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A randomized trial of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation
A randomized trial of ritodrine tocolysis versus expectant management in patients with premature rupture of membranes at 25 to 30 weeks of gestation Thomas J. Garite, M.D., Kirk A. Keegan, M.D., Roger K. Freeman, M.D., and Michael P. Nageotte, M.D. Long Beach, California Expectant management was compared with similar management plus ritodrine tocolysis in a randomized controlled trial in patients with premature rupture of membranes at 25 to 30 weeks of gestation. In the tocolysis group intravenously administered ritodrine was instituted at the onset of labor and then changed to the oral form if successful. Tocolysis was discontinued or not instituted after 31 weeks of gestation. Seventy-nine patients were randomized over a 4-year period, 39 in the tocolysis group and 40 in the expectant group. Twenty-three patients in the tocolysis group actually received ritodrine. No difference between the two groups was demonstrated in the interval between premature rupture of membranes and delivery or in reaching 32 weeks of gestation. No statistical difference was seen in maternal morbidity. Birth weights and gestational ages at delivery were similar between the two groups as were the incidences of neonatal morbidities caused by prematurity and infection and in the duration of neonatal hospital stays. Despite being conducted in those gestational ages in which prolongation of pregnancy might be expected to be of most benefit, no difference could be demonstrated with the addition of tocolytic therapy over expectant management alone. (AM J OssTET GYNECOL 1987;157:388-93.)
Key words: Tocolysis, PROM
Premature rupture of membranes (PROM) is the most common single diagnosis leading to premature delivery and neonatal complications that require admission to a neonatal intensive care unit. Better understanding, newer antibiotics, and improved diagnostic techniques have led to fewer major maternal complications. As a consequence, in recent years there has been an increasing tendency to develop management protocols designed principally to prolong pregnancy and decrease neonatal complications from prematurity. Premature labor is a natural consequence of PROM, since 80% to 90% of preterm patients will go into labor within a week of membrane rupture.' With the availability of effective tocolytic agents it would seem logical to apply this form of therapy to patients with premature labor following PROM. In the past experts have thought that tocolysis was contraindicated in such patients primarily because of the concern of increasing the likelihood of infectious morbidity and mortality. 2 However, to date there have been few data from conFrom the Long Beach Memorial Women's Hospital, and the University of California, Irvine. Supported by a grant from the Long Beach Memorial Medical Center Foundation. Received for publication January 16, 1987; accepted April28, 1987. Reprint requests: Thomas]. Garite, M.D., Long Beach Memorial Women's Hospital, 2801 Atlantic Avenue, Long Beach, CA 90801.
388
trolled studies on which to evaluate the efficacy and safety of attempting to stop labor and delay preterm delivery in patients after PROM. Therefore, a prospective randomized study was developed to evaluate the use of tocolysis in patients with preterm labor after PROM. Because it has been shown that tocolytic therapy is generally less effective in patients with ruptured as opposed to intact membranes, we chose to study patients with PROM in the very premature gestation, in which any benefit from prolongation of pregnancy and the consequent improvement in neonatal outcome might be expected to be most likely demonstrated.
Material and methods All patients admitted to the perinatal service of the Long Beach Memorial Women's Hospital either primarily or as a perinatal and/or maternal transport with PROM and singleton pregnancies between 25 weeks and 30 weeks, 6 days of gestation were requested to consent to randomization. Gestational age was determined by menstrual history and prenatal examinations or if these were questionable, by ultrasound measurements of biparietal diameter, abdominal circumference, and femur length. Patients with heart disease, diabetes mellitus, and thyrotoxicosis were excluded. Ruptre of membranes was documented by speculum examination that confirmed the pooling of fluid in the
posterior vaginal fornix; alkaline pH by Nitrazine paper; ferning; and direct visualization of leakage of fluid from the cervical canal. Cultures for group B Streptococcus and gonorrhea were obtained at this time. No digital examinations were performed unless the patient was thought to be in active labor; although some patients had been examined digitally before maternal transport. Patients with equivocal or undocumented rupture of membranes were not included in the study. Patients in advanced active labor, as defined by regular contractions and clear visibility of the fetal presenting parts on speculum examination, were also excluded. Patients were then evaluated for fetal distress by continuous electronic fetal heart rate monitoring and for clinical chorioamnionitis. The clinical diagnosis of chorioamnionitis required the presence of a temperature elevation of ;:;,: 100.4° F and any one of the following: maternal tachycardia (heart rate > 100 bpm); fetal tachycardia (heart rate > 160 bpm); maternal leukocytosis (white blood cells> 15,000/mm'); uterine tenderness; or foulsmelling amniotic fluid. Patients with irreversible fetal distress or clinical chorioamnionitis were delivered immediately and were not randomized. Consenting patients were randomized to receive either expectant management only or expectant management plus intravenous administration of ritodrine at the onset of contractions. Patients in the expectant management group were delivered for spontaneous labor, clinical chorioamnionitis, or fetal distress. Patients in the tocolytic group were similarly managed except at the onset of contractions with a frequency of three or more per 20 minutes; tocolytic therapy with intravenously administered ritodrine was begun. Patients were started on 150 J.Lg/min, which was increased by 50 J.Lg every 10 minutes until one of the following was achieved: decrease in contraction frequency to
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Table I. Prerandomization characteristics of study groups
N Maternal age (mean) Parity 0 ;;.I
Tocolysis group
Expectant group
p
39 26.4
40 28.9
NS
I9 20
I5 25
NS NS
I I2 27 27.3
NS NS NS NS
28 5 2 5 3
NS NS
5
NS
23 I7 3
NS NS NS
9 22 9
NS
Contractions on admission 4 Regular I3 Irregular 22 None 27.9 Gestational age on admission (wk) Duration of ROM on admission 3I48 hr 9 Underwent amniocentesis Digital cervical ex2 aminations before labor Temperature on admission 24 <98.7° F I5 98.7°-99.9° F I GBS on cervical culture Baseline FHR on admission I3 I50 bpm ROM
=
Rupture of membranes; GBS
=
group B Strepto-
coccus; FHR = fetal heart rate; NS = not significant.
at that point. After 31 weeks of gestation, patients were managed expectantly only as in the first group. No corticosteroids were used in either group; patients who had received corticosteroids before transfer were excluded from randomization. Whenever possible, ultrasound-directed amniocentesis was performed for Gram stain and culture of amniotic fluid as soon as possible after admission. Patients with successful amniocentesis and Gram stain positive for bacteria were excluded from the study. However, patients did not require amniocentesis to be eligible. In general, patients not in labor were kept on continuous fetal heart rate monitoring for at least 24 hours and if stable were then transferred to the antepartum unit and kept in the hospital until delivery. On the antepartum unit they were monitored with frequent temperature readings and daily prolonged (1 hour) nonstress tests. Patients with abnormal or concerning nonstress tests were transferred back to labor and delivery for continuous fetal heart rate monitoring. The route of delivery for both groups was determined by means of the same criteria. All breech presentations were delivered by cesarean section. When induction of labor was necessary or spontaneous labor
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Garite et al.
Table II. Time interval of PROM to delivery Received tocolysis
TG
TG
=
Toco1ytic group; EG
23 6.1 20 (87%) 15 (65%) 6 (26%) 3 (13%)
39 11.5 35 (88%) 30 (77%) 12 (31 %) 8 (21%)
N Mean (days) >24 hr >48 hr >1 wk Reached 32 wk =
EG 40 12.0 36 (90%) 30 (75%) 13 (33%) 6 (15%)
p NS NS NS NS NS
expectant group.
Table III. Reasons for delivery Toco1ysis group Labor/failed tocolysis Infection (with or without labor) Labor/reached 32 wk Advanced labor Labor/refused further tocolysis Expectant group Labor (with or without infection) Antepartum fetal distress Induced because of infection Significant maternal vaginal bleeding
12 14 8 4 1 32 4 3 1
occurred, cesarean section was performed for the usual obstetric indications. The presence of chorioamnionitis did not significantly alter indications for cesarean section or the duration of labor allowed. Prophylactic antibiotics were used on all patients delivered by cesarean section after cord clamping but in no patient who was delivered vaginally. All maternal patient data were coded prospectively. Neonatal data were coded after neonatal discharge. The diagnosis of respiratory distress syndrome (RDS) was made only when clinical signs and chest x-ray films were confirmatory and the newborn infant required at least 24 hours of oxygen therapy. Analysis of data was performed by means of X2 and two-tailed t tests.
Results The study was conducted between january 1983 and September 1986. Seventy-nine patients were randomized; 39 to the tocolysis group and 40 to the expectant management group. Comparison of the prerandomization characteristics of both groups (Table I) would suggest that the two groups were well matched. In addition, there was no significant difference in the number of patients undergoing amniocentesis (nine of 39 in the tocolysis group vs 3 of 40 in the expectant group, X2 = 2.6; not significant) or in the sex of the babies delivered (20 males/19 females in the tocolytic group vs 20 males/20 females in the expectant group) between the two groups. Of the 39 patients randomized to receive tocolysis,
23 actually did receive ritodrine when contractions began. Of the 16 randomized to receive the drug but who did not, seven were ineligible because of clinical chorioamnionitis, five had gone beyond 31 weeks of gestation at the onset oflabor, three had advanced cervical dilation at the time the drug was to be started, and one was infected and the fetus had no heart activity (stillborn). The interval between the rupture of membranes and delivery in the two groups is compared in Table II. In addition, the subgroup of patients who actually received tocolytic therapy is separated for comparison. Both mean and intervallic data fail to show any prolongation of pregnancy with the addition of ritodrine to the more standard expectant management at the onset of labor. In addition, eight of 40 (20%) in the tocolytic group vs six of 40 (15%) in the expectant group (difference, not significant) reached 32 weeks of gestation, which in essence was the goal or point beyond which management in the two groups became similar. The causes and/or indications for delivery in both groups are listed in Table Ill. Of the 23 patients who did receive ritodrine, 10 were delivered in <24 hours from the onset of therapy, six between 24 and 48 hours, one between 2 and 3 days, and six were delivered after the third day from the initiation of tocolytic therapy (4, 5, 6, 8, 11, and 23 days). There were no serious complications directly attributable to the ritodrine therapy in these patients·, although one patient declined to be treated again after one full course when labor recurred because of side effects experienced with the first course. Evaluation of maternal outcome in both groups does not reveal any striking dissimilarities. The cesarean section rate was similar between the two groups (18 of 39 [46%] in the tocolytic group vs 12 of 40 [30%] in the expectant group, X2 = 1.55; not significant). The cesarean section rate was also similar in those patients who actually received ritodrine (eight of23 [35%]). The incidence of chorioamnionitis was 14 of 39 (35%) in the tocolytic group vs seven of 40 ( 18%) in the expectant group; this difference was not statistically significantly different (X2 = 2.54, p = 0.12). The incidence of cho-
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Table IV. Neonatal outcome Tocolytic group
N Mean birth weight (gm) Gestational age at delivery (wk) RDS Sepsis IVH, grades 3 and 4 Low Apgar scores (<7 at 5 min) Hospital stay (days)* Mean >30 >60 Range
Expectant group
p
39 1387 29.5 20 (51%) 1 (3%) 3 (8%) 7 (18%)
40 1340 28.9 23 (58%) 2 (5%) 2 (5%) 2 (5%)
NS NS NS NS NS NS
47.5 20 (60%) 10 (30%) 2-134
57.0 26 (68%) 12 (31%) 2-210
NSt NS NS
RDS = Respiratory distress syndrome; IVH = intraventricular hemorrhage. *Includes only babies discharged home alive (tocolytic group = 33, expectant group tt = 1.89, p = 0.08.
rioamnionitis in those patients who actually received tocolysis was eight of 23 (30% ). The occurrence of postpartum endomyometritis was also similar, with 10 of 39 (26%) in the tocolytic group and six of 40 (15%) in the expectant group but three of 23 (13%) in patients who received ritodrine. The incidence of prolonged postpartum stay (>3 days in vagipally delivered and >6 days for patients who had cesarean sections) was virtually identical between the two (three of 39 [8%] in the tocolytic group vs three of 40 [8%] in the expectant group). Comparisons of neonatal outcome are found in Table IV. It can be seen that the birth weights, gestational ages at delivery, low frequencies of 5-minute Apgar scores, and incidences of significant neonatal complications are quite similar between the two groups. Although the mean hospital stays are numerically dissimilar between the two groups, this is not a normal curve, and the incidences of prolonged stays (>30 and >60 days) are quite similar. There were eight perinatal deaths among the 79 total patients in the study (101 of 1000). Two occurred in the expectant group (5%), including one stillbirth. There were six deaths in the tocolytic group (15%), also with one stillbirth. However, only two deaths (9%), both neonatal, occurred in the group that actually received tocolysis. The causes of death are listed in Table V. Comment
Because prematurity is the leading cause of perinatal mortality in patients with PROM, and since recent studies 3 • 4 have suggested increased maternal safety in those patients not delivered immediately after PROM, most authors 1 have recently recommended various management schemes that are chiefly aimed at prolonging pregnancy. The addition of tocolytic therapy
=
38),
Table V. Causes of perinatal deaths Tocolytic group (6) Severe respiratory distress syndrome Trisomy 21/eqdocardial cushion defect Sepsis-group B Streptococcus (stillbirth) Expectant group (2) Necrotizing enterocolitis Asphyxia/abruptio placentae (stillbirth)
4* I 1
*Possible sepsis (I); possible pulmonary hypoplasia (!). to help achieve these goals in such patients is an obvious alternative. In the past, tocolytic agents were said to be contraindicated in patients with PROM 2 because of presumed lack of efficacy and concern about aggravating infectious morbidity. Although there are indeed theoretical reasons to believe that both of these concerns may be valid, there have been few investigative data on which to corroborate or refute them. Most of the current information refers to the relative effectiveness of tocolytic agents in patients with PROM compared with patients with premature labor with intact membranes. Caritis et al. 5 used terbutaline and were able to gain a week or more in only 14% of patients with ruptured membranes as opposed to 59% of patients with unruptured membranes. Elliott6 evaluated magnesium sulfate as a tocolytic agent and showed that 78% of patients with intact membranes were still undelivered after 48 hours as opposed to only 5% whose membranes were ruptured. In a collaborative study Curet et aP were able to show a reduction of over 50% in the rate of RDS in patients with premature labor who are given ritodrine, but in patients with PROM similarly treated there was no difference between treated patients and controls in the incidence of RDS. Christensen et al." have published a small randomized
392
Garite et al.
clinical trial in patients in preterm labor with PROM, comparing ritodrine therapy with placebo. The only difference shown was a prolongation of pregnancy beyond 24 hours in the tocolytic group, but beyond 48 hours no difference was shown. There was no improvement seen in outcome for any newborn. However, there was no apparent increase in the rate of infectious complications in either mothers or neonates. In designing this randomized clinical study, the question that we asked was whether the planned addition of a tocolytic agent at the onset of labor was of any benefit in terms of prolonging pregnancy and/or improving neonatal outcome as compared with expectant management alone. Because it is probably true that tocolysis with PROM cannot be expected to be as effective as with preterm labor with intact membranes, we chose to study only those patients with very early gestational ages for whom any prolongation of pregnancy would be expected to result in the greatest benefit to the newborn. Goldenberg et aP have suggested that between the gestational ages of 25 and 30 weeks, improvements in survival of 0.9% to 3% per day and 6% to 21% per week could be expected. The results of this clinical trial do not suggest that there is any benefit to adding tocolysis to expectant management either in terms of prolonging the interval between PROM and delivery or in reducing morbidity from prematurity or perinatal mortality. As seen in Table II, there is a striking similarity in the time intervals between PROM and delivery for the two groups both in terms of mean days gained and in the intervallic data. In terms of the overall goal, that is, to reach 32 weeks of gestation, since that was the time when management became similar in the two groups, no difference was seen. With respect to neonatal outcome, virtually all parameters evaluated were similar between the two groups. This is true for birth weights and gestational ages at delivery and for morbidity of prematurity and the duration of neonatal hospital stay. It would be expected that any neonatal benefit from prolonging pregnancy with tocolysis in these patients would be shown in these outcome parameters, and none were seen. It is tempting to try to compare the 23 patients who actually received ritodrine with a similar group of patients from the expectant management group. However, one cannot validly extract from the expectant group which patients should be compared and at what point in time the onset of labor for these patients should be defined, since no attempt was made prospectively to identify them. Valid comparisons should not be made between this group that actually received tocolysis and the overall expectant group, since the latter includes patients who went beyond 32 weeks of gestation, in-
August 1987 Am J Obstet Gynecol
fected patients, and those who were in advanced labor when their labors were first discovered. Therefore one cannot conclude from this study that tocolysis in laboring patients with PROM shows no apparent benefit over no tocolysis, as was suggested in the study by Christensen et al. 8 Rather, what was shown was that the addition of planned tocolysis to expectant management did not demonstrate any apparent benefit over expectant management alone. One additional point that this study illustrates is not only lack of apparent efficacy but limited applicability, since only 23 of 39 (59%) patients randomized to receive ritodrine actually did so. Most frequently this was because of infection or advanced labor at the time that diagnosis of labor was made. The impact of this consideration is important, since even if limited efficacy could be shown with tocolysis in patients with PROM in larger studies, the fact would remain that the overall impact would be limited by lack of complete applicability. This problem has also been identified in premature labor in general! Although this study does not demonstrate any apparent benefit from tocolysis, it does not suggest any deleterious effect from such treatment in patients with PROM. There was no increase in the incidence of any infectious complication. Though there is a numerical trend toward more chorioamnionitis in the tocolytic group, this trend was not limited to those patients who actually received tocolysis, for whom the incidence was actually less (seven of 23 [30%]) than in the overall tocolytic group (14 of 39 [35%]). However, it is possible that a larger study might demonstrate such deleterious effects. Additionally, there were no other apparent harmful maternal or neonatal effects. Perhaps the reason that no benefit was shown with the addition of tocolytic therapy in this study is that once labor has been estabished in patients with PROM it is already too late. Perhaps earlier detection of contractions and earlier institution of therapy might improve efficacy. One choice might be frequent contraction monitoring with a device such as that described by Katz et al., 10 the "ambulatory tokodynamometer." Alternatively or additionally, prophylactic oral agents might be of benefit as shown by Levy and Warsof, 11 who showed in a prospective randomized study that oral ritodrine given to patients not in labor with PROM substantially prolonged pregnancy over control patients; however, although babies were slightly larger in the treatment group, no other improvement in neonatal outcome was shown. Although current studies may show that short-term gains such as 24 or 48 hours may be accomplished with intravenous therapy once labor is started, there is a question of whether there are any benefits to be derived
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from such short delays. The benefit of corticosteroids given to the mother to reduce neonatal RDS is at best cjuestionabie in patients with PROM and may increase the risk of infection.' Delaying delivery 24 to 48 hours alone in the presence of PROM has been suggested to lower the chances of RDS, but again these effects are controversial. 12 In conclusion, although this study is limited by relatively small numbers, it was conducted in those gestational ages during which prolongation of pregnancy might have been expected to produce the greatest benefit in neonatal outcome. Nevertheless, no benefit could be demonstrated with the addition of a proved effective tocolytic agent after the onset of labor over expectant management alone in the patient with PROM in the very premature gestational period. Some form of expectant management with careful attention to avoiding complications from infection and asphyxia remains the management of choice for providing the best outcome in patients with PROM. It appears that tocolysis at the onset of labor will do little to improve on this form of management although further studies certainly should be done to confirm or refute this conclusion. REFERENCES l. Garite TJ. Premature rupture of membranes. Curr Probl Obstet Gynecol 1984; 7: l.
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2. Zlatnik FJ. The applicability of labor inhibition to the problem of prematurity. AM j 0BSTET GYNECOL 1972; 113:704. 3. Koh KS, Chan FH, Manfared AH, et a!. The changing maternal and perinatal outcome in chorioamnionitis. Obstet Gynecol 1979;53:730. 4. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol 1982;54:539. 5. Caritis SN, Toig G, Heddinger LA, eta!. A double-blind study comparing ritodrine and terbutaline in the treatment of preterm labor. AM j 0BSTET GYNECOL 1984; 150:7. 6. Elliott JP. Magnesium sulfate as a tocolytic agent. AM J 0BSTET GYNECOL 1983;147:277. 7. Curet LB, Rao AV, Zachman RD, et a!. Association between ruptured membranes, tocolytic therapy, and respiratory distress syndrome. AM J OBSTET GYNECOL 1984; 148:263. 8. Christensen KK, Ingemarsson I, Leideman T, eta!. Effect of ritodrine on labor after premature rupture of membranes. Obstet Gynecol 1980;55:187. 9. Goldenberg RL, Nelson KG, Davis RO, et a!. Delay in delivery: influence on gestational age and the duration of delay on perinatal outcome. Obstet Gynecol 1984;64:480. 10. Katz M, Newman RB, Gill PJ. Assessment of uterine activity in ambulatory patients at risk of preterm labor and delivery. AMJ 0BSTET GYNECOL 1986;154:44. 11. Levy DL, Warsof SL. Oral ritodrine and preterm premature rupture of membranes. Obstet Gynecol 1985; 66:621. 12. Mead PB. Management of the patient with premature rupture of the membranes. Clin Perinatol 1980;7:243.
Key words: Tocolysis, PROM
Premature rupture of membranes (PROM) is the most common single diagnosis leading to premature delivery and neonatal complications that require admission to a neonatal intensive care unit. Better understanding, newer antibiotics, and improved diagnostic techniques have led to fewer major maternal complications. As a consequence, in recent years there has been an increasing tendency to develop management protocols designed principally to prolong pregnancy and decrease neonatal complications from prematurity. Premature labor is a natural consequence of PROM, since 80% to 90% of preterm patients will go into labor within a week of membrane rupture.' With the availability of effective tocolytic agents it would seem logical to apply this form of therapy to patients with premature labor following PROM. In the past experts have thought that tocolysis was contraindicated in such patients primarily because of the concern of increasing the likelihood of infectious morbidity and mortality. 2 However, to date there have been few data from conFrom the Long Beach Memorial Women's Hospital, and the University of California, Irvine. Supported by a grant from the Long Beach Memorial Medical Center Foundation. Received for publication January 16, 1987; accepted April28, 1987. Reprint requests: Thomas]. Garite, M.D., Long Beach Memorial Women's Hospital, 2801 Atlantic Avenue, Long Beach, CA 90801.
388
trolled studies on which to evaluate the efficacy and safety of attempting to stop labor and delay preterm delivery in patients after PROM. Therefore, a prospective randomized study was developed to evaluate the use of tocolysis in patients with preterm labor after PROM. Because it has been shown that tocolytic therapy is generally less effective in patients with ruptured as opposed to intact membranes, we chose to study patients with PROM in the very premature gestation, in which any benefit from prolongation of pregnancy and the consequent improvement in neonatal outcome might be expected to be most likely demonstrated.
Material and methods All patients admitted to the perinatal service of the Long Beach Memorial Women's Hospital either primarily or as a perinatal and/or maternal transport with PROM and singleton pregnancies between 25 weeks and 30 weeks, 6 days of gestation were requested to consent to randomization. Gestational age was determined by menstrual history and prenatal examinations or if these were questionable, by ultrasound measurements of biparietal diameter, abdominal circumference, and femur length. Patients with heart disease, diabetes mellitus, and thyrotoxicosis were excluded. Ruptre of membranes was documented by speculum examination that confirmed the pooling of fluid in the
posterior vaginal fornix; alkaline pH by Nitrazine paper; ferning; and direct visualization of leakage of fluid from the cervical canal. Cultures for group B Streptococcus and gonorrhea were obtained at this time. No digital examinations were performed unless the patient was thought to be in active labor; although some patients had been examined digitally before maternal transport. Patients with equivocal or undocumented rupture of membranes were not included in the study. Patients in advanced active labor, as defined by regular contractions and clear visibility of the fetal presenting parts on speculum examination, were also excluded. Patients were then evaluated for fetal distress by continuous electronic fetal heart rate monitoring and for clinical chorioamnionitis. The clinical diagnosis of chorioamnionitis required the presence of a temperature elevation of ;:;,: 100.4° F and any one of the following: maternal tachycardia (heart rate > 100 bpm); fetal tachycardia (heart rate > 160 bpm); maternal leukocytosis (white blood cells> 15,000/mm'); uterine tenderness; or foulsmelling amniotic fluid. Patients with irreversible fetal distress or clinical chorioamnionitis were delivered immediately and were not randomized. Consenting patients were randomized to receive either expectant management only or expectant management plus intravenous administration of ritodrine at the onset of contractions. Patients in the expectant management group were delivered for spontaneous labor, clinical chorioamnionitis, or fetal distress. Patients in the tocolytic group were similarly managed except at the onset of contractions with a frequency of three or more per 20 minutes; tocolytic therapy with intravenously administered ritodrine was begun. Patients were started on 150 J.Lg/min, which was increased by 50 J.Lg every 10 minutes until one of the following was achieved: decrease in contraction frequency to
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Table I. Prerandomization characteristics of study groups
N Maternal age (mean) Parity 0 ;;.I
Tocolysis group
Expectant group
p
39 26.4
40 28.9
NS
I9 20
I5 25
NS NS
I I2 27 27.3
NS NS NS NS
28 5 2 5 3
NS NS
5
NS
23 I7 3
NS NS NS
9 22 9
NS
Contractions on admission 4 Regular I3 Irregular 22 None 27.9 Gestational age on admission (wk) Duration of ROM on admission 3I
=
Rupture of membranes; GBS
=
group B Strepto-
coccus; FHR = fetal heart rate; NS = not significant.
at that point. After 31 weeks of gestation, patients were managed expectantly only as in the first group. No corticosteroids were used in either group; patients who had received corticosteroids before transfer were excluded from randomization. Whenever possible, ultrasound-directed amniocentesis was performed for Gram stain and culture of amniotic fluid as soon as possible after admission. Patients with successful amniocentesis and Gram stain positive for bacteria were excluded from the study. However, patients did not require amniocentesis to be eligible. In general, patients not in labor were kept on continuous fetal heart rate monitoring for at least 24 hours and if stable were then transferred to the antepartum unit and kept in the hospital until delivery. On the antepartum unit they were monitored with frequent temperature readings and daily prolonged (1 hour) nonstress tests. Patients with abnormal or concerning nonstress tests were transferred back to labor and delivery for continuous fetal heart rate monitoring. The route of delivery for both groups was determined by means of the same criteria. All breech presentations were delivered by cesarean section. When induction of labor was necessary or spontaneous labor
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Table II. Time interval of PROM to delivery Received tocolysis
TG
TG
=
Toco1ytic group; EG
23 6.1 20 (87%) 15 (65%) 6 (26%) 3 (13%)
39 11.5 35 (88%) 30 (77%) 12 (31 %) 8 (21%)
N Mean (days) >24 hr >48 hr >1 wk Reached 32 wk =
EG 40 12.0 36 (90%) 30 (75%) 13 (33%) 6 (15%)
p NS NS NS NS NS
expectant group.
Table III. Reasons for delivery Toco1ysis group Labor/failed tocolysis Infection (with or without labor) Labor/reached 32 wk Advanced labor Labor/refused further tocolysis Expectant group Labor (with or without infection) Antepartum fetal distress Induced because of infection Significant maternal vaginal bleeding
12 14 8 4 1 32 4 3 1
occurred, cesarean section was performed for the usual obstetric indications. The presence of chorioamnionitis did not significantly alter indications for cesarean section or the duration of labor allowed. Prophylactic antibiotics were used on all patients delivered by cesarean section after cord clamping but in no patient who was delivered vaginally. All maternal patient data were coded prospectively. Neonatal data were coded after neonatal discharge. The diagnosis of respiratory distress syndrome (RDS) was made only when clinical signs and chest x-ray films were confirmatory and the newborn infant required at least 24 hours of oxygen therapy. Analysis of data was performed by means of X2 and two-tailed t tests.
Results The study was conducted between january 1983 and September 1986. Seventy-nine patients were randomized; 39 to the tocolysis group and 40 to the expectant management group. Comparison of the prerandomization characteristics of both groups (Table I) would suggest that the two groups were well matched. In addition, there was no significant difference in the number of patients undergoing amniocentesis (nine of 39 in the tocolysis group vs 3 of 40 in the expectant group, X2 = 2.6; not significant) or in the sex of the babies delivered (20 males/19 females in the tocolytic group vs 20 males/20 females in the expectant group) between the two groups. Of the 39 patients randomized to receive tocolysis,
23 actually did receive ritodrine when contractions began. Of the 16 randomized to receive the drug but who did not, seven were ineligible because of clinical chorioamnionitis, five had gone beyond 31 weeks of gestation at the onset oflabor, three had advanced cervical dilation at the time the drug was to be started, and one was infected and the fetus had no heart activity (stillborn). The interval between the rupture of membranes and delivery in the two groups is compared in Table II. In addition, the subgroup of patients who actually received tocolytic therapy is separated for comparison. Both mean and intervallic data fail to show any prolongation of pregnancy with the addition of ritodrine to the more standard expectant management at the onset of labor. In addition, eight of 40 (20%) in the tocolytic group vs six of 40 (15%) in the expectant group (difference, not significant) reached 32 weeks of gestation, which in essence was the goal or point beyond which management in the two groups became similar. The causes and/or indications for delivery in both groups are listed in Table Ill. Of the 23 patients who did receive ritodrine, 10 were delivered in <24 hours from the onset of therapy, six between 24 and 48 hours, one between 2 and 3 days, and six were delivered after the third day from the initiation of tocolytic therapy (4, 5, 6, 8, 11, and 23 days). There were no serious complications directly attributable to the ritodrine therapy in these patients·, although one patient declined to be treated again after one full course when labor recurred because of side effects experienced with the first course. Evaluation of maternal outcome in both groups does not reveal any striking dissimilarities. The cesarean section rate was similar between the two groups (18 of 39 [46%] in the tocolytic group vs 12 of 40 [30%] in the expectant group, X2 = 1.55; not significant). The cesarean section rate was also similar in those patients who actually received ritodrine (eight of23 [35%]). The incidence of chorioamnionitis was 14 of 39 (35%) in the tocolytic group vs seven of 40 ( 18%) in the expectant group; this difference was not statistically significantly different (X2 = 2.54, p = 0.12). The incidence of cho-
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Table IV. Neonatal outcome Tocolytic group
N Mean birth weight (gm) Gestational age at delivery (wk) RDS Sepsis IVH, grades 3 and 4 Low Apgar scores (<7 at 5 min) Hospital stay (days)* Mean >30 >60 Range
Expectant group
p
39 1387 29.5 20 (51%) 1 (3%) 3 (8%) 7 (18%)
40 1340 28.9 23 (58%) 2 (5%) 2 (5%) 2 (5%)
NS NS NS NS NS NS
47.5 20 (60%) 10 (30%) 2-134
57.0 26 (68%) 12 (31%) 2-210
NSt NS NS
RDS = Respiratory distress syndrome; IVH = intraventricular hemorrhage. *Includes only babies discharged home alive (tocolytic group = 33, expectant group tt = 1.89, p = 0.08.
rioamnionitis in those patients who actually received tocolysis was eight of 23 (30% ). The occurrence of postpartum endomyometritis was also similar, with 10 of 39 (26%) in the tocolytic group and six of 40 (15%) in the expectant group but three of 23 (13%) in patients who received ritodrine. The incidence of prolonged postpartum stay (>3 days in vagipally delivered and >6 days for patients who had cesarean sections) was virtually identical between the two (three of 39 [8%] in the tocolytic group vs three of 40 [8%] in the expectant group). Comparisons of neonatal outcome are found in Table IV. It can be seen that the birth weights, gestational ages at delivery, low frequencies of 5-minute Apgar scores, and incidences of significant neonatal complications are quite similar between the two groups. Although the mean hospital stays are numerically dissimilar between the two groups, this is not a normal curve, and the incidences of prolonged stays (>30 and >60 days) are quite similar. There were eight perinatal deaths among the 79 total patients in the study (101 of 1000). Two occurred in the expectant group (5%), including one stillbirth. There were six deaths in the tocolytic group (15%), also with one stillbirth. However, only two deaths (9%), both neonatal, occurred in the group that actually received tocolysis. The causes of death are listed in Table V. Comment
Because prematurity is the leading cause of perinatal mortality in patients with PROM, and since recent studies 3 • 4 have suggested increased maternal safety in those patients not delivered immediately after PROM, most authors 1 have recently recommended various management schemes that are chiefly aimed at prolonging pregnancy. The addition of tocolytic therapy
=
38),
Table V. Causes of perinatal deaths Tocolytic group (6) Severe respiratory distress syndrome Trisomy 21/eqdocardial cushion defect Sepsis-group B Streptococcus (stillbirth) Expectant group (2) Necrotizing enterocolitis Asphyxia/abruptio placentae (stillbirth)
4* I 1
*Possible sepsis (I); possible pulmonary hypoplasia (!). to help achieve these goals in such patients is an obvious alternative. In the past, tocolytic agents were said to be contraindicated in patients with PROM 2 because of presumed lack of efficacy and concern about aggravating infectious morbidity. Although there are indeed theoretical reasons to believe that both of these concerns may be valid, there have been few investigative data on which to corroborate or refute them. Most of the current information refers to the relative effectiveness of tocolytic agents in patients with PROM compared with patients with premature labor with intact membranes. Caritis et al. 5 used terbutaline and were able to gain a week or more in only 14% of patients with ruptured membranes as opposed to 59% of patients with unruptured membranes. Elliott6 evaluated magnesium sulfate as a tocolytic agent and showed that 78% of patients with intact membranes were still undelivered after 48 hours as opposed to only 5% whose membranes were ruptured. In a collaborative study Curet et aP were able to show a reduction of over 50% in the rate of RDS in patients with premature labor who are given ritodrine, but in patients with PROM similarly treated there was no difference between treated patients and controls in the incidence of RDS. Christensen et al." have published a small randomized
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clinical trial in patients in preterm labor with PROM, comparing ritodrine therapy with placebo. The only difference shown was a prolongation of pregnancy beyond 24 hours in the tocolytic group, but beyond 48 hours no difference was shown. There was no improvement seen in outcome for any newborn. However, there was no apparent increase in the rate of infectious complications in either mothers or neonates. In designing this randomized clinical study, the question that we asked was whether the planned addition of a tocolytic agent at the onset of labor was of any benefit in terms of prolonging pregnancy and/or improving neonatal outcome as compared with expectant management alone. Because it is probably true that tocolysis with PROM cannot be expected to be as effective as with preterm labor with intact membranes, we chose to study only those patients with very early gestational ages for whom any prolongation of pregnancy would be expected to result in the greatest benefit to the newborn. Goldenberg et aP have suggested that between the gestational ages of 25 and 30 weeks, improvements in survival of 0.9% to 3% per day and 6% to 21% per week could be expected. The results of this clinical trial do not suggest that there is any benefit to adding tocolysis to expectant management either in terms of prolonging the interval between PROM and delivery or in reducing morbidity from prematurity or perinatal mortality. As seen in Table II, there is a striking similarity in the time intervals between PROM and delivery for the two groups both in terms of mean days gained and in the intervallic data. In terms of the overall goal, that is, to reach 32 weeks of gestation, since that was the time when management became similar in the two groups, no difference was seen. With respect to neonatal outcome, virtually all parameters evaluated were similar between the two groups. This is true for birth weights and gestational ages at delivery and for morbidity of prematurity and the duration of neonatal hospital stay. It would be expected that any neonatal benefit from prolonging pregnancy with tocolysis in these patients would be shown in these outcome parameters, and none were seen. It is tempting to try to compare the 23 patients who actually received ritodrine with a similar group of patients from the expectant management group. However, one cannot validly extract from the expectant group which patients should be compared and at what point in time the onset of labor for these patients should be defined, since no attempt was made prospectively to identify them. Valid comparisons should not be made between this group that actually received tocolysis and the overall expectant group, since the latter includes patients who went beyond 32 weeks of gestation, in-
August 1987 Am J Obstet Gynecol
fected patients, and those who were in advanced labor when their labors were first discovered. Therefore one cannot conclude from this study that tocolysis in laboring patients with PROM shows no apparent benefit over no tocolysis, as was suggested in the study by Christensen et al. 8 Rather, what was shown was that the addition of planned tocolysis to expectant management did not demonstrate any apparent benefit over expectant management alone. One additional point that this study illustrates is not only lack of apparent efficacy but limited applicability, since only 23 of 39 (59%) patients randomized to receive ritodrine actually did so. Most frequently this was because of infection or advanced labor at the time that diagnosis of labor was made. The impact of this consideration is important, since even if limited efficacy could be shown with tocolysis in patients with PROM in larger studies, the fact would remain that the overall impact would be limited by lack of complete applicability. This problem has also been identified in premature labor in general! Although this study does not demonstrate any apparent benefit from tocolysis, it does not suggest any deleterious effect from such treatment in patients with PROM. There was no increase in the incidence of any infectious complication. Though there is a numerical trend toward more chorioamnionitis in the tocolytic group, this trend was not limited to those patients who actually received tocolysis, for whom the incidence was actually less (seven of 23 [30%]) than in the overall tocolytic group (14 of 39 [35%]). However, it is possible that a larger study might demonstrate such deleterious effects. Additionally, there were no other apparent harmful maternal or neonatal effects. Perhaps the reason that no benefit was shown with the addition of tocolytic therapy in this study is that once labor has been estabished in patients with PROM it is already too late. Perhaps earlier detection of contractions and earlier institution of therapy might improve efficacy. One choice might be frequent contraction monitoring with a device such as that described by Katz et al., 10 the "ambulatory tokodynamometer." Alternatively or additionally, prophylactic oral agents might be of benefit as shown by Levy and Warsof, 11 who showed in a prospective randomized study that oral ritodrine given to patients not in labor with PROM substantially prolonged pregnancy over control patients; however, although babies were slightly larger in the treatment group, no other improvement in neonatal outcome was shown. Although current studies may show that short-term gains such as 24 or 48 hours may be accomplished with intravenous therapy once labor is started, there is a question of whether there are any benefits to be derived
Volume 157 Number 2
from such short delays. The benefit of corticosteroids given to the mother to reduce neonatal RDS is at best cjuestionabie in patients with PROM and may increase the risk of infection.' Delaying delivery 24 to 48 hours alone in the presence of PROM has been suggested to lower the chances of RDS, but again these effects are controversial. 12 In conclusion, although this study is limited by relatively small numbers, it was conducted in those gestational ages during which prolongation of pregnancy might have been expected to produce the greatest benefit in neonatal outcome. Nevertheless, no benefit could be demonstrated with the addition of a proved effective tocolytic agent after the onset of labor over expectant management alone in the patient with PROM in the very premature gestational period. Some form of expectant management with careful attention to avoiding complications from infection and asphyxia remains the management of choice for providing the best outcome in patients with PROM. It appears that tocolysis at the onset of labor will do little to improve on this form of management although further studies certainly should be done to confirm or refute this conclusion. REFERENCES l. Garite TJ. Premature rupture of membranes. Curr Probl Obstet Gynecol 1984; 7: l.
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2. Zlatnik FJ. The applicability of labor inhibition to the problem of prematurity. AM j 0BSTET GYNECOL 1972; 113:704. 3. Koh KS, Chan FH, Manfared AH, et a!. The changing maternal and perinatal outcome in chorioamnionitis. Obstet Gynecol 1979;53:730. 4. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation. Obstet Gynecol 1982;54:539. 5. Caritis SN, Toig G, Heddinger LA, eta!. A double-blind study comparing ritodrine and terbutaline in the treatment of preterm labor. AM j 0BSTET GYNECOL 1984; 150:7. 6. Elliott JP. Magnesium sulfate as a tocolytic agent. AM J 0BSTET GYNECOL 1983;147:277. 7. Curet LB, Rao AV, Zachman RD, et a!. Association between ruptured membranes, tocolytic therapy, and respiratory distress syndrome. AM J OBSTET GYNECOL 1984; 148:263. 8. Christensen KK, Ingemarsson I, Leideman T, eta!. Effect of ritodrine on labor after premature rupture of membranes. Obstet Gynecol 1980;55:187. 9. Goldenberg RL, Nelson KG, Davis RO, et a!. Delay in delivery: influence on gestational age and the duration of delay on perinatal outcome. Obstet Gynecol 1984;64:480. 10. Katz M, Newman RB, Gill PJ. Assessment of uterine activity in ambulatory patients at risk of preterm labor and delivery. AMJ 0BSTET GYNECOL 1986;154:44. 11. Levy DL, Warsof SL. Oral ritodrine and preterm premature rupture of membranes. Obstet Gynecol 1985; 66:621. 12. Mead PB. Management of the patient with premature rupture of the membranes. Clin Perinatol 1980;7:243.