonates with Apgar score <7 at 5 rain Neonatal admission to special unit
11 (13.9%) 2 1 6
12 (15.8%) 1 0 6
the PG g r o u p a n d 34 of 75 in the placebo g r o u p took antibiotics for 3 days until the results of the swabs a n d blood culture were s h o w n to be negative for neonatal infection. Cesarean delivery rates were not statistically different in the two g r o u p s (13.9% in the PG g r o u p a n d 15.8% in the placebo group, P = .744). The neonatal outcomes, as judged by low 1- and 5 - m i n u t e A p g a r scores and a d m i s s i o n to the special care baby unit, were similar in the two g r o u p s (Table 4).
Discussion Most w o m e n (65-73%) with PROM at term will enter labor w i t h i n 24 hours. 4 M a n a g e m e n t of those w h o present in labor or go into labor shortly after PROM does not pose a problem. In those w h o do not establish labor, most clinicians i n d u c e labor if it has not b e g u n b y the end of an arbitrary period. Such latency periods vary b e t w e e n i m m e d i a t e s t i m u l a t i o n at a d m i s s i o n to several days later. 19 Reports of m a t e r n a l and perinatal m o r b i d i t y and mortality in term p r e g n a n c y with delayed delivery after PROM 9-13"2° p r o v i d e an incentive to deliver as early as possible after PROM. Good obstetric o u t c o m e can be achieved by i m m e d i a t e s t i m u l a t i o n with oxytocin in m u l t i p a r o u s w o m e n with high cervical scores. 2 Such a policy for nulliparas, especially for those with poor cervical scores, results in longer labor, the need for a higher dose of oxytocin, more o m i n o u s fetal heart rate changes in labor, a n d an increased incidence of dystocia, often..leading to cesarean delivery. 2 A n alternative w o u l d be conservative m a n a g e m e n t by vaginal application of PGE2 pessaries or gel. Treatm e n t with PGE2 has been reported to be effective in r e d u c i n g the cesarean delivery rate in w o m e n with u n f a v o r a b l e cervices, w i t h o u t increasing the risk of infection. 14-17 However, our p r e v i o u s s t u d y is f o u n d no benefit from PG w h e n 94 n u l l i p a r a s with poor cervical scores a n d PROM at term were r a n d o m i z e d to either i m m e d i a t e s t i m u l a t i o n of labor with oxytocin or to two PGE2 pessaries 4 hours apart, followed b y oxytocin infusion 4 hours after the second pessary if regular
Obstetrics & Gynecology
painful contractions and progressive cervical changes were not observed. The cesarean rate in the latter study 1~ did not differ significantly between the two groups and was almost twice the cesarean rate of 10-12% reported in other studies. 3'1s'16 The reason for the lower cesarean delivery rate reported in other studies may be due to the use of PGE2 pessaries or gels being left to act for 18-24 hours in other studies, compared with only 8 hours in our earlier study, is In the present study in which labor was not stimulated until 12 hours after admission, the cesarean delivery rate was lower than that in a similar population in our previous study ~8 in the same center when labor was stimulated immediately on admission (15% in the group stimulated immediately with oxytocin and 19% of those who had PGE 2 pessaries inserted 4 hours apart, followed, if necessary, by oxytocin induction 4 hours later). In the present study, the cesarean rates were not significantly different in the PG and placebo groups. In nulliparas with PROM and poor cervical scores, perhaps waiting for a limited period with or without a PG pessary resulted in ~ lower cesarean rate than when labor was stimulated immediately on admission. 1'6"21-23 Women who received PG on admission to the study were more likely to enter labor earlier, without the need for stimulation with oxytocin. The latent interval between rupture of membranes and onset of labor was significantly shorter in the PG group than in the placebo group. This translated to a shorter admission-todelivery interval in women who received PG pessary on admission compared with those who received placebo. Because the risk of infection for both mother and neonate is greater with an increase in rupture-todelivery interval, use of a PG pessary should be helpful in decreasing the incidence of maternal and neonatal infectious morbidity and mortality. The incidence of maternal and neonatal infection was small in both PG and placebo groups. In all cases in which there was evidence of maternal or neonatal infection, the interval from PROM to delivery exceeded 18 hours. Larger numbers will be needed to show any significant change in the incidence of infection with the two modalities of management.
4.
5. 6.
7.
8.
9.
10. 11. 12. 13.
14.
15.
16.
17.
18.
19.
References I. Duff P, Huff RW, Gibbs RS. Management of premature rupture of membranes and unfavorable cervix in term pregnancy. Obstet Gynecol 1984;63:697-702. 2. Rydhstrom H, Arulkumaran S, Ingermarsson [, Kumar J, Ratnam SS. Premature rupture of membranes at term: Obstetric outcome with oxytocin stimulation in relation to parity and cervical dilatation at admission. Acta Obstet Gynecol Scand 1986;65:587-91. 3. Van der Waalt D, Venter PF. Management of term pregnancy with
VOL. 86, NO. 4, PART 1, OCTOBER 1995
20.
21. 22.
23.
premature rupture of the membranes and unfavourable cervix. S Afr Med J 1989;75:54-6. Grant J, Keirse MJNC. Prelabour rupture of the membranes at term. In: Chalmers I, Einken M, Keirse MJNC, eds. Effective care in pregnancy and childbirth. 1st ed. Oxford: Oxford University Press, 1989:1112-7. Morales WJ, Lazar AJ. Expectant management of rupture of membranes at term. South Med J 1986;79:955-8. Grant JM, Serle E, Mahmood T, Sarmandal P', Conway DI. Management of prelabour rupture of the membranes in term primigravidae: Report of a randomized prospective trial. Br J Obstet Gynaecol 1992;99:557-62. Conway DI, Prendiville WJ, Morris A, Speller DCE, Stirrat GM. Management of spontaneous rupture of the membranes in the absence of labor in primigravid women at term. Am J Obstet Gynecol 1984;150:947-51. Arulkumaran S, Khashoggi YT, Thavarasah AS, Ra~am SS. Obstetric outcome of overnight conservative and immediate stimulation policies for premature rupture of membranes. Sing J Obstet Gynecol 1988;19:163-8. Johnson JWC, Daikoko NH, Niebyl JR, Johnson TRB, Khuzami VA, Witter FR. Premature rupture of the membranes and prolonged latency. Obstet Gynecol 1981;57:547-56. Russel KP, Anderson GV. The aggressive management of rupture of membranes. Am J Obstet Gynecol 1962;83:930-7. Gunn GC, Mishell DR, Morton DG. Premature rupture of the fetal membranes--A review. Am J Obstet Gynecol 1970;106:469-83. Fayez JA, Hasan AA, Jonas HS, Miller GL. Management of premature rupture of the membranes. Obstet Gynecol 1978;52:17-21. Schutte MF, Treffers PE, Kloosterman GJ, Soepa~ni S. Management of premature rupture of membranes: The risk of vaginal examination to the infant. Am J Obstet Gynecol 1983;146:395-400. Ekman-Ordeberg G, Uldbjerg S, Ulmsten U. Comparison of intravenous oxytocin and vaginal prostaglandin E2 gel in women with unripe cervixes and premature rupture of the membranes. Obstet Gynecol 1985;66:307-10. Granstr6m L, Ekman G, Ulmsten U. Cervical priming and labor induction with vaginal application of 3 mg PGE2 in suppositories in term pregnant women with premature rupture of amniotic membranes and unfavourable cervix. Acta Obstet Gynecol Scand 1987;66:429-31. Mahmood TA, Dick MJ, Smith NC, Templeton AA. Role of prostaglandin in the management of prelabour rupture of the membranes at term. Br J Obstet Gynaecol 1992;99:112-7. Ray DA, Garite TJ. Prostaglandin E 2 for induction of labor in patients with premature rupture of membranes at term. Am J Obstet Gynecol 1992;166:836-43. Chua S, Arulkumaran S, Kurup A, Anandakumar C, Tay D, Ratnam SS. Does prostaglandin confer significant advantage over oxytocin infusion for nulliparas with pre-labor rupture of membranes at term? Obstet Gynecol 1991;77:664-7. Garite TJ. Premature rupture of the membranes: The enigma of the obstetrician. Am J Obstet Gynecol 1985;151:1001-5. Lanier RL, Scarborough RW, Fillingim DW, Baker RE. Incidence of maternal and fetal complication associated with rupture of the membranes before onset of labor. Am J Obstet Gynecol 1965;93: 398-404. Duncan SLG, Beckley S. Prelabour rupture of membranes--Why hurry? Br J Obstet Gynaecol 1992;99:543-5. Kappy KA, Cetrulo CL, Knuppel RA, et al. Premature rupture of the membranes: A conservative approach. Am J Obstet Gynecol 1979;134:655-61. Kappy KA, CetTulo CL, Knuppel RA, et al. Premature rupture of
C h u a et al
PROM and Nulliparas
553
the membranes at term. A comparison of induced and spontaneous labors. J Reprod Med 1982;27:29-33.
Received March 1, 1995. Received in revised form May 22, 1995. Accepted June 19, 1995.
Address reprint requests to:
Selina Chua, MD Department of Obstetrics and Gynaecolo~/ National University Hospital Lower Kent Ridge Road Singapore 0511
554
Chua et al
PROM and Nulliparas
Copyright © 1995 by The American College of Obstetricians and Gynecologists.
Obstetrics & Gynecology
From the Department of Obstetrics and Gynaecology, National University Hospital, Singapore.
550 0029-7844/95/$9.50 SSDI 0029-7844(95)00214-C
N u l l i p a r o u s w o m e n at term with p r e m a t u r e r u p t u r e of m e m b r a n e s (PROM), especially those with poor cervical scores, have a high cesarean delivery rate w h e n labor is i n d u c e d with oxytocin i n f u s i o n on admission. 1-6 With an o v e r n i g h t conservative policy, those w h o establish s p o n t a n e o u s labor fare well, b u t a substantial p r o p o r t i o n of those w h o require s t i m u l a t i o n of labor the next m o r n i n g will be delivered by cesarean for dystocia. 7 A c o m p a r a t i v e s t u d y s of i m m e d i a t e oxytocin stimulation, as opposed to oxytocin s t i m u l a t i o n after o v e r n i g h t conservative m a n a g e m e n t , did not find a reduction in the cesarean delivery rate. C o n s e r v a t i v e m a n a g e m e n t has been reported to reduce the cesarean rate over that with i m m e d i a t e oxytocin induction. 4 However, traditional teaching a n d reports from large retrospective series 9-~3 p o i n t to an increased possibility of m a t e r n a l a n d neonatal infectious m o r b i d i t y with u n l i m i t e d conservative m a n a g e m e n t in term p r e g n a n cies, Some authors I4-~7 claimed that the use of prostaglandins (PG) results in a better obstetric outcome, whilst others ~s found that the use of two 3-rag PGE2 pessaries 4 hours apart, followed by oxytocin infusion, if necessary, did not confer benefit over the use of i n t r a v e n o u s (IV) oxytocin started a few hours after PROM. The m a i n difference b e t w e e n the s t u d y designs of those w h o have claimed success with PGE 2 a n d those who were u n s u c cessful was the period of latency after the use of PG before oxytocin infusion. Therefore, we c o n d u c t e d a d o u b l e - b l i n d placebo-controlled r a n d o m i z e d trial in n u l l i p a r a s at term with poor cervical scores a n d with PROM. In one s t u d y arm, we used a PGE2 3-mg pessary, and, in the other, a n identical-looking placebo pessary followed 12 hours later by s t i m u l a t i o n with
Obstetrics & Gynecology
oxytocin to determine whether the use of PG improves obstetric outcome.
Table 1. Maternal Characteristics
Materials and Methods
Mean (-+-SD) maternal age (y) Mean (+SD) gestational age (wk) Median interval PROM and a d m i s s i o n to s t u d y (h) Median cervical score
Nulliparous women who presented to the National University Hospital labor ward after 36 weeks' gestation and who had PROM more than 2 hours earlier and poor cervical scores, were considered for the study. Eighty percent of the women were from middle and high socioeconomic groups, whilst the others were from lower-income groups. We recruited 155 women for the study. To halve the cesarean delivery rate found in our earlier study is by lengthening the time between PG insertion and stimulation to 12 hours and, considering alpha 0.05 and power 0.9, we estimated that the sample size required to detect this increase would be 152. A sterile speculum examination was performed to confirm obvious leakage of amniotic fluid (AF). Cases in which there was doubt about the diagnosis of PROM and women with antenatal medical or obstetric complications (such as multiple pregnancy, malpresentation, meconium-stained AF, or evidence of intrauterine infection) were excluded from the study. A cardiotocograph was performed to assess fetal well-being and to confirm the absence of contractions. Women with no contractions in 10 minutes (any contractions being painless) were recruited for the study after informed consent was obtained, as approved by the department ethics committee. A digital examination was performed to assess the cervical score and to exclude occult cord prolapse. Cervical scoring was based on a modified Bishop score, with a rating of 0-2 given for each of the cervical characteristics of position, length, consistency, and dilation, in addition to station of the head. A poor cervical score was assessed as one below 6 of a possible 10 points. A PGE2 (Prostin; Upjohn, Crawley, UK) 3-mg pessary and an identical-looking placebo pessary prepared by the National University Hospital pharmacy were placed in dark bottles. The bottles were randomly numbered by computer-generated lists, and the master list was not revealed to the clinical investigators until the study was completed. On admission to the study, each subject was allocated a numbered bottle in consecutive sequence. The pessary was inserted into the posterior fornix, and the women were monitored in the delivery suite for an additional 2 hours. If the cardiotocographic tracing was normal and the woman was not in labor, she was sent to the antenatal ward to ambulate. If labor did not start in the next 12 hours or if symptoms and signs of infection were evident, she was brought to
VOL. 86, NO. 4, P A R T 1, O C T O B E R 1995
Prostaglandin 01 = 79)
Placebo (n = 76)
28 (5.1) 39 (1.3) 3 [2-131
28 (4.8) 39 (1.3) 3 [2-13]
3 [1-5] '
3 [1-5]
SD = s t a n d a r d deviation; PROM = p r e m a t u r e rupture of m e m branes. Data are presented as m e a n (-+SD) or m e d i a n [range between fifth and 95th percentiles].
the delivery suite for stimulation of labor with oxytocin infusion. Details of labor and maternal and neonatal outcome data were collected on a coding sheet. When rupture of membranes occurred more than 12 hours earlier, tile women were given prophylactic IV ampicillin (if they were not allergic) in labor. If delivery occurred more than 24 hours after PROM, the neonate was treated prophylactically with intramuscular ampicillin and gentamycin after taking ear, nose, and umbilical swabs for sepsis, and blood for culture and white cell count. At the end of the study, the randomization was unblinded and the details of labor and maternal and neonatal outcome of women who received PG pessaries were compared with those of women who received placebo pessaries. Statistical significance was calculated using X2, Fisher exact, and Wilcoxon rank-sum tests.
Results During the 3-year study period between January 1992 and December 1994, 155 women were randomly allocated to one of two treatment arms. There were no significant differences between the two groups in mean maternal age and mean gestational age at time of rupture of membranes. The median cervical scores and interval between rupture of membranes and admission to the study were similar in the two groups (Table 1). Women in whom a PG pessary was inserted were significantly less likely to require stimulation of labor at the end of 12 hours compared with those given a placebo pessary (29 of 79 [37%] in the PG group versus 44 of 76 [58%] in the placebo group, P = .002). If oxytocin was necessary at any time in labor, the mean maximum doses of oxytocin used in the two groups of w o m e n (9 m U / m i n u t e in the PG group and 12 m U / m i n u t e in the placebo group) were not significantly different (P = .09). As indicated in Table 2, women who had PG pessaries inserted on admission had a shorter interval between admission to the study and the onset of labor. Consequently, the latent period from rupture of mem-
Chua et a l
PROM and Nulliparas
551
T a b l e 2. Interval From Rupture of Membranes to Delivery
Prostaglandin Placebo (11 = 79) (11 = 76) Median interval from admission* to labor onset (h) Median interval from PROM to labor onset (h) Median length of labor (h) Median interval from ROIVlto delivery (h) Median interval from admission* to delivery (h)
8 12-161
12 11-931 <.001 15 [5-941
.009
7 [2-131 19 [8-381
7 [2-141 23 [9-441
.6 .05
15 [6-291
19 [6-991
.01
PROM = premature rupture of membranes; ROM = rupture of membranes. Data are presented as median [range between fifth and 95th percentiles]. *Admission to the study at time of randomization.
branes to onset of labor was significantly shorter in the PG g r o u p (P = .009). The lengths of labor of the two g r o u p s were not significantly different. The interval from r u p t u r e of m e m b r a n e s to delivery tended to be shorter in the PG group, b u t this difference did not reach statistical significance (P = .054). However, the m e d i a n interval b e t w e e n a d m i s s i o n to the s t u d y and delivery was significantly shorter in the PG g r o u p compared with those who received placebo (P = .01). There were no instances of h y p e r s t i m u l a t i o n in either
group,. There was no statistically significant difference in the rates of maternal a n d neonatal infection in the PG and placebo g r o u p s (Table 3). A l t h o u g h fewer mothers a n d neonates in the PG g r o u p received antibiotics c o m p a r e d with the placebo group, the difference did not reach statistical significance. Two w o m e n in the PG g r o u p and one in the placebo g r o u p were g i v e n IV ampicillin because of maternal pyrexia. The other w o m e n (56 of 77 in the PG g r o u p and 64 of 75 in the placebo group) received antibiotics prophylactically. Two neonates, one in each group, were given antibiotics for 7 days because of a positive blood culture. Twenty-five of 78 in
T a b l e 3. Maternal and Neonatal Infection
Maternal pyrexia (n) Prophylactic antibiotics to mother (n) Symptoms and signs of infection in neonate (11) Positive blood culture in neonate (n) Prophylactic antibiotics to neonate 01)
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Placebo (n = 76)
P
2 58
1 65
1.0 .063
1
3
.361
1
1
26
35
PROM and Nulliparas
Prostaglandin Placebo 01 = 79) (n = 76)
P
12 I4-291
Prostaglandin (11 = 79)
Table 4. Indices of Maternal and Neonatal Outcorne in the Two Groups
1.0 .094
Cesarean delivery (11) Neonates with Apgar score <5 at 1 min Neonates with Apgar score <7 at 5 rain Neonatal admission to special unit
11 (13.9%) 2 1 6
12 (15.8%) 1 0 6
the PG g r o u p a n d 34 of 75 in the placebo g r o u p took antibiotics for 3 days until the results of the swabs a n d blood culture were s h o w n to be negative for neonatal infection. Cesarean delivery rates were not statistically different in the two g r o u p s (13.9% in the PG g r o u p a n d 15.8% in the placebo group, P = .744). The neonatal outcomes, as judged by low 1- and 5 - m i n u t e A p g a r scores and a d m i s s i o n to the special care baby unit, were similar in the two g r o u p s (Table 4).
Discussion Most w o m e n (65-73%) with PROM at term will enter labor w i t h i n 24 hours. 4 M a n a g e m e n t of those w h o present in labor or go into labor shortly after PROM does not pose a problem. In those w h o do not establish labor, most clinicians i n d u c e labor if it has not b e g u n b y the end of an arbitrary period. Such latency periods vary b e t w e e n i m m e d i a t e s t i m u l a t i o n at a d m i s s i o n to several days later. 19 Reports of m a t e r n a l and perinatal m o r b i d i t y and mortality in term p r e g n a n c y with delayed delivery after PROM 9-13"2° p r o v i d e an incentive to deliver as early as possible after PROM. Good obstetric o u t c o m e can be achieved by i m m e d i a t e s t i m u l a t i o n with oxytocin in m u l t i p a r o u s w o m e n with high cervical scores. 2 Such a policy for nulliparas, especially for those with poor cervical scores, results in longer labor, the need for a higher dose of oxytocin, more o m i n o u s fetal heart rate changes in labor, a n d an increased incidence of dystocia, often..leading to cesarean delivery. 2 A n alternative w o u l d be conservative m a n a g e m e n t by vaginal application of PGE2 pessaries or gel. Treatm e n t with PGE2 has been reported to be effective in r e d u c i n g the cesarean delivery rate in w o m e n with u n f a v o r a b l e cervices, w i t h o u t increasing the risk of infection. 14-17 However, our p r e v i o u s s t u d y is f o u n d no benefit from PG w h e n 94 n u l l i p a r a s with poor cervical scores a n d PROM at term were r a n d o m i z e d to either i m m e d i a t e s t i m u l a t i o n of labor with oxytocin or to two PGE2 pessaries 4 hours apart, followed b y oxytocin infusion 4 hours after the second pessary if regular
Obstetrics & Gynecology
painful contractions and progressive cervical changes were not observed. The cesarean rate in the latter study 1~ did not differ significantly between the two groups and was almost twice the cesarean rate of 10-12% reported in other studies. 3'1s'16 The reason for the lower cesarean delivery rate reported in other studies may be due to the use of PGE2 pessaries or gels being left to act for 18-24 hours in other studies, compared with only 8 hours in our earlier study, is In the present study in which labor was not stimulated until 12 hours after admission, the cesarean delivery rate was lower than that in a similar population in our previous study ~8 in the same center when labor was stimulated immediately on admission (15% in the group stimulated immediately with oxytocin and 19% of those who had PGE 2 pessaries inserted 4 hours apart, followed, if necessary, by oxytocin induction 4 hours later). In the present study, the cesarean rates were not significantly different in the PG and placebo groups. In nulliparas with PROM and poor cervical scores, perhaps waiting for a limited period with or without a PG pessary resulted in ~ lower cesarean rate than when labor was stimulated immediately on admission. 1'6"21-23 Women who received PG on admission to the study were more likely to enter labor earlier, without the need for stimulation with oxytocin. The latent interval between rupture of membranes and onset of labor was significantly shorter in the PG group than in the placebo group. This translated to a shorter admission-todelivery interval in women who received PG pessary on admission compared with those who received placebo. Because the risk of infection for both mother and neonate is greater with an increase in rupture-todelivery interval, use of a PG pessary should be helpful in decreasing the incidence of maternal and neonatal infectious morbidity and mortality. The incidence of maternal and neonatal infection was small in both PG and placebo groups. In all cases in which there was evidence of maternal or neonatal infection, the interval from PROM to delivery exceeded 18 hours. Larger numbers will be needed to show any significant change in the incidence of infection with the two modalities of management.
4.
5. 6.
7.
8.
9.
10. 11. 12. 13.
14.
15.
16.
17.
18.
19.
References I. Duff P, Huff RW, Gibbs RS. Management of premature rupture of membranes and unfavorable cervix in term pregnancy. Obstet Gynecol 1984;63:697-702. 2. Rydhstrom H, Arulkumaran S, Ingermarsson [, Kumar J, Ratnam SS. Premature rupture of membranes at term: Obstetric outcome with oxytocin stimulation in relation to parity and cervical dilatation at admission. Acta Obstet Gynecol Scand 1986;65:587-91. 3. Van der Waalt D, Venter PF. Management of term pregnancy with
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Received March 1, 1995. Received in revised form May 22, 1995. Accepted June 19, 1995.
Address reprint requests to:
Selina Chua, MD Department of Obstetrics and Gynaecolo~/ National University Hospital Lower Kent Ridge Road Singapore 0511
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Copyright © 1995 by The American College of Obstetricians and Gynecologists.
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