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Oral terbutaline in the outpatient management of preterm labor
Oral terbutaline in the outpatient management of preterm labor Helen Y. How, MD, Sarah A. Hughes, RN, Robert L. Vogel, PhD, Stanley A. Gall, MD, and Joseph A. Spinnato, MD Louisville, Kentucky OBJECTIVE: Our purpose was to prove our hypothesis that once preterm uterine contractions and/or labor is controlled with intravenous tocolysis, oral terbutaline, as a maintenance drug, does not prolong pregnancy. STUDY DESIGN: Before discharge, 184 patients between 24 and 35 completed weeks' gestation were prospectively randomized to continued bed rest either With or without oral terbutaline. Assignment was made with stratification into four groups: group 1, those patients with a Bishop score ->5 with oral terbutaline (n = 50); group 2, those with a Bishop score ->5 without oral terbutaline (n = 53); group 3, those with a Bishop score < 5 with oral terbutaline (n = 41); group 4, those with a Bishop score < 5 without oral terbutaline (n = 40). Oral terbutaline was discontinued at 37 completed weeks. RESULTS: No statistically significant differences were found in the number of readmissions, the number of unscheduled hospital visits, and the neonatal outcomes among the four groups. The gestational age at delivery and percent of deliveries at -> 37 weeks were not significantly different when group 1 was compared with group 2 and group 3 was compared with group 4. CONCLUSION: Oral terbutaline maintenance does not improve pregnancy outcome in patients who have had initial successful intravenous tocolysis. (AM J OBSTETGYNECOL1995;173:1518-22.)
Key words: Oral terbutaline, preterm labor, premature uterine contractions Approximately 10% of neonates in the United States are delivered before 37 weeks' gestation. They account for 75% to 80% of the perinatal deaths not caused by congenital malformation? Ten percent to 30% of these preterm newborns will have a persistent mental, neurologic, or respiratory deficit. 2' 3 Because of the high morbidity and mortality associated with preterm birth, significant effort is directed toward both inhibiting and preventing it. Parenteral tocolytic agents such as [3-sympathomimetic agents and magnesium sulfate enjoy reasonable support in the recent literature as primary therapy, 4' 5 but the effectiveness of subsequent oral [3-sympathomimetic tocoylsis is uncertain. 6-~2 The objective of our study was to prove the hypothesis that once preterm uterine contractions and/or labor is controlled with intravenous tocolysis, oral terbutaline, as a maintenance drug, does not prolong the pregnancy. Material and m e t h o d s
Patients who were between 24 and 35 completed weeks of gestation and were seen in the University of From the Department of Obstetrics and Gynecology, University of Louisville School of Medicine. Received for publication June 27, 1994; revised August 17, 1994; accepted February 14, 1995. Reprint requests: Helen Y. How, MD, Department of Obstetrics and Gynecology, Marshall University School of Medicine, 1801 6th Ave., Huntington, WV 25703. Copyright © 1995 by Mosby-Yea~"Book, Inc. 0002-9378/95 $5.00 + 0 6/1/64291 1518
Louisville hospital between September 1989 and September 1993 were eligible for the study. Enrollment required one of the following three conditions: (1) persistent uterine contractions (->6 contractions per hour) that were unresponsive to intravenous hydration (500 ml to 1 L of 5% dextrose in half-normal saline solution) or subcutaneous terbutaline (0.25 mg every 15 minutes for three doses); (2) progressive cervical dilatation and/or effacement; or (3) dilatation -> 2 cm and 50% effacement on the initial cervical examination in the presence of uterine contractions. All patients initially received intravenous magnesium sulfate, a 6 gm loading dose followed by a maintenance dose of 2 to 5 gm/hr, to stop uterine contractions and/or labor. Gestational age was determined by best obstetric estimates. Ultrasonography was performed on admission to rule out anomalies, confirm dates, and obtain an estimated fetal weight. All patients were given two intramuscular doses of betamethasone (12 mg) at 12hour intervals '3 and intravenous ampicillin or clindamycin, if allergic to ampicillin, pending the results of group B streptococci vaginal cultures. After uterine quiescence was achieved for 12 to 24 hours, the patients were weaned from intravenous magnesium sulfate to oral terbutaline and observed for 24 to 48 hours. Before discharge and after informed consent was obtained, as approved by the Human Studies Committee at the University of Louisville, the patients were assigned to one of two arms of the study protocol on the basis of the degree of cervical change (Bishop
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T a b l e I. D e m o g r a p h i c a n d clinical characteristics*
Maternal age (yr, mean + SD) Race (% nonwhite) Parity Median Range of values Bishop score before going home Median Range of values Gestational age at enrollment (wk) Median Range of values Duration of intravenous magnesium sulfate (hr) Median Range of values Hospital stay (days) Median Range of values Previous preterm delivery (%)
Group 1 (n = 50)
Group 2 (n = 53)
Group 3 (n = 41)
Group 4 (n = 40)
22 -4- 4.7" 62"
21.4 -+ 5.1 ~ 64"
23.7 -4- 4.7" 734
22.3 -+ 5.4" 72"
0 (1)" 0-7
1 (1)" 0-3
1 (1)a 0-4
1 (2)a 0-6
6 (2)b 5-10
6 (2)b 5-9
4 (1)" 2-4
4 (1)" 2-4
32.4 (2.8) b 27.8-34.8
32.3 (3.2) b 24-34.8
30.6 (2.6) a 24.6-34.1
30.7 (4.6)" 23.8-35
16 (14)" 0-96
13.5 (23) ~ 0-104
14 (18)" 0-54
15 (14) a 2-168
2 (1)" 1-7 16~
2 (2)a 1-16 11"
2 (1)a 1-11 10"
2 (1)" 1-9 5a
Group 1, Patients with a Bishop score ->5 with oral terbutaline; group 2, patients with a Bishop score ->5 without oral terbutaline; group 3, patients with a Bishop score < 5 with oral terbutaline; group 4, patients with a Bishop score < 5 without oral terbutaline. Values designated with different letters (a, b, or c) are statistically different from one another according to Bonferroni's simultaneous t test, c~ = 0.05). *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses. score). T h e y were t h e n prospectively r a n d o m i z e d by sealed envelope g e n e r a t e d from a table of r a n d o m n u m b e r s to c o n t i n u e d b e d rest either with or without oral terbutaline (5 to 10 m g every 4 to 6 hours). T h u s there were four groups of patients: group 1, those with a Bishop score >_5 with oral terbutaline; group 2, those with a Bishop score -> 5 without oral terbutaline; group 3, those with a Bishop score < 5 with oral terbutaline; a n d group 4, those with a Bishop score < 5 without oral terbutaline. Weekly pelvic e x a m i n a t i o n s were p e r f o r m e d by the first a u t h o r 80% of the time a n d by the obstetrics a n d gynecology residents assigned to the university clinic 20% of the time. T h e dose of oral terbutaline, 5 to 10 m g every 4 to 6 hours, was adjusted to keep the pulse rate above 90 beats/min a n d decreased if the p a t i e n t c o m p l a i n e d of intolerable side effects such as palpitation, chest pains, or tremors. Oral terbutaline was disc o n t i n u e d at 37 c o m p l e t e d weeks. Patients who had r e c u r r e n t p r e t e r m labor were restarted on parenteral therapy. If the t r e a t m e n t was successful, the p a t i e n t was placed in the group to which she was originally rand o m i z e d irrespective of the presence or absence of cervical change. Patients in all four groups were given similar instruction at entry a n d before discharge o n the signs a n d symptoms of p r e t e r m labor. T h e y were instructed to c o n t i n u e with strict bed rest at h o m e a n d to place a t e l e p h o n e call to the primary investigator or the labor a n d delivery u n i t if symptoms a n d / o r increased contractions ( > 6/hr) were n o t e d a n d persisted for 2 hours despite lateral b e d rest a n d oral hydration. A h o m e u t e r i n e m o n i t o r i n g device was n o t used by any of
the patients. These patients were contacted by telep h o n e if they failed to a p p e a r for the scheduled clinic visit. U n s c h e d u l e d hospital visits were defined as hospital visits for complaints of possible p r e m a t u r e u t e r i n e contractions that required external fetal m o n i t o r i n g for 2 to 3 hours with or without the use of subcutaneous terbutaline (0.25 mg) to abate the symptoms. Readmission to the hospital was defined as hospital admission for > 24 hours for intravenous tocolysis. Exclusion criteria were p r e t e r m p r e m a t u r e r u p t u r e of m e m b r a n e s o n the initial examination, p r e m a t u r e t e r m i n a t i o n for obstetric indications, or inability to reliably assess cervical change (e.g., placenta previa, persistent n o n c o m pliance, or p a t i e n t refusal). Data with n o r m a l distribution were analyzed by Stud e n t t test a n d one-way analysis of variance. Wilcoxon's two-sample test a n d Kruskal-Wallis test were used for data with skewed distribution. T h e ×'~ test was used for categoric data. All variables were tested for normality with the Wilks-Shapiro test; when the data were not normally distributed, we r e p o r t e d the m e d i a n value a n d expressed distribution by m e a n s of the interquartile range. A p value < 0.05 was r e g a r d e d as significant. Results In the 4-year period studied, 212 patients fulfilled the inclusion criteria a n d were enrolled into the study. Eighty-one patients had persistent u t e r i n e contractions that were unresponsive to intravenous hydration or subcutaneous terbutaline; 18 had progressive cervical dilatation a n d / o r effacement; a n d 85 had dilatation
1520
HOW Otal.
November 1995 Am J Obstet Gynecol
Table I I . Delivery statistics*
Prolongation of gestation (wk) Median Range of values Gestational age at delivery (wk) Median Range of values Delivered _>37 wk (%) Cesarean section (%)
Group 1 (n = 50)
Group 2 (n = 53)
Group 3 (n = 41)
Group 4 (n = 40)
3.5 (2.9) a 0.2-7.3
3.9 (3.7)" 0.4-11.4
6.4 (3.8) b 1-13.6
7.0 (5.2) b 1.6-16
36.1 (3.6) ~ 28.1-40.1 32 ~ 14~
35.8 (2.4)" 30.7-42 28" 17"
37.6 (2.6) a'b 26.6-41.3 61 b 19.5"
38.4 (2.8) b 30.4-41.1 75 h 12.5 ~
Values designated with different letters (a, b, or c) are statistically different from one another (according to Bonferroni's simultaneous t test, cL = 0.05). *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses.
Table I I L R e a d m i s s i o n s a n d h o s p i t a l visits
Readmissions (%) One time (No.) Two times (No.) Unscheduled hospital visits (%) One time (No.) Two times (No.)
Group 1 (n = 50)
Group 2 (n = 53)
Group 3 (n = 41)
Group 4 (n = 40)
14 (7) a 2 (1)a
7.5 (4)" 3.8 (2)"
12.2 (5)a 2.4 (1)~
12.5 (5)" 2.5 (1)"
10 (5) a 6 (3)a
13 (7)" 1 (1)"
19.5 (8)" 4 (2y
25 (10) ~ 2 (1)a
Values designated with different letters (a, b, or c) are statistically different from one another (according to Bonferroni's simultaneous t test, ct = 0.05).
T a b l e IV. N e o n a t a l o u t c o m e
Morbidity (No.) Hyaline membrane disease Transient tachypnea Necrotizing enterocolitis Intraventricular hemorrhage Others Length of nursery stay (days) Median* Range of values Birth weight gm, mean - SD Ventilatory support (days) Median* Range of values Oxygen required (days) Median* Range of values
Group 1 (n = 50)
Group 2 (n = 53)
1 0 1 2 1
(1.8%) (1.8%) (3.6%) (1.8%)
2 (3.5) ~ 2-66 2558 - 584"
I
[ ]
Group 3 (n = 41)
Group 4 (n = 40)
0 2 (3.4%) 0 1 (1.7%) 1 (1.7%)
0 0 0 0 1 (2.2%)
1 (2.3%) 2 (4.7%) 0 0 0
2 (3) ~ 2-38 2793 - 544"' b
2 (0)" 2-94 2759 -+- 692 a' s
2 (0)a 2-25 2865 - 675 b
0 (0)* 0-2
0 (0) * 0-2
0 (0)a 0-66
0 (0)" 0-7
0 (0) a 0-10
0 (0) a 0-3
0 (0)" 0-79
0 (0) a 0-7
Values designated with different letters (a, b, or c) are statistically different from one another (according to Bonferroni's simultaneous t test, et = 0.05). *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses.
> 2 c m a n d 50% e f f a c e m e n t o n t h e initial cervical e x a m i n a t i o n in t h e p r e s e n c e o f u t e r i n e c o n t r a c t i o n s . Fifty w e r e r a n d o m i z e d to g r o u p 1, 53 to g r o u p 2, 41 to g r o u p 3, a n d 4 0 to g r o u p 4. T h e r e w e r e 166 s i n g l e t o n g e s t a t i o n s a n d 18 m u l t i p l e gestations. O n e set o f triplets was in g r o u p 2, a n d o f t h e r e m a i n i n g 17 twin p r e g n a n c i e s , 6 were in g r o u p 1, 3 in g r o u p 2, 5 in g r o u p 3, a n d 3 in g r o u p 4. T w e n t y - e i g h t p a t i e n t s (13%)
were excluded because of noncompliance. Four of these were in g r o u p 1, 6 in g r o u p 2, 11 in g r o u p 3, a n d 7 in g r o u p 4. C o m p a r i s o n o f d e m o g r a p h i c a n d clinical c h a r acteristics ( T a b l e I) r e v e a l e d n o statistically significant d i f f e r e n c e in m a t e r n a l age, parity, race, d u r a t i o n o f i n t r a v e n o u s m a g n e s i u m sulfate, a n d h o s p i t a l stay a m o n g t h e f o u r g r o u p s . T h e g e s t a t i o n a l a g e at enrollm e n t was significantly y o u n g e r a n d t h e B i s h o p score
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before discharge was significantly lower for the groups with a Bishop score < 5 (3 and 4) when compared with the groups with a Bishop score ->5 (1 and 2). No significant differences were found in the mode of delivery (Table II), the n u m b e r of times patients were readmitted for intravenous tocolysis, or the n u m b e r of unscheduled hospital visits (Table III) among the four groups. The percent of patients who subsequently presented with preterm premature rupture of membranes was 16% in group 1, 5.7% in group 2, 2.4% in group 3, and 5% in group 4. The gestational age at delivery was significantly younger and the percent of deliveries at ->37 weeks (Table II) was significantly less in the patients with a Bishop score -> 5 (groups 1 and 2) than in those patients with a Bishop score < 5 (groups 3 and 4). However, there was no statistically significant difference when group 1 patients were compared with group 2 and group 3 patients were compared with group 4. There was no statistically significant difference in the n u m b e r of positive perineat gonorrhea, chlamydia, group B streptococci, and urine cultures among the four groups. The neonatal outcome variables (Table IV) revealed no difference with respect to neonatal morbidity. There was one neonatal death (at 26.6 weeks in a twin gestation) in group 3. The groups were similar in hospital stay, duration of oxygen use, and ventilator use. A comparison of patients randomized to the oral terbutaline arm (groups 1 and 3) and the no oral terbutaline arm (groups 2 and 4) revealed no statistically significant differences in relevant maternal clinical characteristics or in pregnancy and neonatal outcomes (Table V).
Comment Patients who have regular contractions with a Bishop score < 5 are frequently encountered by obstetricians and often sent home with an oral tocolytic agent. Our data suggest that oral terbutaline maintenance beyond 1 to 2 days did not improve pregnancy outcome in these patients when initial successful intravenous tocolysis was achieved. Forty-four percent (81/184) of our study patients had premature uterine contractions without cervical change that were refractory to intravenous hydration' and/or subcutaneous terbutaline. One could argue that these patients did not need any tocolysis and that the terbutaline would not be expected to work any better than a placebo if preterm labor was not present. However, these are the patients frequently encountered by clinicians. The practicing physican must be reassured that these patients truly do not need pharmacologic agents, which is why they were included in our study. Likewise, for the patients with a Bishop score -> 5, our data suggest no significant beneficial effect of oral terbutaline maintenance and confirm the findings of the previously published studies of Spellacy et al. ~° Larsen et al., 'j and Howard et al. ''~
HOW el al. 1521
Table V. Comparison of terbutaline groups (1 and 3) and no terbutaline groups (2 and 4) via Wilcoxon two-sample test*
Variable
Terbutaline (groups 1 and 3)
Maternal age (yr, 22.4 _+ 4.7 mean - SD) Parity Median 0.5 (1) Range of values 0-7 Bishop score before going home Median 5 (2) Range of values 2-10 Unscheduled hospital visits Median 0 (0) Range of values 0-8 Gestational age at enrollment (wk) Median 31.7 (3.7) Range of values 24.6-34.8 Duration of intravenous magnesium sulfate (hr) Median 14 (15) Range of values 0-96 Hospital stay (days) Median 2 ( 1) Range of values 1-11 No. of readmissions Median 0 (0) Range of values 0-2 Prolongation of gestation (wk) Median 5.0 (3.8) Range of values 0.2-13.6 Gestational age at delivery (wk) Median 36.4 (3.8) Range of values 26.6-41.3 Length of nursery stay (days) Median 2 (2) Range of values 2-94 Birth weight (gm, 2648 -+ 640 mean ± SD) Ventilatory support (days) Median 0 (0) Range of values 0-66 Oxygen requirement (days) Median 0 (0) Range of values 0-79
No terbutaline (groups 2 and 4)
21.6 + 5.1 1 (2) 0-6 5 (2) 2-9
0 (0) 0-4 31.7 (3.7) 23.8-35.4
14.5 (19) 0-168 2 (1) 1-16 0 (0) 0-2 5.0 (4.2) 0.4-16 36.8 (4.0) 30.4-42.0 2 (2) 2-38 2651 ± 628
0 (0) 0-7 0 (0) 0-7
p not significant. *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses. Creasy et al. ~ in a randomized double-blind study protocol (n = 70) also have demonstrated that once preterm labor was arrested with intravenous ritodrine, the use of either oral ritodrine or a placebo did not result in any significant difference in the mean gestational age at delivery and the n u m b e r of days gained in utero. However, they found an increased n u m b e r of
1522 HOW0t al.
November 1995 Am J Obstet Gynecol
Table VI. Power calculations based on results (ct = 0.05)
Variable
Power
Sample size for power = 0.80
Gestational age at enrollment (wk) Bishop score before going home Birth weight (gm) Gestational age at delivery (wk) No. of readmissions Length of nursery stay (days) Ventilatory support (days) Oxygen requirement (days)
0.995
-*
1.000
-*
0.830 0.790
- * 47 per group*
0.080 0.080
627 per groupf 635 per groupf
0.180
239 per groupf
0.210
201 per groupt
*Based on one-way analysis of variance for normally distributed data. tBased on Kruskal-Wallis test for skewed data.
recurrent preterm labor episodes in the placebo group (2.7 vs 1.1). Our study did not show any significant difference a m o n g the four groups with regard to the n u m b e r of readmissions for r e c u r r e n t preterm labor necessitating intravenous tocolysis or the n u m b e r of unscheduled hospital visits. This may have been, in part, because of a reduction in unnecessary hospital visits achieved by an education process. Our neonatal outcomes (Table IV) were excellent. There was only one neonatal death at 26.6 weeks (a twin gestation, group 3) and a > 90% intact survival rate in all four groups. These outcomes could reflect that the neonates were cared for in a level III nursery, that most patients were > 28 weeks' gestation when they entered the study, and that few patients were delivered at -< 32 weeks. The influence on outcome of universal betamethasone and antibiotic therapy p e n d i n g culture results is uncertain, but our study design largely eliminated them as a confounding variables. With our sample size there was at least a power of 80% for detecting a difference in the mean gestational age at delivery, the Bishop score before discharge, the gestational age at enrollment, and the infant's birth weight a m o n g the four groups. However, a much larger sample size would have been necessary to detect any difference in the n u m b e r of readmissions, the length of nursery stay, and the duration of oxygen and ventilatory support (Table VI). Although we did not measure the serum level of terbutaline, the dose of oral terbutaline was adjusted to
keep the pulse rate between 90 and 120 beats/min. Patients who persistently had a pulse rate < 80 beats/min despite a frequent dose adjustment were excluded because of possible noncompliance. In summary, our data suggest that oral terbutaline maintenance does not improve pregnancy outcome in patients whose preterm labor was successfully controlled by intravenous tocolysis. In addition, it produces side effects such as impairment of glucose tolerance in pregnancy j4 and subjective feelings of palpitations and tremors, which are often annoying to patients. The lack of demonstrable benefit of terbutaline may be specific to that agent. The possible efficacy of other agents (e.g., nifedipine and indocin) remains to be tested. REFERENCES
1. Creasy RK. Preterm labor and delivery. In: Creasy RK, Resnik R, eds. Maternal-fetal medicine. Principles and practice. 3rd ed. Philadelphia: WB Saunders, 1994:494520. 2. Nwaesei CG, Young DC, Byrne JM, et al. Preterm birth at 23 to 26 weeks' gestation: is active obstetric management justified? AMJ OBSTEXGVNECOL1987;157:890-7. 3. Whyte HE, Fitzhardinge PM, Shennan AT, Lennox K, Smith L, Lacy J. Extreme immaturity: outcome of 568 pregnancies of 23-26 weeks' gestation. Obstet Gynecol 1993;82:1-7. 4. Beall MH, Edgar BW, Paul RH, et al. A comparison of ritodrine, terbutaline, and magnesium sulfate for the suppression of preterm labor. AMJ OaSTETGYNECOL1985; 153: 854-9. 5. Hollander DI, Nagey DA, Pupkin MJ. Magnesium sulfate and ritodrine: a randomized comparison. AM J OBSTET GVNECOL1987; 156:631-7. 6. Brown SM, Tejani NA. Terbutaline sulfate in the prevention of premature labor. Obstet Gynecol 1981;57:22-5. 7. Caritis SN, Toig G, Heddiger LA, Ashmead G. A doubleblind study comparing ritodrine and terbutaline in the treatment of preterm labor. AM J OBSTETGVNECOL1984; 150:7-14. 8. Creasy RK, Golbus MS, Laros RK, Parer JT, Roberts JM. Oral ritodrine maintenance in the treatment of preterm labor. AMJ OBSTETGVNECOL1980;137:212-6. 9. MerkatzJR, PeterJB, Barden TP. Ritodrine hydrochloride: a betamimetic agent for use in preterm labor. Obstet Gynecol 1980;56:7-12. 10. Spellacy WN, Cruz AC, Birk SA, Buhi WC. Treatment of premature labor with ritodrine: a randomized controlled study. Obstet Gynecol 1979;54:220-3. 11. Larsen JF, Eldon K, Lange AP, et al. Ritodrine treatment of preterm labor: second Danish multicenter study. Obstet Gynecol 1986;67:607-13. 12. Howard TE, Killam AP, Penny LL, Daniell WC. A double blind random study of terbutaline in premature labor. Milit Med 1984;147:305-7. 13. Cordero L, Semchysshyn S. Administration of glucocorticoids to the pregnant patient. In: Zuspan FP, Christian CD, eds. Volume 3: Reid's controversy in obstetrics and gynecology. Philadelphia: WB Saunders, 1983:192-9. 14. Main DM, Main EK, Strong SE, Gabbe SG. The effect of oral ritodrine therapy on glucose tolerance in pregnancy. AMJ OBSTETGYNECOL1985;152:1031-3.
Key words: Oral terbutaline, preterm labor, premature uterine contractions Approximately 10% of neonates in the United States are delivered before 37 weeks' gestation. They account for 75% to 80% of the perinatal deaths not caused by congenital malformation? Ten percent to 30% of these preterm newborns will have a persistent mental, neurologic, or respiratory deficit. 2' 3 Because of the high morbidity and mortality associated with preterm birth, significant effort is directed toward both inhibiting and preventing it. Parenteral tocolytic agents such as [3-sympathomimetic agents and magnesium sulfate enjoy reasonable support in the recent literature as primary therapy, 4' 5 but the effectiveness of subsequent oral [3-sympathomimetic tocoylsis is uncertain. 6-~2 The objective of our study was to prove the hypothesis that once preterm uterine contractions and/or labor is controlled with intravenous tocolysis, oral terbutaline, as a maintenance drug, does not prolong the pregnancy. Material and m e t h o d s
Patients who were between 24 and 35 completed weeks of gestation and were seen in the University of From the Department of Obstetrics and Gynecology, University of Louisville School of Medicine. Received for publication June 27, 1994; revised August 17, 1994; accepted February 14, 1995. Reprint requests: Helen Y. How, MD, Department of Obstetrics and Gynecology, Marshall University School of Medicine, 1801 6th Ave., Huntington, WV 25703. Copyright © 1995 by Mosby-Yea~"Book, Inc. 0002-9378/95 $5.00 + 0 6/1/64291 1518
Louisville hospital between September 1989 and September 1993 were eligible for the study. Enrollment required one of the following three conditions: (1) persistent uterine contractions (->6 contractions per hour) that were unresponsive to intravenous hydration (500 ml to 1 L of 5% dextrose in half-normal saline solution) or subcutaneous terbutaline (0.25 mg every 15 minutes for three doses); (2) progressive cervical dilatation and/or effacement; or (3) dilatation -> 2 cm and 50% effacement on the initial cervical examination in the presence of uterine contractions. All patients initially received intravenous magnesium sulfate, a 6 gm loading dose followed by a maintenance dose of 2 to 5 gm/hr, to stop uterine contractions and/or labor. Gestational age was determined by best obstetric estimates. Ultrasonography was performed on admission to rule out anomalies, confirm dates, and obtain an estimated fetal weight. All patients were given two intramuscular doses of betamethasone (12 mg) at 12hour intervals '3 and intravenous ampicillin or clindamycin, if allergic to ampicillin, pending the results of group B streptococci vaginal cultures. After uterine quiescence was achieved for 12 to 24 hours, the patients were weaned from intravenous magnesium sulfate to oral terbutaline and observed for 24 to 48 hours. Before discharge and after informed consent was obtained, as approved by the Human Studies Committee at the University of Louisville, the patients were assigned to one of two arms of the study protocol on the basis of the degree of cervical change (Bishop
Volume 173, Number 5 Am J Obstet Gynecol
HOW et al.
1519
T a b l e I. D e m o g r a p h i c a n d clinical characteristics*
Maternal age (yr, mean + SD) Race (% nonwhite) Parity Median Range of values Bishop score before going home Median Range of values Gestational age at enrollment (wk) Median Range of values Duration of intravenous magnesium sulfate (hr) Median Range of values Hospital stay (days) Median Range of values Previous preterm delivery (%)
Group 1 (n = 50)
Group 2 (n = 53)
Group 3 (n = 41)
Group 4 (n = 40)
22 -4- 4.7" 62"
21.4 -+ 5.1 ~ 64"
23.7 -4- 4.7" 734
22.3 -+ 5.4" 72"
0 (1)" 0-7
1 (1)" 0-3
1 (1)a 0-4
1 (2)a 0-6
6 (2)b 5-10
6 (2)b 5-9
4 (1)" 2-4
4 (1)" 2-4
32.4 (2.8) b 27.8-34.8
32.3 (3.2) b 24-34.8
30.6 (2.6) a 24.6-34.1
30.7 (4.6)" 23.8-35
16 (14)" 0-96
13.5 (23) ~ 0-104
14 (18)" 0-54
15 (14) a 2-168
2 (1)" 1-7 16~
2 (2)a 1-16 11"
2 (1)a 1-11 10"
2 (1)" 1-9 5a
Group 1, Patients with a Bishop score ->5 with oral terbutaline; group 2, patients with a Bishop score ->5 without oral terbutaline; group 3, patients with a Bishop score < 5 with oral terbutaline; group 4, patients with a Bishop score < 5 without oral terbutaline. Values designated with different letters (a, b, or c) are statistically different from one another according to Bonferroni's simultaneous t test, c~ = 0.05). *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses. score). T h e y were t h e n prospectively r a n d o m i z e d by sealed envelope g e n e r a t e d from a table of r a n d o m n u m b e r s to c o n t i n u e d b e d rest either with or without oral terbutaline (5 to 10 m g every 4 to 6 hours). T h u s there were four groups of patients: group 1, those with a Bishop score >_5 with oral terbutaline; group 2, those with a Bishop score -> 5 without oral terbutaline; group 3, those with a Bishop score < 5 with oral terbutaline; a n d group 4, those with a Bishop score < 5 without oral terbutaline. Weekly pelvic e x a m i n a t i o n s were p e r f o r m e d by the first a u t h o r 80% of the time a n d by the obstetrics a n d gynecology residents assigned to the university clinic 20% of the time. T h e dose of oral terbutaline, 5 to 10 m g every 4 to 6 hours, was adjusted to keep the pulse rate above 90 beats/min a n d decreased if the p a t i e n t c o m p l a i n e d of intolerable side effects such as palpitation, chest pains, or tremors. Oral terbutaline was disc o n t i n u e d at 37 c o m p l e t e d weeks. Patients who had r e c u r r e n t p r e t e r m labor were restarted on parenteral therapy. If the t r e a t m e n t was successful, the p a t i e n t was placed in the group to which she was originally rand o m i z e d irrespective of the presence or absence of cervical change. Patients in all four groups were given similar instruction at entry a n d before discharge o n the signs a n d symptoms of p r e t e r m labor. T h e y were instructed to c o n t i n u e with strict bed rest at h o m e a n d to place a t e l e p h o n e call to the primary investigator or the labor a n d delivery u n i t if symptoms a n d / o r increased contractions ( > 6/hr) were n o t e d a n d persisted for 2 hours despite lateral b e d rest a n d oral hydration. A h o m e u t e r i n e m o n i t o r i n g device was n o t used by any of
the patients. These patients were contacted by telep h o n e if they failed to a p p e a r for the scheduled clinic visit. U n s c h e d u l e d hospital visits were defined as hospital visits for complaints of possible p r e m a t u r e u t e r i n e contractions that required external fetal m o n i t o r i n g for 2 to 3 hours with or without the use of subcutaneous terbutaline (0.25 mg) to abate the symptoms. Readmission to the hospital was defined as hospital admission for > 24 hours for intravenous tocolysis. Exclusion criteria were p r e t e r m p r e m a t u r e r u p t u r e of m e m b r a n e s o n the initial examination, p r e m a t u r e t e r m i n a t i o n for obstetric indications, or inability to reliably assess cervical change (e.g., placenta previa, persistent n o n c o m pliance, or p a t i e n t refusal). Data with n o r m a l distribution were analyzed by Stud e n t t test a n d one-way analysis of variance. Wilcoxon's two-sample test a n d Kruskal-Wallis test were used for data with skewed distribution. T h e ×'~ test was used for categoric data. All variables were tested for normality with the Wilks-Shapiro test; when the data were not normally distributed, we r e p o r t e d the m e d i a n value a n d expressed distribution by m e a n s of the interquartile range. A p value < 0.05 was r e g a r d e d as significant. Results In the 4-year period studied, 212 patients fulfilled the inclusion criteria a n d were enrolled into the study. Eighty-one patients had persistent u t e r i n e contractions that were unresponsive to intravenous hydration or subcutaneous terbutaline; 18 had progressive cervical dilatation a n d / o r effacement; a n d 85 had dilatation
1520
HOW Otal.
November 1995 Am J Obstet Gynecol
Table I I . Delivery statistics*
Prolongation of gestation (wk) Median Range of values Gestational age at delivery (wk) Median Range of values Delivered _>37 wk (%) Cesarean section (%)
Group 1 (n = 50)
Group 2 (n = 53)
Group 3 (n = 41)
Group 4 (n = 40)
3.5 (2.9) a 0.2-7.3
3.9 (3.7)" 0.4-11.4
6.4 (3.8) b 1-13.6
7.0 (5.2) b 1.6-16
36.1 (3.6) ~ 28.1-40.1 32 ~ 14~
35.8 (2.4)" 30.7-42 28" 17"
37.6 (2.6) a'b 26.6-41.3 61 b 19.5"
38.4 (2.8) b 30.4-41.1 75 h 12.5 ~
Values designated with different letters (a, b, or c) are statistically different from one another (according to Bonferroni's simultaneous t test, cL = 0.05). *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses.
Table I I L R e a d m i s s i o n s a n d h o s p i t a l visits
Readmissions (%) One time (No.) Two times (No.) Unscheduled hospital visits (%) One time (No.) Two times (No.)
Group 1 (n = 50)
Group 2 (n = 53)
Group 3 (n = 41)
Group 4 (n = 40)
14 (7) a 2 (1)a
7.5 (4)" 3.8 (2)"
12.2 (5)a 2.4 (1)~
12.5 (5)" 2.5 (1)"
10 (5) a 6 (3)a
13 (7)" 1 (1)"
19.5 (8)" 4 (2y
25 (10) ~ 2 (1)a
Values designated with different letters (a, b, or c) are statistically different from one another (according to Bonferroni's simultaneous t test, ct = 0.05).
T a b l e IV. N e o n a t a l o u t c o m e
Morbidity (No.) Hyaline membrane disease Transient tachypnea Necrotizing enterocolitis Intraventricular hemorrhage Others Length of nursery stay (days) Median* Range of values Birth weight gm, mean - SD Ventilatory support (days) Median* Range of values Oxygen required (days) Median* Range of values
Group 1 (n = 50)
Group 2 (n = 53)
1 0 1 2 1
(1.8%) (1.8%) (3.6%) (1.8%)
2 (3.5) ~ 2-66 2558 - 584"
I
[ ]
Group 3 (n = 41)
Group 4 (n = 40)
0 2 (3.4%) 0 1 (1.7%) 1 (1.7%)
0 0 0 0 1 (2.2%)
1 (2.3%) 2 (4.7%) 0 0 0
2 (3) ~ 2-38 2793 - 544"' b
2 (0)" 2-94 2759 -+- 692 a' s
2 (0)a 2-25 2865 - 675 b
0 (0)* 0-2
0 (0) * 0-2
0 (0)a 0-66
0 (0)" 0-7
0 (0) a 0-10
0 (0) a 0-3
0 (0)" 0-79
0 (0) a 0-7
Values designated with different letters (a, b, or c) are statistically different from one another (according to Bonferroni's simultaneous t test, et = 0.05). *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses.
> 2 c m a n d 50% e f f a c e m e n t o n t h e initial cervical e x a m i n a t i o n in t h e p r e s e n c e o f u t e r i n e c o n t r a c t i o n s . Fifty w e r e r a n d o m i z e d to g r o u p 1, 53 to g r o u p 2, 41 to g r o u p 3, a n d 4 0 to g r o u p 4. T h e r e w e r e 166 s i n g l e t o n g e s t a t i o n s a n d 18 m u l t i p l e gestations. O n e set o f triplets was in g r o u p 2, a n d o f t h e r e m a i n i n g 17 twin p r e g n a n c i e s , 6 were in g r o u p 1, 3 in g r o u p 2, 5 in g r o u p 3, a n d 3 in g r o u p 4. T w e n t y - e i g h t p a t i e n t s (13%)
were excluded because of noncompliance. Four of these were in g r o u p 1, 6 in g r o u p 2, 11 in g r o u p 3, a n d 7 in g r o u p 4. C o m p a r i s o n o f d e m o g r a p h i c a n d clinical c h a r acteristics ( T a b l e I) r e v e a l e d n o statistically significant d i f f e r e n c e in m a t e r n a l age, parity, race, d u r a t i o n o f i n t r a v e n o u s m a g n e s i u m sulfate, a n d h o s p i t a l stay a m o n g t h e f o u r g r o u p s . T h e g e s t a t i o n a l a g e at enrollm e n t was significantly y o u n g e r a n d t h e B i s h o p score
Volume 173, Number 5 Am J Obstet Gynecol
before discharge was significantly lower for the groups with a Bishop score < 5 (3 and 4) when compared with the groups with a Bishop score ->5 (1 and 2). No significant differences were found in the mode of delivery (Table II), the n u m b e r of times patients were readmitted for intravenous tocolysis, or the n u m b e r of unscheduled hospital visits (Table III) among the four groups. The percent of patients who subsequently presented with preterm premature rupture of membranes was 16% in group 1, 5.7% in group 2, 2.4% in group 3, and 5% in group 4. The gestational age at delivery was significantly younger and the percent of deliveries at ->37 weeks (Table II) was significantly less in the patients with a Bishop score -> 5 (groups 1 and 2) than in those patients with a Bishop score < 5 (groups 3 and 4). However, there was no statistically significant difference when group 1 patients were compared with group 2 and group 3 patients were compared with group 4. There was no statistically significant difference in the n u m b e r of positive perineat gonorrhea, chlamydia, group B streptococci, and urine cultures among the four groups. The neonatal outcome variables (Table IV) revealed no difference with respect to neonatal morbidity. There was one neonatal death (at 26.6 weeks in a twin gestation) in group 3. The groups were similar in hospital stay, duration of oxygen use, and ventilator use. A comparison of patients randomized to the oral terbutaline arm (groups 1 and 3) and the no oral terbutaline arm (groups 2 and 4) revealed no statistically significant differences in relevant maternal clinical characteristics or in pregnancy and neonatal outcomes (Table V).
Comment Patients who have regular contractions with a Bishop score < 5 are frequently encountered by obstetricians and often sent home with an oral tocolytic agent. Our data suggest that oral terbutaline maintenance beyond 1 to 2 days did not improve pregnancy outcome in these patients when initial successful intravenous tocolysis was achieved. Forty-four percent (81/184) of our study patients had premature uterine contractions without cervical change that were refractory to intravenous hydration' and/or subcutaneous terbutaline. One could argue that these patients did not need any tocolysis and that the terbutaline would not be expected to work any better than a placebo if preterm labor was not present. However, these are the patients frequently encountered by clinicians. The practicing physican must be reassured that these patients truly do not need pharmacologic agents, which is why they were included in our study. Likewise, for the patients with a Bishop score -> 5, our data suggest no significant beneficial effect of oral terbutaline maintenance and confirm the findings of the previously published studies of Spellacy et al. ~° Larsen et al., 'j and Howard et al. ''~
HOW el al. 1521
Table V. Comparison of terbutaline groups (1 and 3) and no terbutaline groups (2 and 4) via Wilcoxon two-sample test*
Variable
Terbutaline (groups 1 and 3)
Maternal age (yr, 22.4 _+ 4.7 mean - SD) Parity Median 0.5 (1) Range of values 0-7 Bishop score before going home Median 5 (2) Range of values 2-10 Unscheduled hospital visits Median 0 (0) Range of values 0-8 Gestational age at enrollment (wk) Median 31.7 (3.7) Range of values 24.6-34.8 Duration of intravenous magnesium sulfate (hr) Median 14 (15) Range of values 0-96 Hospital stay (days) Median 2 ( 1) Range of values 1-11 No. of readmissions Median 0 (0) Range of values 0-2 Prolongation of gestation (wk) Median 5.0 (3.8) Range of values 0.2-13.6 Gestational age at delivery (wk) Median 36.4 (3.8) Range of values 26.6-41.3 Length of nursery stay (days) Median 2 (2) Range of values 2-94 Birth weight (gm, 2648 -+ 640 mean ± SD) Ventilatory support (days) Median 0 (0) Range of values 0-66 Oxygen requirement (days) Median 0 (0) Range of values 0-79
No terbutaline (groups 2 and 4)
21.6 + 5.1 1 (2) 0-6 5 (2) 2-9
0 (0) 0-4 31.7 (3.7) 23.8-35.4
14.5 (19) 0-168 2 (1) 1-16 0 (0) 0-2 5.0 (4.2) 0.4-16 36.8 (4.0) 30.4-42.0 2 (2) 2-38 2651 ± 628
0 (0) 0-7 0 (0) 0-7
p not significant. *Interquartile range (difference between third quartile and first quartile; i.e., spread of middle 50%) is shown in parentheses. Creasy et al. ~ in a randomized double-blind study protocol (n = 70) also have demonstrated that once preterm labor was arrested with intravenous ritodrine, the use of either oral ritodrine or a placebo did not result in any significant difference in the mean gestational age at delivery and the n u m b e r of days gained in utero. However, they found an increased n u m b e r of
1522 HOW0t al.
November 1995 Am J Obstet Gynecol
Table VI. Power calculations based on results (ct = 0.05)
Variable
Power
Sample size for power = 0.80
Gestational age at enrollment (wk) Bishop score before going home Birth weight (gm) Gestational age at delivery (wk) No. of readmissions Length of nursery stay (days) Ventilatory support (days) Oxygen requirement (days)
0.995
-*
1.000
-*
0.830 0.790
- * 47 per group*
0.080 0.080
627 per groupf 635 per groupf
0.180
239 per groupf
0.210
201 per groupt
*Based on one-way analysis of variance for normally distributed data. tBased on Kruskal-Wallis test for skewed data.
recurrent preterm labor episodes in the placebo group (2.7 vs 1.1). Our study did not show any significant difference a m o n g the four groups with regard to the n u m b e r of readmissions for r e c u r r e n t preterm labor necessitating intravenous tocolysis or the n u m b e r of unscheduled hospital visits. This may have been, in part, because of a reduction in unnecessary hospital visits achieved by an education process. Our neonatal outcomes (Table IV) were excellent. There was only one neonatal death at 26.6 weeks (a twin gestation, group 3) and a > 90% intact survival rate in all four groups. These outcomes could reflect that the neonates were cared for in a level III nursery, that most patients were > 28 weeks' gestation when they entered the study, and that few patients were delivered at -< 32 weeks. The influence on outcome of universal betamethasone and antibiotic therapy p e n d i n g culture results is uncertain, but our study design largely eliminated them as a confounding variables. With our sample size there was at least a power of 80% for detecting a difference in the mean gestational age at delivery, the Bishop score before discharge, the gestational age at enrollment, and the infant's birth weight a m o n g the four groups. However, a much larger sample size would have been necessary to detect any difference in the n u m b e r of readmissions, the length of nursery stay, and the duration of oxygen and ventilatory support (Table VI). Although we did not measure the serum level of terbutaline, the dose of oral terbutaline was adjusted to
keep the pulse rate between 90 and 120 beats/min. Patients who persistently had a pulse rate < 80 beats/min despite a frequent dose adjustment were excluded because of possible noncompliance. In summary, our data suggest that oral terbutaline maintenance does not improve pregnancy outcome in patients whose preterm labor was successfully controlled by intravenous tocolysis. In addition, it produces side effects such as impairment of glucose tolerance in pregnancy j4 and subjective feelings of palpitations and tremors, which are often annoying to patients. The lack of demonstrable benefit of terbutaline may be specific to that agent. The possible efficacy of other agents (e.g., nifedipine and indocin) remains to be tested. REFERENCES
1. Creasy RK. Preterm labor and delivery. In: Creasy RK, Resnik R, eds. Maternal-fetal medicine. Principles and practice. 3rd ed. Philadelphia: WB Saunders, 1994:494520. 2. Nwaesei CG, Young DC, Byrne JM, et al. Preterm birth at 23 to 26 weeks' gestation: is active obstetric management justified? AMJ OBSTEXGVNECOL1987;157:890-7. 3. Whyte HE, Fitzhardinge PM, Shennan AT, Lennox K, Smith L, Lacy J. Extreme immaturity: outcome of 568 pregnancies of 23-26 weeks' gestation. Obstet Gynecol 1993;82:1-7. 4. Beall MH, Edgar BW, Paul RH, et al. A comparison of ritodrine, terbutaline, and magnesium sulfate for the suppression of preterm labor. AMJ OaSTETGYNECOL1985; 153: 854-9. 5. Hollander DI, Nagey DA, Pupkin MJ. Magnesium sulfate and ritodrine: a randomized comparison. AM J OBSTET GVNECOL1987; 156:631-7. 6. Brown SM, Tejani NA. Terbutaline sulfate in the prevention of premature labor. Obstet Gynecol 1981;57:22-5. 7. Caritis SN, Toig G, Heddiger LA, Ashmead G. A doubleblind study comparing ritodrine and terbutaline in the treatment of preterm labor. AM J OBSTETGVNECOL1984; 150:7-14. 8. Creasy RK, Golbus MS, Laros RK, Parer JT, Roberts JM. Oral ritodrine maintenance in the treatment of preterm labor. AMJ OBSTETGVNECOL1980;137:212-6. 9. MerkatzJR, PeterJB, Barden TP. Ritodrine hydrochloride: a betamimetic agent for use in preterm labor. Obstet Gynecol 1980;56:7-12. 10. Spellacy WN, Cruz AC, Birk SA, Buhi WC. Treatment of premature labor with ritodrine: a randomized controlled study. Obstet Gynecol 1979;54:220-3. 11. Larsen JF, Eldon K, Lange AP, et al. Ritodrine treatment of preterm labor: second Danish multicenter study. Obstet Gynecol 1986;67:607-13. 12. Howard TE, Killam AP, Penny LL, Daniell WC. A double blind random study of terbutaline in premature labor. Milit Med 1984;147:305-7. 13. Cordero L, Semchysshyn S. Administration of glucocorticoids to the pregnant patient. In: Zuspan FP, Christian CD, eds. Volume 3: Reid's controversy in obstetrics and gynecology. Philadelphia: WB Saunders, 1983:192-9. 14. Main DM, Main EK, Strong SE, Gabbe SG. The effect of oral ritodrine therapy on glucose tolerance in pregnancy. AMJ OBSTETGYNECOL1985;152:1031-3.