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A randomized trial of extra-amniotic saline infusion versus laminaria for cervical ripening
A Randomized Trial of Extra-Amniotic Saline Infusion Versus Laminaria for Cervical Ripening ALEXANDER LIN, MD, MICHAEL KUPFERMINC, MD, AND SHARON L. DOOLEY, MD Objective: To compare extra-amniotic saline infusion versus laminaria for cervical ripening and labor induction. Methods: Patients of at least 34 weeks' gestation with a Bishop score of 3 or less were randomized to either laminaria ripening for 6 hours or more followed by oxytocin induction versus initiation of extra-amniotic saline infusion at the start of oxytocin induction. Indications for induction included 41 weeks' gestation or greater, hypertensive disease, diabetes, oligohydramnios, suspect fetal growth, and nonreassuring fetal testing. Results: There were no significant differences in maternal age, race, parity, gestational age, or indications for induction between the two groups (extra-amniotic saline infusion group, n = 26, laminaria group, n = 26). After only 3 hours of oxytocin induction, patients in the extra-amniotic saline infusion group achieved an identical distribution of Bishop scores compared with the patients in the laminaria group after 6 hours or more of pre-induction ripening as well as 3 hours of oxytocin induction. There were no differences in rates of cesarean delivery (extra-amniotic saline infusion 35%, laminaria 35%), infectious complications, or neonatal outcomes between the two groups. The induction-todelivery interval (± standard deviation) was significantly shortened with extra-amniotic saline infusion (extraamniotic saline infusion 12.9 ± 5.7 hours versus laminaria 16.9 ± 7.1 hours, P = .03). In addition, fewer cesarean deliveries were performed for failed inductions (cervix less than 5 cm dilated) in the extra-amniotic saline infusion group (one of 26 versus six of 26, P = .049). Conclusion: Extra-amniotic saline infusion offers potential advantages over the use of laminaria. Extra-amniotic saline infusion saves a significant amount of time both by obviating the need for pre-induction cervical ripening and in shortening the induction-to-delivery interval. Also, fewer patients required cesarean delivery for failed induction of labor with extra-amniotic saline infusion. (Obstet Gynecol 1995;86:545-9)
From the Department of Obstetrics and Gynecology, Northwestern University Medical School and Northwestern Memorial Hospital, Chicago, Illinois.
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Labor i n d u c t i o n is necessary in a variety of circumstances for either m a t e r n a l or fetal indications. These p r e g n a n c i e s are s o m e t i m e s a c c o m p a n i e d b y an unfav o r a b l e cervix. The i m p o r t a n c e of cervical dilation, effacement, consistency, position, a n d the station of the p r e s e n t i n g p a r t as p r e d i c t o r s of success a n d o p t i m a l timing of i n d u c t i o n w a s first d e s c r i b e d b y Bishop. 1 M a n y i n v e s t i g a t o r s h a v e since d e v e l o p e d .different m e a n s of artificial cervical ripening. Intracervical mechanical devices, such as the cervical balloon, laminaria, a n d D i l a p a n (Gynotech, M i d d l e s e x , NJ), h a v e been used safely. 2-6 P r e p a r a t i o n s of v a g i n a l p r o s t a g l a n d i n (PG) E2, intracervical PGE2, v a g i n a l PGF2~, and porcine relaxin have been used in a variety of concentrations a n d a p p l i c a t i o n techniques to p h a r m a c o l o g i c a l l y r i p e n the cervix. 7-19 Oral mifepristone, an a n t i p r o g e s t e r o n e , has also been s h o w n to be a p r o m i s i n g i n d u c t i o n a g e n t in w o m e n at term. 2° A l t h o u g h all of these m e t h o d s can ripen the cervix, n o n e has e m e r g e d as an ideal m e t h o d , a n d n o n e has been s h o w n to r e d u c e the cesarean d e l i v e r y rate. In 1979, Blum 21 first d e s c r i b e d a technique u s i n g extra-amniotic saline infusion in p e r f o r m i n g secondtrimester abortions. Subsequently, there have been two r a n d o m i z e d trials c o m p a r i n g the efficacy of extraa m n i o t i c saline infusion versus vaginal PGE2 .22"23 Both studies d e m o n s t r a t e d safety a n d greater efficacy in cervical r i p e n i n g with the extra-amniotic saline infusion c o m p a r e d with vaginal PG. A t o u r institution, w e prefer to use l a m i n a r i a for p r e - i n d u c t i o n cervical ripening. This a p p r o a c h has p r o v e n to be safe a n d efficacious, 3-5 a v o i d i n g the risk of uterine h y p e r s t i m u l a t i o n a n d other systemic effects r e p o r t e d with PG use. 6"1°'11'13-16"18 As a n o n p h a r m a c o logic technique, extra-amniotic saline infusion potentially affords the s a m e a d v a n t a g e . In a d d i t i o n , p r e v i o u s studies 22'23 h a v e s u g g e s t e d that it m a y save time as well. In the setting of p r e c a r i o u s or d e t e r i o r a t i n g m a ternal or fetal status, s a v i n g time m a y be a d v a n t a g e o u s . In this r a n d o m i z e d trial, w e c o m p a r e d the efficacy of
0029-7844/95/$9.50 545 SSDI 0029-7844(95)00234-I
the extra-amniotic saline infusion v e r s u s l a m i n a r i a for cervical r i p e n i n g in patients with an u n f a v o r a b l e cervix and the need for delivery.
Materials and Methods For this s t u d y , w e recruited both p r i v a t e a n d n o n p r i vate patients w h o m e t o u r inclusion criteria of gestational age at least 34 weeks, obstetric or m e d i c a l indication for induction, a Bishop score of 3 or less, a singleton vertex fetus, and intact m e m b r a n e s . Patients w i t h k n o w n placenta previa, l o w - l y i n g placenta, or o t h e r w i s e u n e x p l a i n e d vaginal b l e e d i n g w e r e excluded. C o n s e n t i n g patients w e r e r a n d o m i z e d u s i n g sequential, sealed o p a q u e e n v e l o p e s c o n t a i n i n g c o m p u t e r - g e n erated a s s i g n m e n t to either l a m i n a r i a or e x t r a - a m n i o t i c saline infusion. This s t u d y w a s a p p r o v e d b y the N o r t h western University Institutional Review Board. Patients r a n d o m i z e d to the l a m i n a r i a g r o u p had insertion of the m a x i m u m n u m b e r of l a m i n a r i a that the cervix could a c c o m m o d a t e u s i n g s t a n d a r d sterile technique. The laminaria were k e p t in place for a m i n i m u m of 6 hours. At the time of removal, the Bishop score w a s reassessed, a n d oxytocin i n d u c t i o n w a s started. Patients r a n d o m i z e d to the extra-amniotic saline infusion g r o u p had a 26-Fr Foley catheter t h r e a d e d t h r o u g h the cervix into the potential space b e t w e e n the amfliotic m e m b r a n e a n d l o w e r uterine segment. The catheter balloon was inflated with 40 m L of sterile w a t e r , a n d sterile saline w a s then i n f u s e d at 40 m L / h o u r via the catheter by m e a n s of an infusion p u m p . Oxytocin i n d u c t i o n w a s also started concomitantly. The saline infusion was s t o p p e d and the catheter r e m o v e d in 6 h o u r s or at the time of s p o n t a n e o u s expulsion or r u p t u r e of m e m b r a n e s , w h i c h e v e r occ u r r e d first. All patients were e x a m i n e d 3 a n d 6 h o u r s after the start of oxytocin induction. The timing of a m n i o t o m y , use of labor analgesia, and decision to p e r f o r m cesarean d e l i v e r y w e r e left to the discretion of the m a n a g i n g physician. This s t u d y was d e s i g n e d to test the h y p o t h e s i s that the i n d u c t i o n - t o - d e l i v e r y interval, defined as the time of oxytocin initiation to the time of delivery, is shorter w h e n a patient with an u n r i p e cervix u n d e r g o e s cervical r i p e n i n g with extra-amniotic saline infusion at the time of oxytocin i n d u c t i o n c o m p a r e d with u n d e r g o i n g oxytocin i n d u c t i o n after l a m i n a r i a ripening. A c c o r d ingly, w e used the i n d u c t i o n - t o - d e l i v e r y interval as the o u t c o m e variable u p o n which the p o w e r calculation w a s based. A calculated s a m p l e size of 52 patients w a s n e e d e d to d e m o n s t r a t e a 3-hour difference in the i n d u c t i o n - t o - d e l i v e r y i n t e r v a l w i t h a p o w e r of 80% a n d an a = .05. Other outcome variables to be analyzed in-
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Table
1. Patient Demographic Characteristics
Age (y) Race White Other Payer status Private Non-private Parity 0 ->1 Gestational age (wk) All 34-36 ->37
EASI (n = 26)
LAM 01 = 26)
32.1 -+ 7.0
28.4 ± 7.3
14 (54%) 12 (46%)
17 (65%) 9 (35%)
19 (73%) 7 (27%)
20 (77%) 6 (23%)
20 (77%) 6 (23~.)
18 (69%) 8 (31%)
40.4 -+ 1.7 1 (4c/() 25 (96%)
40.0 --_1.8 0 (0%) 26 (100%)
EASI = extra-amniotic saline infusion; LAM= laminaria. Data are presented as mean -+ standard deviation or n (%). Data did not reach level of significance.
c l u d e d cervical r i p e n i n g as assessed b y Bishop scores 3 a n d 6 h o u r s after initiation of oxytocin, rates of cesarean delivery, rates of failed i n d u c t i o n (defined as less than 5 cm dilation a n d c o m p l e t e effacement), and m a t e r n a l a n d fetal m o r b i d i t y . C o n t i n u o u s variables w e r e anal y z e d by S t u d e n t t test, a n d categorical d a t a were a n a l y z e d b y )(2 or Fisher exact test. P < .05 w a s c o n s i d e r e d to be statistically significant.
Results Fifty-two patients were enrolled, w i t h 26 patients rand o m i z e d to extra-amniotic saline infusion a n d 26 p a tients to laminaria. There w e r e no significant differences with respect to m a t e r n a l age, race, p a y e r status, parity, or gestational age b e t w e e n the two g r o u p s (Table 1). Table 2 lists the indications for i n d u c t i o n of labor. The d i s t r i b u t i o n of these indications w a s similar for the two g r o u p s , with a d v a n c e d gestational age b e i n g the m o s t c o m m o n indication. Figure I illustrates the d i s t r i b u t i o n of Bishop scores in the t w o . g r o u p s . The d i s t r i b u t i o n of Bishop scores at the
Table
2. Indication for Induction of Labor
Gestational age :"41 wk Hypertensive disease Diabetes Oligohydramnios Suspected growth restriction Nonreassuring fetal testing Other
EASI
LAM
(. = 26)
(n = 26)
10 3 2 4 2 2 3
6 6 4 3 3 2 2
EASI = extra-amniotic saline infusion; LAM = laminaria.
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Table 3. Delivery Outcome
30
Number o f Patients
EASI 01 = 26)
20 Vaginal delivery Cesarean delivery Birth w e i g h t (g) 5-min Apgar <7 C o r d arterial p H < 7 . 1 0 SCN admissions
10 0
(0-3)
(4-6) Bishop Score
(7-13)
30. 20. 10
(0-3)
(4-6)
(7-13)
Bishop Score B
3019
Number of Patients
20-
~ 1 4
10
3 o
!. . . . . .
.
0 10-31
14-61 Bishop Score
17-131
C Figure 1. Bishop score d i s t r i b u t i o n s of b o t h e x t r a - a m n i o t i c saline infusion (EASI) a n d l a m i n a r i a (LAM) g r o u p s at the initiation of o x y t o c i n i n d u c t i o n (A), after 3 h o u r s of o x y t o c i n i n d u c t i o n (B), a n d after 6 h o u r s of o x y t o c i n i n d u c t i o n (C).
time of randomization is not illustrated, because by study design, all patients had a Bishop score of 3 or less. Patients in the laminaria group demonstrated the expected benefit of 6-15 hours of pre-ripening at the time of initiating oxytocin induction (Figure 1A). However, by 3 hours after induction, the extra-amniOtic saline infusion group had already achieved an identical degree of cervical ripening as the laminaria group (Figure 1B). By 6 hours, no patients in the extra-amniotic saline infusion group had a Bishop score of 3 or less, whereas
V O L . 86, N O . 4, P A R T 1, O C T O B E R 1995
(65%) (35%) --. 618 (4%) (8%) (25%)
17 9 3469 0 2 4
(65%) (35%) -- 608 (0%) (8%) (16%)
EAS1 = e x t r a - a m n i o t i c saline infusion; L A M = l a m i n a r i a ; S C N = special care n u r s e r y . Data are p r e s e n t e d as n (%) or m e a n +- s t a n d a r d deviation.
A
Number of Patients
17 9 3452 1 2 6
LAM (11 = 26)
there were still three patients with a score of 3 or less in the laminaria group (Figure 1C). The rates of vaginal and cesarean birth were the same, with a cesarean birth rate of 35% (nine of 26) in both groups. No significant differences in neonatal birth weight, rates of depressed 5-minute Apgar scores (less than 7), umbilical artery acidemia (pH less than 7.10), or special care nursery admissions were observed (Table 3). Only two infants were admitted for more" than 24 hours. No neonates in this study population experienced infectious morbidity. Maternal morbidity was comparable between groups, with chorioamnionitis observed in five (19%) of the extra-amniotic saline infusion patients and seven (27%) of the laminaria patients. Each group had one patient diagnosed with postpartum endometritis, and one patient in the laminaria group experienced a postpartum hemorrhage. Table 4 shows the induction-to-delivery intervals. Compared with the laminaria group, a significant decrease in the induction-to-delivery interval was found in the extra-amniotic saline infusion group (extraamniotic saline infusion 12.9 -+ 5.7 hours versus laminaria 16.9 + 7.1 hours, P = .03). This advantage in the induction-to-delivery interval was most apparent in the group requiring cesarean delivery (extra-amniotic saline infusion 10.9 --- 4.0 hours versus laminaria 19.1 + 8.1 hours, P = .02). Further analysis of this subgroup of patients requiring cesarean delivery demonstrated that the patients in the extra-amniotic saline infusion group
Table 4. Induction-to-Delivery Interval
All p a t i e n t s (h) V a g i n a l d e l i v e r y (h) C e s a r e a n d e l i v e r y (h)
EASI
LAM
P
12.9 + 5.7 01 = 26) 14.0 -+ 6.3 (11 = 17) 10.9 -+ 4.0 (11=9)
16.9 - 7.1 01 = 26) 15.7 -+ 5.9 (11 = 17) 19.1 -+ 8.1 (n=9)
.03 NS .02
EASI = e x t r a - a m n i o t i c saline infusion; L A M = l a m i n a r i a ; NS = n o t significant. Data are p r e s e n t e d as m e a n --- s t a n d a r d d e v i a t i o n .
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Extra-Amniotic Saline Ripening 547
Table
5. Distribution of Cervical Dilation and Indications for Operative Delivery at Time of Cesarean Delivery
Cervical dilatation (cm) 1-4 5-10 Indications Arrest disorder Nonreassuring fetal status Failed induction
EASI
LAM
(n = 26)
(n = 26)
P
4 5
7 2
NS NS
4 (15%) 4 (15'7~:) 1 (4%)
2 (8%) 1 (4%) 6 (23%)
NS NS .049
EASI = extra-amniotic saline infusion; LAM = laminaria; NS = not significant.
achieved a similar distribution of cervical dilation despite lab.oring for a shorter period of time (Table 5). Although the number of patients in this group is small, fewer patients required a cesarean delivery for a failed induction in the extra-amniotic saline infusion group (one of 26 versus six of 26, P = .049). We noted technical or procedure-related difficulties in both groups. One patient in the extra-amniotic saline infusion group had the Foley bulb placed inadvertently in the cervical canal rather than the extra-amniotic space, which was ascertained at the time of catheter removal. Eight patients in the laminaria group had Bisl~op scores of less than 4 after a minimum of 6 hours of laminaria placement. These cases may have represented suboptimal initial placement or subsequent displacement of the laminaria.
Discussion Based on this randomized trial, we found extraamniotic saline infusion to be a safe method of cervical ripening when inducing labor in patients with an unfavorable cervix, and it saved a significant amount of time when compared with laminaria. Because the laminaria group had the advantage of 6 hours or more of pre-induction ripening and the extra-amniotic saline infusion group had simultaneous initiation of induction and mechanical ripening, the two study groups were not expected to be comparable at the start of induction. We recognized that this lack of comparability at the start of induction conferred a bias toward the null hypothesis. However, an identical degree of cervical ripening was achieved with extra-amniotic saline infusion within the first 3 hours of oxytocin induction. Furthermore, the overall induction-todelivery interval, which does not include the minimum of 6 hours of laminaria pre~induction ripening, was significantly reduced in the extra-amniotic saline infusion group. Therefore, extra-amniotic saline infusion was found tO save a significant amount of time, both in obviating the
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minimum 6 hours of pre-induction cervical ripening necessary with laminaria use and in shortening the overall induction-to-delivery interval. The amount of time saved in the induction-todelivery interval with extra-amniotic saline infusion was most apparent in patients requiring cesarean delivery, and these patients achieved a similar distribution of cervical dilation within a shorter time period. In addition, there were fewer failed inductions in the extraamniotic saline infusion group. This study did not have the power to detect a difference in rates of cesarean delivery. Nonpharmacologic methods of cervical ripening possess the advantages of low cost, lack of systemic side effects, and easy reversibility. The movement toward hormonal methods of cervical ripening has gained momentum since the commercial availability of dinoprostone 0.5 mg intracervical gel (Prepidil Gel; Upjohn, Kalamazoo, MI). Considerable time and resources have been devoted to developing systems of local PGE 2 delivery. Differing doses, gel vehicles, application devices, and locations of delivery have been studied to circumvent the problems that have been reported with PGE 2 use, such as variable absorption, unpredictable patient response, uterine hypercontractility, nausea, vomiting, diarrhea, and fever. "'7'1°-~8Prostaglandins are unstable compounds that may lose potency if not stored properly, and their effects are not readily reversible. Although intracervical dinoprostone 0.5 mg gel is better tolerated than high doses of intravaginal PGE2, the gastrointestinal side effects and uterine hypercontractility when compared to placebo are not insignificant, ls'I" After comparing costs, the shortcomings of hormonal cervical ripening methods are further magnified and the appeal of nonpharmacologic methods is even greater. At our institution, a large university-based teaching hospital, the hospital cost for a single dose of Prepidil Gel is $75.00, compared with $2.18 for a Foley catheter and a 500-mL bag of saline used with extraamniotic saline infusion and $3.50 for each laminaria. One must also consider the costs of additional fetal monitoring recommended with PG use. When comparing extra-amniotic saline infusion and laminaria, a shortened induction-to-delivery interval would also result in a cost savings when patients are charged on an hourly basis in labor and delivery. Because previous trials have demonstrated equivalent efficacy of mechanical versus hormonal methods of cervical ripening, 6'w'~'z~ we believe that cost warrants major consideration. We propose that extra-amniotic saline infusion is a safe and cost-effective method of cervical ripening. Maternal and fetal morbidity were similar in the extraamniotic saline infusion and laminaria groups. Extraamniotic saline infusion offers an advantage in settings
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whereby the potential side effects of PGs, such as uterine hyperstimulation with a compromised fetus, are undesirable or when waiting for laminaria ripening may not be advisable because of fetal or maternal risk.
References 1. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266- 8. 2. Embrey MP, Mollison BG. The unfavorable cervix and induction of labour using a cervical balloon. J Obstet Gynaecol Br Commonweal 1967;74:44 -8. 3. Manabe Y. Laminaria tent for gradual and safe cervical dilatation. Am J Obstet Gynecol 1971;110:743-5. 4. Tohan N, Tejani NA, Varanasi M, Robins J. Ripening of the term cervix with laminaria. Obstet Gynecol 1979;54:588-90. 5. Blumenthal PD, Ramanauskas R. Randomized trial of Dilapan and laminaria as cervical ripening agents before induction of labor. Obstet Gynecol 1990;75:365-- 8. 6. Johnson IR, Macpherson MBA, Welch CC, Filshie GM. A comparison of lamicel and prostaglandin E2 vaginal gel for cervical ripening before induction of labor. Am J Obstet Gynecol 1985;151: 604 -7. 7. MacKenzie IZ, Embrey MP. Cervical ripening with intravaginal prostaglandin E2 gel. BMJ 1977;2:1381-4. 8. MacLennan AH, Green RC. Cervical ripening and induction of labour with intravaginal prostaglandin F2,. Lancet 1979;i:117-9. 9. Neilson DR, Prins RP, Bolton RN, Mack C 111, Watson P. A comparison of prostaglandin E2 gel and prostaglandin Fa,' gel for preinduction cervical ripening. Am J Obstet Gyneco11983;146:52630. 10. Graves GR, Baskett TF, Gray JH, Luther ER. The effect of vaginal administration of various doses of prostaglandin E2 gel on cervical ripening and induction of labor. Am J Obstet Gynecol 1985;151: 178-81. 11. Owen J, Winkler CL, Harris BA, Hauth JC, Smith MC. A randomized, double-blind trial of prostaglandin E2 gel for cervical ripening and meta-analysis. Am J Obstet Gynecol 1991;165:991-6. 12. Ulmsten U, Wingerup L, Belfrage P, Ekman G, Wiqvist N. Intracervical application of prostaglandin gel for induction of term labor. Obstet Gynecol 1982;59:336-9. 13. Ekman G, Forman A, Marsal K, Ulmsten U. Intravaginal versus intracervical application of prostaglandin E~ in viscous gel for cervical priming and induction of labor at term in patients with an unfavorable cervical state. Am J Obstet Gynecol 1983;147:657-61. 14. Nimrod C, Currie J, Yee J, Dodd G, Persaud D. Cervical ripening and labor induction with intracervical triacetin base prostaglandin E2 gel: A placebo-controlled study. Obstet Gynecol 1984;64:476-8.
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15. Trofatter KF, Bowers D, Gall SA, Killam AP. Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel. Am J Obstet Gyne'col 1985;153:268 -71. 16. Trofatter KF. Effect of preinduction cervical softening with dinoprostone gel on outcome of oxytocin-induced labor. Clin Ther 1993;15:838-44. 17. Atad J, Bornstein J, Calderon I, Petrikovsky BM, Sorokin Y, Abramovici H. Nonpharmaceutical ripening of the unfavorable cervix and induction of labor by a novel double balloon device. Obstet Gynecol 1991 ;77:146-52. 18. Witter FR, Rocco LE, Johnson TRB. A randomized trial of prostaglandin E2 in a controlled-release vaginal pessary for cervical ripening at term. Am J Obstet Gynecol 1992;166:830-4. 19. Evans MI, Dougan M-B, Moawad AH, Evans WJ, BryantGreenwood GD, Greenwood FC. Ripening of the h u m a n cervix with porcine ovarian relaxin. Am J Obstet Gynecol 1983;147:410-4. 20. Frydman R, Lelaidier C, Baton-Saint-Mleux C, Fernandez I-t, Vial M, Bourget P. Labor induction in women at term with mifepristone (RU 486): A double-blind, randomized, placebo-controlled study. Obstet Gynecol 1992;80:972-5. 21. Blum M. Indication du travail par perfusion extra-amniotique d ' u n e solution saline isotonique dans un cas particulier de mort prenatale. Rev Fr Gynecol Obstet 1982;77:137-9. 22. Schreyer P, Sherman DJ, Ariely S, Herman A, Caspi E. Ripening the highly unfavorable cervix with extra-amniotic saline instillation or vaginal prostaglandin E, application. Obstet Gynecol 1989;73:938 - 42. 23. Rouben D, Arias F. A randomized trial of extra-amniotic saline infusion plus intracervical Foley catheter balloon versus prostaglandin E2 vaginal gel for ripening the cervix and inducing labor in patients with unfavorable cervices. Obstet Gynecol 1993;82:290-4.
A d d r e s s r e p r i n t r e q u e s t s to:
Alexander Lin, MD 333 East Superior Street Suite 444 Chicago, IL 60611
Receiw,d March 27, 1995. Received in revised form June 16, 1995. Accepted June 21, 1995.
Copyright © 1995 by The American College of Obstetricians and Gynecologists.
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From the Department of Obstetrics and Gynecology, Northwestern University Medical School and Northwestern Memorial Hospital, Chicago, Illinois.
VOL. 86, NO. 4, PART 1, OCTOBER 1995
Labor i n d u c t i o n is necessary in a variety of circumstances for either m a t e r n a l or fetal indications. These p r e g n a n c i e s are s o m e t i m e s a c c o m p a n i e d b y an unfav o r a b l e cervix. The i m p o r t a n c e of cervical dilation, effacement, consistency, position, a n d the station of the p r e s e n t i n g p a r t as p r e d i c t o r s of success a n d o p t i m a l timing of i n d u c t i o n w a s first d e s c r i b e d b y Bishop. 1 M a n y i n v e s t i g a t o r s h a v e since d e v e l o p e d .different m e a n s of artificial cervical ripening. Intracervical mechanical devices, such as the cervical balloon, laminaria, a n d D i l a p a n (Gynotech, M i d d l e s e x , NJ), h a v e been used safely. 2-6 P r e p a r a t i o n s of v a g i n a l p r o s t a g l a n d i n (PG) E2, intracervical PGE2, v a g i n a l PGF2~, and porcine relaxin have been used in a variety of concentrations a n d a p p l i c a t i o n techniques to p h a r m a c o l o g i c a l l y r i p e n the cervix. 7-19 Oral mifepristone, an a n t i p r o g e s t e r o n e , has also been s h o w n to be a p r o m i s i n g i n d u c t i o n a g e n t in w o m e n at term. 2° A l t h o u g h all of these m e t h o d s can ripen the cervix, n o n e has e m e r g e d as an ideal m e t h o d , a n d n o n e has been s h o w n to r e d u c e the cesarean d e l i v e r y rate. In 1979, Blum 21 first d e s c r i b e d a technique u s i n g extra-amniotic saline infusion in p e r f o r m i n g secondtrimester abortions. Subsequently, there have been two r a n d o m i z e d trials c o m p a r i n g the efficacy of extraa m n i o t i c saline infusion versus vaginal PGE2 .22"23 Both studies d e m o n s t r a t e d safety a n d greater efficacy in cervical r i p e n i n g with the extra-amniotic saline infusion c o m p a r e d with vaginal PG. A t o u r institution, w e prefer to use l a m i n a r i a for p r e - i n d u c t i o n cervical ripening. This a p p r o a c h has p r o v e n to be safe a n d efficacious, 3-5 a v o i d i n g the risk of uterine h y p e r s t i m u l a t i o n a n d other systemic effects r e p o r t e d with PG use. 6"1°'11'13-16"18 As a n o n p h a r m a c o logic technique, extra-amniotic saline infusion potentially affords the s a m e a d v a n t a g e . In a d d i t i o n , p r e v i o u s studies 22'23 h a v e s u g g e s t e d that it m a y save time as well. In the setting of p r e c a r i o u s or d e t e r i o r a t i n g m a ternal or fetal status, s a v i n g time m a y be a d v a n t a g e o u s . In this r a n d o m i z e d trial, w e c o m p a r e d the efficacy of
0029-7844/95/$9.50 545 SSDI 0029-7844(95)00234-I
the extra-amniotic saline infusion v e r s u s l a m i n a r i a for cervical r i p e n i n g in patients with an u n f a v o r a b l e cervix and the need for delivery.
Materials and Methods For this s t u d y , w e recruited both p r i v a t e a n d n o n p r i vate patients w h o m e t o u r inclusion criteria of gestational age at least 34 weeks, obstetric or m e d i c a l indication for induction, a Bishop score of 3 or less, a singleton vertex fetus, and intact m e m b r a n e s . Patients w i t h k n o w n placenta previa, l o w - l y i n g placenta, or o t h e r w i s e u n e x p l a i n e d vaginal b l e e d i n g w e r e excluded. C o n s e n t i n g patients w e r e r a n d o m i z e d u s i n g sequential, sealed o p a q u e e n v e l o p e s c o n t a i n i n g c o m p u t e r - g e n erated a s s i g n m e n t to either l a m i n a r i a or e x t r a - a m n i o t i c saline infusion. This s t u d y w a s a p p r o v e d b y the N o r t h western University Institutional Review Board. Patients r a n d o m i z e d to the l a m i n a r i a g r o u p had insertion of the m a x i m u m n u m b e r of l a m i n a r i a that the cervix could a c c o m m o d a t e u s i n g s t a n d a r d sterile technique. The laminaria were k e p t in place for a m i n i m u m of 6 hours. At the time of removal, the Bishop score w a s reassessed, a n d oxytocin i n d u c t i o n w a s started. Patients r a n d o m i z e d to the extra-amniotic saline infusion g r o u p had a 26-Fr Foley catheter t h r e a d e d t h r o u g h the cervix into the potential space b e t w e e n the amfliotic m e m b r a n e a n d l o w e r uterine segment. The catheter balloon was inflated with 40 m L of sterile w a t e r , a n d sterile saline w a s then i n f u s e d at 40 m L / h o u r via the catheter by m e a n s of an infusion p u m p . Oxytocin i n d u c t i o n w a s also started concomitantly. The saline infusion was s t o p p e d and the catheter r e m o v e d in 6 h o u r s or at the time of s p o n t a n e o u s expulsion or r u p t u r e of m e m b r a n e s , w h i c h e v e r occ u r r e d first. All patients were e x a m i n e d 3 a n d 6 h o u r s after the start of oxytocin induction. The timing of a m n i o t o m y , use of labor analgesia, and decision to p e r f o r m cesarean d e l i v e r y w e r e left to the discretion of the m a n a g i n g physician. This s t u d y was d e s i g n e d to test the h y p o t h e s i s that the i n d u c t i o n - t o - d e l i v e r y interval, defined as the time of oxytocin initiation to the time of delivery, is shorter w h e n a patient with an u n r i p e cervix u n d e r g o e s cervical r i p e n i n g with extra-amniotic saline infusion at the time of oxytocin i n d u c t i o n c o m p a r e d with u n d e r g o i n g oxytocin i n d u c t i o n after l a m i n a r i a ripening. A c c o r d ingly, w e used the i n d u c t i o n - t o - d e l i v e r y interval as the o u t c o m e variable u p o n which the p o w e r calculation w a s based. A calculated s a m p l e size of 52 patients w a s n e e d e d to d e m o n s t r a t e a 3-hour difference in the i n d u c t i o n - t o - d e l i v e r y i n t e r v a l w i t h a p o w e r of 80% a n d an a = .05. Other outcome variables to be analyzed in-
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Table
1. Patient Demographic Characteristics
Age (y) Race White Other Payer status Private Non-private Parity 0 ->1 Gestational age (wk) All 34-36 ->37
EASI (n = 26)
LAM 01 = 26)
32.1 -+ 7.0
28.4 ± 7.3
14 (54%) 12 (46%)
17 (65%) 9 (35%)
19 (73%) 7 (27%)
20 (77%) 6 (23%)
20 (77%) 6 (23~.)
18 (69%) 8 (31%)
40.4 -+ 1.7 1 (4c/() 25 (96%)
40.0 --_1.8 0 (0%) 26 (100%)
EASI = extra-amniotic saline infusion; LAM= laminaria. Data are presented as mean -+ standard deviation or n (%). Data did not reach level of significance.
c l u d e d cervical r i p e n i n g as assessed b y Bishop scores 3 a n d 6 h o u r s after initiation of oxytocin, rates of cesarean delivery, rates of failed i n d u c t i o n (defined as less than 5 cm dilation a n d c o m p l e t e effacement), and m a t e r n a l a n d fetal m o r b i d i t y . C o n t i n u o u s variables w e r e anal y z e d by S t u d e n t t test, a n d categorical d a t a were a n a l y z e d b y )(2 or Fisher exact test. P < .05 w a s c o n s i d e r e d to be statistically significant.
Results Fifty-two patients were enrolled, w i t h 26 patients rand o m i z e d to extra-amniotic saline infusion a n d 26 p a tients to laminaria. There w e r e no significant differences with respect to m a t e r n a l age, race, p a y e r status, parity, or gestational age b e t w e e n the two g r o u p s (Table 1). Table 2 lists the indications for i n d u c t i o n of labor. The d i s t r i b u t i o n of these indications w a s similar for the two g r o u p s , with a d v a n c e d gestational age b e i n g the m o s t c o m m o n indication. Figure I illustrates the d i s t r i b u t i o n of Bishop scores in the t w o . g r o u p s . The d i s t r i b u t i o n of Bishop scores at the
Table
2. Indication for Induction of Labor
Gestational age :"41 wk Hypertensive disease Diabetes Oligohydramnios Suspected growth restriction Nonreassuring fetal testing Other
EASI
LAM
(. = 26)
(n = 26)
10 3 2 4 2 2 3
6 6 4 3 3 2 2
EASI = extra-amniotic saline infusion; LAM = laminaria.
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Table 3. Delivery Outcome
30
Number o f Patients
EASI 01 = 26)
20 Vaginal delivery Cesarean delivery Birth w e i g h t (g) 5-min Apgar <7 C o r d arterial p H < 7 . 1 0 SCN admissions
10 0
(0-3)
(4-6) Bishop Score
(7-13)
30. 20. 10
(0-3)
(4-6)
(7-13)
Bishop Score B
3019
Number of Patients
20-
~ 1 4
10
3 o
!. . . . . .
.
0 10-31
14-61 Bishop Score
17-131
C Figure 1. Bishop score d i s t r i b u t i o n s of b o t h e x t r a - a m n i o t i c saline infusion (EASI) a n d l a m i n a r i a (LAM) g r o u p s at the initiation of o x y t o c i n i n d u c t i o n (A), after 3 h o u r s of o x y t o c i n i n d u c t i o n (B), a n d after 6 h o u r s of o x y t o c i n i n d u c t i o n (C).
time of randomization is not illustrated, because by study design, all patients had a Bishop score of 3 or less. Patients in the laminaria group demonstrated the expected benefit of 6-15 hours of pre-ripening at the time of initiating oxytocin induction (Figure 1A). However, by 3 hours after induction, the extra-amniOtic saline infusion group had already achieved an identical degree of cervical ripening as the laminaria group (Figure 1B). By 6 hours, no patients in the extra-amniotic saline infusion group had a Bishop score of 3 or less, whereas
V O L . 86, N O . 4, P A R T 1, O C T O B E R 1995
(65%) (35%) --. 618 (4%) (8%) (25%)
17 9 3469 0 2 4
(65%) (35%) -- 608 (0%) (8%) (16%)
EAS1 = e x t r a - a m n i o t i c saline infusion; L A M = l a m i n a r i a ; S C N = special care n u r s e r y . Data are p r e s e n t e d as n (%) or m e a n +- s t a n d a r d deviation.
A
Number of Patients
17 9 3452 1 2 6
LAM (11 = 26)
there were still three patients with a score of 3 or less in the laminaria group (Figure 1C). The rates of vaginal and cesarean birth were the same, with a cesarean birth rate of 35% (nine of 26) in both groups. No significant differences in neonatal birth weight, rates of depressed 5-minute Apgar scores (less than 7), umbilical artery acidemia (pH less than 7.10), or special care nursery admissions were observed (Table 3). Only two infants were admitted for more" than 24 hours. No neonates in this study population experienced infectious morbidity. Maternal morbidity was comparable between groups, with chorioamnionitis observed in five (19%) of the extra-amniotic saline infusion patients and seven (27%) of the laminaria patients. Each group had one patient diagnosed with postpartum endometritis, and one patient in the laminaria group experienced a postpartum hemorrhage. Table 4 shows the induction-to-delivery intervals. Compared with the laminaria group, a significant decrease in the induction-to-delivery interval was found in the extra-amniotic saline infusion group (extraamniotic saline infusion 12.9 -+ 5.7 hours versus laminaria 16.9 + 7.1 hours, P = .03). This advantage in the induction-to-delivery interval was most apparent in the group requiring cesarean delivery (extra-amniotic saline infusion 10.9 --- 4.0 hours versus laminaria 19.1 + 8.1 hours, P = .02). Further analysis of this subgroup of patients requiring cesarean delivery demonstrated that the patients in the extra-amniotic saline infusion group
Table 4. Induction-to-Delivery Interval
All p a t i e n t s (h) V a g i n a l d e l i v e r y (h) C e s a r e a n d e l i v e r y (h)
EASI
LAM
P
12.9 + 5.7 01 = 26) 14.0 -+ 6.3 (11 = 17) 10.9 -+ 4.0 (11=9)
16.9 - 7.1 01 = 26) 15.7 -+ 5.9 (11 = 17) 19.1 -+ 8.1 (n=9)
.03 NS .02
EASI = e x t r a - a m n i o t i c saline infusion; L A M = l a m i n a r i a ; NS = n o t significant. Data are p r e s e n t e d as m e a n --- s t a n d a r d d e v i a t i o n .
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Extra-Amniotic Saline Ripening 547
Table
5. Distribution of Cervical Dilation and Indications for Operative Delivery at Time of Cesarean Delivery
Cervical dilatation (cm) 1-4 5-10 Indications Arrest disorder Nonreassuring fetal status Failed induction
EASI
LAM
(n = 26)
(n = 26)
P
4 5
7 2
NS NS
4 (15%) 4 (15'7~:) 1 (4%)
2 (8%) 1 (4%) 6 (23%)
NS NS .049
EASI = extra-amniotic saline infusion; LAM = laminaria; NS = not significant.
achieved a similar distribution of cervical dilation despite lab.oring for a shorter period of time (Table 5). Although the number of patients in this group is small, fewer patients required a cesarean delivery for a failed induction in the extra-amniotic saline infusion group (one of 26 versus six of 26, P = .049). We noted technical or procedure-related difficulties in both groups. One patient in the extra-amniotic saline infusion group had the Foley bulb placed inadvertently in the cervical canal rather than the extra-amniotic space, which was ascertained at the time of catheter removal. Eight patients in the laminaria group had Bisl~op scores of less than 4 after a minimum of 6 hours of laminaria placement. These cases may have represented suboptimal initial placement or subsequent displacement of the laminaria.
Discussion Based on this randomized trial, we found extraamniotic saline infusion to be a safe method of cervical ripening when inducing labor in patients with an unfavorable cervix, and it saved a significant amount of time when compared with laminaria. Because the laminaria group had the advantage of 6 hours or more of pre-induction ripening and the extra-amniotic saline infusion group had simultaneous initiation of induction and mechanical ripening, the two study groups were not expected to be comparable at the start of induction. We recognized that this lack of comparability at the start of induction conferred a bias toward the null hypothesis. However, an identical degree of cervical ripening was achieved with extra-amniotic saline infusion within the first 3 hours of oxytocin induction. Furthermore, the overall induction-todelivery interval, which does not include the minimum of 6 hours of laminaria pre~induction ripening, was significantly reduced in the extra-amniotic saline infusion group. Therefore, extra-amniotic saline infusion was found tO save a significant amount of time, both in obviating the
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minimum 6 hours of pre-induction cervical ripening necessary with laminaria use and in shortening the overall induction-to-delivery interval. The amount of time saved in the induction-todelivery interval with extra-amniotic saline infusion was most apparent in patients requiring cesarean delivery, and these patients achieved a similar distribution of cervical dilation within a shorter time period. In addition, there were fewer failed inductions in the extraamniotic saline infusion group. This study did not have the power to detect a difference in rates of cesarean delivery. Nonpharmacologic methods of cervical ripening possess the advantages of low cost, lack of systemic side effects, and easy reversibility. The movement toward hormonal methods of cervical ripening has gained momentum since the commercial availability of dinoprostone 0.5 mg intracervical gel (Prepidil Gel; Upjohn, Kalamazoo, MI). Considerable time and resources have been devoted to developing systems of local PGE 2 delivery. Differing doses, gel vehicles, application devices, and locations of delivery have been studied to circumvent the problems that have been reported with PGE 2 use, such as variable absorption, unpredictable patient response, uterine hypercontractility, nausea, vomiting, diarrhea, and fever. "'7'1°-~8Prostaglandins are unstable compounds that may lose potency if not stored properly, and their effects are not readily reversible. Although intracervical dinoprostone 0.5 mg gel is better tolerated than high doses of intravaginal PGE2, the gastrointestinal side effects and uterine hypercontractility when compared to placebo are not insignificant, ls'I" After comparing costs, the shortcomings of hormonal cervical ripening methods are further magnified and the appeal of nonpharmacologic methods is even greater. At our institution, a large university-based teaching hospital, the hospital cost for a single dose of Prepidil Gel is $75.00, compared with $2.18 for a Foley catheter and a 500-mL bag of saline used with extraamniotic saline infusion and $3.50 for each laminaria. One must also consider the costs of additional fetal monitoring recommended with PG use. When comparing extra-amniotic saline infusion and laminaria, a shortened induction-to-delivery interval would also result in a cost savings when patients are charged on an hourly basis in labor and delivery. Because previous trials have demonstrated equivalent efficacy of mechanical versus hormonal methods of cervical ripening, 6'w'~'z~ we believe that cost warrants major consideration. We propose that extra-amniotic saline infusion is a safe and cost-effective method of cervical ripening. Maternal and fetal morbidity were similar in the extraamniotic saline infusion and laminaria groups. Extraamniotic saline infusion offers an advantage in settings
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whereby the potential side effects of PGs, such as uterine hyperstimulation with a compromised fetus, are undesirable or when waiting for laminaria ripening may not be advisable because of fetal or maternal risk.
References 1. Bishop EH. Pelvic scoring for elective induction. Obstet Gynecol 1964;24:266- 8. 2. Embrey MP, Mollison BG. The unfavorable cervix and induction of labour using a cervical balloon. J Obstet Gynaecol Br Commonweal 1967;74:44 -8. 3. Manabe Y. Laminaria tent for gradual and safe cervical dilatation. Am J Obstet Gynecol 1971;110:743-5. 4. Tohan N, Tejani NA, Varanasi M, Robins J. Ripening of the term cervix with laminaria. Obstet Gynecol 1979;54:588-90. 5. Blumenthal PD, Ramanauskas R. Randomized trial of Dilapan and laminaria as cervical ripening agents before induction of labor. Obstet Gynecol 1990;75:365-- 8. 6. Johnson IR, Macpherson MBA, Welch CC, Filshie GM. A comparison of lamicel and prostaglandin E2 vaginal gel for cervical ripening before induction of labor. Am J Obstet Gynecol 1985;151: 604 -7. 7. MacKenzie IZ, Embrey MP. Cervical ripening with intravaginal prostaglandin E2 gel. BMJ 1977;2:1381-4. 8. MacLennan AH, Green RC. Cervical ripening and induction of labour with intravaginal prostaglandin F2,. Lancet 1979;i:117-9. 9. Neilson DR, Prins RP, Bolton RN, Mack C 111, Watson P. A comparison of prostaglandin E2 gel and prostaglandin Fa,' gel for preinduction cervical ripening. Am J Obstet Gyneco11983;146:52630. 10. Graves GR, Baskett TF, Gray JH, Luther ER. The effect of vaginal administration of various doses of prostaglandin E2 gel on cervical ripening and induction of labor. Am J Obstet Gynecol 1985;151: 178-81. 11. Owen J, Winkler CL, Harris BA, Hauth JC, Smith MC. A randomized, double-blind trial of prostaglandin E2 gel for cervical ripening and meta-analysis. Am J Obstet Gynecol 1991;165:991-6. 12. Ulmsten U, Wingerup L, Belfrage P, Ekman G, Wiqvist N. Intracervical application of prostaglandin gel for induction of term labor. Obstet Gynecol 1982;59:336-9. 13. Ekman G, Forman A, Marsal K, Ulmsten U. Intravaginal versus intracervical application of prostaglandin E~ in viscous gel for cervical priming and induction of labor at term in patients with an unfavorable cervical state. Am J Obstet Gynecol 1983;147:657-61. 14. Nimrod C, Currie J, Yee J, Dodd G, Persaud D. Cervical ripening and labor induction with intracervical triacetin base prostaglandin E2 gel: A placebo-controlled study. Obstet Gynecol 1984;64:476-8.
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15. Trofatter KF, Bowers D, Gall SA, Killam AP. Preinduction cervical ripening with prostaglandin E2 (Prepidil) gel. Am J Obstet Gyne'col 1985;153:268 -71. 16. Trofatter KF. Effect of preinduction cervical softening with dinoprostone gel on outcome of oxytocin-induced labor. Clin Ther 1993;15:838-44. 17. Atad J, Bornstein J, Calderon I, Petrikovsky BM, Sorokin Y, Abramovici H. Nonpharmaceutical ripening of the unfavorable cervix and induction of labor by a novel double balloon device. Obstet Gynecol 1991 ;77:146-52. 18. Witter FR, Rocco LE, Johnson TRB. A randomized trial of prostaglandin E2 in a controlled-release vaginal pessary for cervical ripening at term. Am J Obstet Gynecol 1992;166:830-4. 19. Evans MI, Dougan M-B, Moawad AH, Evans WJ, BryantGreenwood GD, Greenwood FC. Ripening of the h u m a n cervix with porcine ovarian relaxin. Am J Obstet Gynecol 1983;147:410-4. 20. Frydman R, Lelaidier C, Baton-Saint-Mleux C, Fernandez I-t, Vial M, Bourget P. Labor induction in women at term with mifepristone (RU 486): A double-blind, randomized, placebo-controlled study. Obstet Gynecol 1992;80:972-5. 21. Blum M. Indication du travail par perfusion extra-amniotique d ' u n e solution saline isotonique dans un cas particulier de mort prenatale. Rev Fr Gynecol Obstet 1982;77:137-9. 22. Schreyer P, Sherman DJ, Ariely S, Herman A, Caspi E. Ripening the highly unfavorable cervix with extra-amniotic saline instillation or vaginal prostaglandin E, application. Obstet Gynecol 1989;73:938 - 42. 23. Rouben D, Arias F. A randomized trial of extra-amniotic saline infusion plus intracervical Foley catheter balloon versus prostaglandin E2 vaginal gel for ripening the cervix and inducing labor in patients with unfavorable cervices. Obstet Gynecol 1993;82:290-4.
A d d r e s s r e p r i n t r e q u e s t s to:
Alexander Lin, MD 333 East Superior Street Suite 444 Chicago, IL 60611
Receiw,d March 27, 1995. Received in revised form June 16, 1995. Accepted June 21, 1995.
Copyright © 1995 by The American College of Obstetricians and Gynecologists.
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