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Randomized comparison of intravenous nitroglycerin and subcutaneous terbutaline for external cephalic version under tocolysis
American Journal of Obstetrics and Gynecology (2004) 191, 2051e5
www.ajog.org
Randomized comparison of intravenous nitroglycerin and subcutaneous terbutaline for external cephalic version under tocolysis Yasser Y. El-Sayed, MD,* Kristin Pullen, MD, Edward T. Riley, MD, Deirdre Lyell, MD, Maurice L. Druzin, MD, Sheila E. Cohen, MD, Usha Chitkara, MD Departments of Obstetrics and Gynecology and Anesthesia, Stanford University, Stanford, Calif Received for publication January 12, 2004; revised April 15, 2004; accepted April 29, 2004
KEY WORDS Nitroglycerin Terbutaline Breech External cephalic version
Objective: The purpose of this study was to compare the efficacy and safety of intravenous nitroglycerin with that of subcutaneous terbutaline as a tocolytic agent for external cephalic version at term. Study design: We performed a prospective randomized trial. Patients between 37 and 42 weeks of gestation were assigned randomly to receive either 200 mg of intravenous nitroglycerin therapy or 0.25 mg of subcutaneous terbutaline therapy for tocolysis during external cephalic version. The rate of successful external cephalic version and side effects were compared between groups. Results: Of 59 randomly assigned patients, 30 patients received intravenous nitroglycerin, and 29 patients received subcutaneous terbutaline. The overall success rate of external cephalic version in the study was 39%. The rate of successful external cephalic version was significantly higher in the terbutaline group (55% vs 23%; P Z .01). The incidence of palpitations was significantly higher in patients who received terbutaline therapy (17.2% vs 0%; P Z .02), as was the mean maternal heart rate at multiple time periods. Conclusion: Compared with intravenous nitroglycerin, subcutaneous terbutaline was associated with a significantly higher rate of successful external cephalic version at term. Ó 2004 Elsevier Inc. All rights reserved.
Breech presentation occurs in 3% to 4% of term pregnancies. Recent evidence suggests that a policy of planned cesarean delivery may be safer for the singleton fetus in breech presentation at term as compared with a policy of planned vaginal birth.1 In an effort to reduce * Reprint requests: Yasser Y. El-Sayed, MD, Department of Obstetrics and Gynecology, Stanford University, Room HH333, 300 Pasteur Dr, Stanford, CA 94305. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.04.040
potential maternal complications of cesarean delivery, a trial of external cephalic version (ECV) is a reasonable option to offer a term patient with a breech fetal presentation.2 The reported success rates with ECV are quite broad, ranging from 24% to 86%.2,3 The most commonly used tocolytics for ECV have been the b-mimetics. Several randomized controlled trials have demonstrated enhanced ECV success rates with this category of tocolytics.4-7 More recently, investigators have studied nitroglycerin for use in ECV.
2052 Yanny et al8 performed a randomized controlled study that compared nitroglycerin spray to placebo for ECV. They found no differences in ECV success rates between groups. Bujold et al9 demonstrated a trend toward a lower success rate and higher rates of some side effects with sublingual nitroglycerin as compared with intravenous ritodrine for ECV. In another randomized trial, Bujold et al10 compared sublingual nitroglycerin to placebo for ECV in parous women and showed a higher incidence of headaches in the nitroglycerin group and a trend toward more ECV failures. We performed a prospective randomized study that compared the efficacy and safety of subcutaneous terbutaline therapy to intravenous nitroglycerin therapy for ECV.
Material and methods This randomized trial was conducted on labor and delivery at Stanford University Medical Center, after approval by the hospital Institutional Review Board. Eligible patients for this study included women between 37 and 42 weeks of gestation with a fetus in breech presentation. Maternal exclusion criteria included chronic hypertension, preeclampsia, placental abruption, placenta previa, maternal cardiac disease, chorioamnionitis, or previous uterine surgery. Fetal exclusion criteria included ruptured membranes, intrauterine growth restriction (estimated fetal weight, !10th percentile for gestational age by ultrasonography), decreased amniotic fluid or oligohydramnios (amniotic fluid index, !8 cm), fetal anomalies incompatible with life, or an extended fetal head. Before randomization, each potential study patient had a nonstress test and an ultrasound scan for position and amniotic fluid index measurement. In addition, a recent ultrasound examination (within the last 2 weeks) for estimated fetal weight and anatomy was required. After giving informed consent, 60 women were assigned randomly to intravenous nitroglycerin therapy or subcutaneous terbutaline therapy. Randomization was performed by a third party who was not involved in the conduct or analysis of the trial, who prepared 30 labels bearing the word nitroglycerin and 30 labels bearing the word terbutaline. The labels were placed in 60 unmarked, opaque envelopes that were sealed, shuffled thoroughly, and numbered sequentially. Terbutaline was administered as a 0.25 mg subcutaneous injection, and the ECV started approximately 5 minutes after drug administration. Because of its short serum half-life (approximately 3 minutes), 100 mg of nitroglycerin was administered intravenously immediately before and again just after beginning the ECV procedure, for a total of 200 mg of nitroglycerin. ECV was performed in the labor and delivery suite. Both a forward and backward roll was attempted before
El-Sayed et al the procedure was called unsuccessful. Attending obstetricians, maternal-fetal medicine fellows, and attending maternal-fetal medicine specialists performed the ECV procedures. Maternal blood pressures and heart rates were recorded before each ECV procedure, every minute after either nitroglycerin or terbutaline administration for 5 minutes, then every 5 minutes for 30 minutes. The fetal heart rate was monitored intermittently by ultrasound scanning during the procedure, followed by electronic fetal heart rate monitoring for at least 1 hour after the procedure. After successful ECV, the decision regarding immediate induction versus discharge to await labor was left to the discretion of the patient’s physician. Similarly, after a failed ECV procedure, further treatment that included a second ECV procedure with the alternate drug, discharge with scheduled cesarean delivery, or immediate cesarean delivery was left to the discretion of the patient’s physician. The primary outcome was the success or failure of the first ECV procedure with the use of either terbutaline or nitroglycerin. Assuming a 30% success rate with terbutaline therapy, we calculated that a total of at least 56 patients would be required to detect a 50% reduction in failed ECV with nitroglycerin therapy, with an a value of .05 and a power of 80%. Statistical analysis of the data was performed using Student t tests and c2 and Fisher exact tests where appropriate.
Results One patient was randomly assigned improperly to receive terbutaline therapy before the ultrasound that confirmed a breech presentation was performed. The fetus was in vertex presentation; therefore, the patient was removed from the study, which left 59 subjects. Thirty patients were assigned randomly to the nitroglycerin group, and 29 patients were assigned randomly to the terbutaline group. There were no statistically significant differences in pretreatment maternal or fetal characteristics (Table I). Successful initial ECV was achieved in 16 of 29 patients who received terbutaline therapy, compared with 7 of 30 patients who received nitroglycerin therapy (55% vs 23%; P Z .01; Table II). After successful initial ECV, 86% of patients who were assigned to nitroglycerin therapy had a vaginal delivery, compared with 69% of patients who were assigned to terbutaline therapy (P Z .6). The vaginal delivery rate for the entire group of patients was 36%. Two patients who were assigned randomly to nitroglycerin therapy had successful planned vaginal breech deliveries after unsuccessful ECV. Eight patients who were assigned randomly to
El-Sayed et al Table I
2053
Maternal and fetal characteristics
Characteristic
Nitroglycerin (n = 30)
Terbutaline (n = 29)
P value
Maternal age (y)* Gestational age at ECV (wk)* Multiparity (n) Estimated fetal weight (g)* Body mass index (kg/m2)*y Anterior placenta (n)y ECV by maternal-fetal medicine attending (n)
31.1 G 5.6 38.4 G 0.7 13 (43%) 3266 G 336 28.6 G 4 13 (46%) 21 (70%)
31.7 G 4.8 38.4 G 0.8 11 (38%) 3227 G 398 30.2 G 7 14 (40%) 24 (83%)
.66 .93 .67 .69 .3 .79 .36
* Data are represented as mean G SD. y Data were available on 56 of 59 cases.
Table II
Outcomes of pregnancies after attempted ECV
Outcome
Nitroglycerin (n = 30)
Terbutaline (n = 29)
P value
Successful ECV (n) Expectant treatment after ECV (n) Cesarean delivery (n) Indication for cesarean delivery Failed ECV Reversion Hand presentation Labor arrest Birth weight (g)*
7 (23%) 9 (30%) 20 (67%)
16 (55%) 16 (55%) 18 (62%)
.01 .05 .71
19 (95%) 1 (4.8%) 0 0 3325 G 349
13 (72%) 3 (17%) 1 (5.6%) 1 (5.6) 3501 G 386
.08 .32 .46 .46 .07
* Data are represented as mean G SD.
Table III
Characteristics of successful and failed ECV
Characteristic 2
Body mass index (kg/m )*y Anterior placenta (n)* ECV by maternal-fetal medicine attending (n) Multiparity (n)
Successful ECV (n = 23)
Failed ECV (n = 36)
P value
29 11 17 15
34 16 28 9
.65 .83 .73 .002
G4 (50%) (74%) (65%)
G6 (47%) (78%) (25%)
* Data were available on 56 of 59 cases. y Data are represented as mean G SD.
terbutaline therapy and 12 patients who were assigned randomly to nitroglycerin therapy underwent another ECV trial with the alternate drug after an initial failed attempt. Of these 20 women, only 2 women subsequently had a successful version, both with terbutaline therapy. Both patients had vaginal deliveries. One patient who was assigned to nitroglycerin therapy required an emergency cesarean delivery for placental abruption after unsuccessful nitroglycerin and terbutaline ECV procedures. Forty-one percent of our patients were nulliparous. There was no difference in the percentage of multiparous women between groups (Table I). ECV success was associated significantly with multiparity (65% vs 25%; P Z .002; Table III). Attending maternal-fetal medicine specialists performed 76% of the ECV procedures. ECV success was
not associated with whether the procedure was performed by an attending maternal-fetal medicine specialist or the presence of an anterior placenta or maternal BMI (Tables II and III). Table IV provides a comparison of the maternal cardiovascular changes, side effects, and fetal heart rate changes that were encountered with nitroglycerin and terbutaline therapy. There were significantly faster maternal heart rates among patients who received terbutaline therapy. In addition, maternal palpitations were significantly more frequent in the terbutaline group (17% vs 0%; P Z .02).
Comment Nitroglycerin, which is a nitric oxide donor and potent smooth muscle relaxant, acts on smooth muscle by
2054 Table IV
El-Sayed et al Vital signs and side effects during and after ECV
Effect Mean blood pressure (mm Hg)*y Baseline 2 min 5 min 10 min 15 min 20 min 25 min 30 min Mean heart rate (beats/min)*y Baseline 2 min 5 min 10 min* 15 min* 20 min* 25 min* 30 min* Flushing (n) Lightheadedness (n) Palpitations (n) Headache (n) Fetal heart rate decelerations (n)
Nitroglycerin (n = 30)
Terbutaline (n = 29)
88 86 81 79 80 79 78 78
87 86 83 84 84 84 81 82
G 10 G13 G 12 G9 G 10 G 11 G8 G 10
82 G 12 91 G 13 81 G 13 78 G 14 77 G 9 76 G 8 77 G 9 77 G 13 3 (10%) 2 (6.7%) 0 (0%) 2 (6.7) 8 (27%)
G G G G G G G G
11 12 13 13 16 13 12 12
81 G 12 87 G 17 90 G 16 91 G 15 94 G 16 95 G 18 93 G 18 89 G 13 6 (21%) 1 (3.4%) 5 (17%) 0 3 (10%)
P value .61 .89 .42 .09 .34 .14 .31 .32 .96 .36 .04 .003 ! .0001 ! .0001 .0002 .0011 .30 .99 .02 .49 .18
* For maternal vital signs, significance is at the probability value of !.006 (Bonferroni correction applied). y Data are represented as mean G SD.
elevating cyclic guanosine monophosphate.11 It has been used increasingly in obstetrics for preterm labor, ECV, internal podalic version, retained placenta, uterine inversion, and fetal extraction at cesarean delivery. Nitroglycerin’s ability to relax the uterus effectively in these and other clinical settings, however, remains a matter of debate.12-15 In our study, intravenous nitroglycerin was less effective than subcutaneous terbutaline as a tocolytic for ECV at term (23% vs 55%; P Z .01). Our findings are consistent with other studies of nitroglycerin for ECV. In the only published study that compared nitroglycerin (sublingual) to a b-mimetic (ritodrine), Bujold et al9 found a trend toward more successful ECV in nulliparous women with ritodrine therapy (45% vs 25%; P Z .075). In a subsequent study in parous women, Bujold et al noted a statistically nonsignificant trend toward more ECV failures with nitroglycerin therapy as compared with placebo (48% vs 63%; P Z .13). This study was stopped prematurely, after an interim analysis demonstrated a significantly higher rate of side effects (headache and hypotension) with nitroglycerin and the trend toward more ECV failures.10 In another study, Yanny et al8 found no significant difference in ECV success with sublingual nitroglycerin therapy compared with placebo in 57 women after the initial attempt at ECV without tocolysis had failed. Forty-one percent of our patients were multiparous, and ECV success was significantly associated with
multiparity (65% vs 25%; P Z .002). ECV success was not associated with maternal-fetal medicine specialty training, the presence of an anterior placenta, or maternal body mass index. Before randomization, all patients underwent a nonstress test and an amniotic fluid index. Aside from documenting the absence of oligohydramnios (amniotic fluid index, !8 cm), we did not record specific numeric values routinely for the amniotic fluid index. The performance of a cervical examination was left to the discretion of the attending physician. Maternal side effects of terbutaline and nitroglycerin have been described in various studies.9,10,12,13,16,17 Side effects of terbutaline include maternal tachycardia, cardiac arrhythmia, myocardial ischemia, hyperglycemia, and death. Nitroglycerin has been associated with headache and hypotension. In our study, the use of terbutaline was associated with significantly higher rates of palpitations than nitroglycerin (17% vs 0%; P Z .02) and a significantly more rapid maternal heart rate. No significant differences in the incidence of headache or in mean arterial pressures were noted between agents. Bujold et al9 did show a more rapid maternal heart rate with intravenous ritodrine compared with sublingual nitroglycerin during ECV. In contrast to our study, the incidence of headaches was significantly higher with nitroglycerin, and the incidence of palpitations was not different between groups. In that study, a lower mean
El-Sayed et al blood pressure at 10 minutes after sublingual nitroglycerin possibly is confounded by significantly different mean blood pressures between groups at admission.9 Transient changes in fetal heart rate patterns are common, regardless of tocolysis during an attempt at ECV. Several studies and case series on ECV have reported up to an 18% incidence of fetal heart rate decelerations.6,9,18-21 We did not find a significant difference in the incidence of fetal heart rate decelerations between nitroglycerin and terbutaline therapies (27% vs 10%; P Z .18). However, we cannot rule out a type II error. One patient required an emergency cesarean delivery for placental abruption after an unsuccessful initial ECV attempt with nitroglycerin and an unsuccessful second ECV attempt with terbutaline. Our overall cesarean delivery rate was 64%. After a successful ECV, the cesarean delivery rate was 14% for the nitroglycerin group and 31% for the terbutaline group (P Z .6), which is consistent with the reported 0 to 31% incidence of cesarean delivery after a successful ECV.22-24 In our study, subcutaneous terbutaline was more effective than intravenous nitroglycerin for ECV at term. However, ECV success rates, even with b-mimetic tocolysis, can still be as low as 26.5%.25 Further studies are needed to investigate the most effective dose, method of administration, and tocolytic agent for ECV, as well as the optimal candidates.
Acknowledgments Abbott Laboratories provided some of the nitroglycerin for this study.
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References 1. Hannah ME, Hannah WJ, Hewson SA, Hodnett ED, Saigal S, Willan A. Planned caesarean section versus planned vaginal birth for breech presentation at term: a randomised multicentre trial Lancet 2000;356:1375-83. 2. The American College of Obstetricians and Gynecologists . External cephalic version Washington (DC): The College; 2000. Technical bulletin No.: 13. 3. Hofmeyer GJ. Interventions to help external cephalic version for breech presentation at term Cochrane Database Syst Rev 2004;1. 4. Marquette GP, Boucher M, Theriault D, Rinfret D. Does the use of a tocolytic agent affect the success rate of external cephalic version? Am J Obstet Gynecol 1996;175:859-61. 5. Chung T, Neale E, Lau TK, Rogers M. A randomized, double blind, controlled trial of tocolysis to assist external cephalic version in late pregnancy Acta Obstet Gynecol Scand 1996;75:720-4. 6. Stock A, Chung T, Rogers M, Ming WW. Randomized control, double blind, placebo controlled comparison of ridodrine and
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hexoprenaline for tocolysis prior to external cephalic version at term Aust N Z J Obstet Gynaecol 1993;33:265-8. Fernandez CO, Bloom SL, Smulian JC, Annath CV, Wendel GD Jr. A randomized placebo-controlled evaluation of terbutaline for external cephalic version Obstet Gynecol 1997;90:775-9. Yanny H, Johanson R, Baldwin KJ, Lucking L, Fitzpatrick R, Jones P. Double-blind randomised controlled trial of glyceryl trinitrate spray for external cephalic version. BJOG 2000;107:562-4. Bujold E, Marquette G, Ferreira E, Gauthier R, Boucher M. Sublingual nitroglycerin versus intravenous ridodrine as tocolytic for external cephalic version: a double-blinded randomized trial Am J Obstet Gynecol 2003;188:1454-9. Bujold E, Boucher M, Rinfret D, Berman S, Ferreira E, Marquette GP. Sublingual nitroglycerin versus placebo as a tocolytic for external cephalic version: a randomized controlled trial in parous women Am J Obstet Gynecol 2003;189:1070-3. Chuprin JR, Rappoport RM. Nitroglycerin-induced desensitization of vascular smooth muscle may be mediated through cyclic GMP-disinhibition of phosphatidylinositol hydrolysis Experientia 1986;43:316-8. Duckitt K, Thornton S. Nitric oxide donors for the treatment of preterm labour Cochrane Database Syst Rev 2002;3:CD002860. Morgan PJ, Kung R, Tarshis J. Nitroglycerin as a uterine relaxant: a systematic review J Obstet Gynaecol Can 2002;24:403-9. Vinatier D, Dufour P, Berard J. Utilization of intravenous nitroglycerin for obstetrical emergencies Int J Gynecol Obstet 1996;55:129-34. Riley ET, Flanagan B, Cohen SE, Chitkara U. Intravenous nitroglycerin: a potent uterine relaxant for emergency obstetric procedures: review of the literature and report of three cases Int J Obstet Anesth 1996;5:264-8. Benedetti TJ. Maternal complications of parenteral betasympathomimetic therapy for premature labor Am J Obstet Gynecol 1983;1451:1-6. Katz M, Robertson PA, Creasy RK. Cardiovascular complications associated with terbutaline treatment for preterm labor Am J Obstet Gynecol 1981;139:605-8. Robertson AW, Kopelman JN, Read JA, Duff P, Magelssen DJ, Dashow EE. External cephalic version at term: is a tocolytic necessary? Obstet Gynecol 1987;70:896-9. Redick LF, Livingston E, Bell E. Sublingual aerosol nitroglycerin for uterine relaxation in attempted external version Am J Obstet Gynecol 1997;176:496-7. Dyson DC, Ferguson JE, Hensleigh P. Antepartum external cephalic version under tocolysis Obstet Gynecol 1986;67:63-8. Morrison JC, Myatt RE, Martin JN, Meeks GR, Martin RW, Bucovaz ET, et al. External cephalic version of the breech presentation under tocolysis Am J Obstet Gynecol 1986;154:900-3. Lau TK, Lo KWK, Rogers M. Pregnancy outcomes after successful external cephalic version for breech presentation at term Am J Obstet Gynecol 1997;176:218-23. Brocks V, Philipsen T, Secher NJ. A randomized trial of external version with tocolysis in late pregnancy BJOG 1984;91:653-6. Laros RK Jr., Flannagan TA, Kilpatrick SJ. Management of term breech presentation: a protocol of external cephalic version and selective trial of labor Am J Obstet Gynecol 1995;172: 1916-23. Thunedborg P, Fischer-Rasmussen W, Tollund L. The benefit of external cephalic version with tocolysis as a routine procedure in late pregnancy Eur J Obstet Gynecol Reprod Biol 1991;42:23-7.
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Randomized comparison of intravenous nitroglycerin and subcutaneous terbutaline for external cephalic version under tocolysis Yasser Y. El-Sayed, MD,* Kristin Pullen, MD, Edward T. Riley, MD, Deirdre Lyell, MD, Maurice L. Druzin, MD, Sheila E. Cohen, MD, Usha Chitkara, MD Departments of Obstetrics and Gynecology and Anesthesia, Stanford University, Stanford, Calif Received for publication January 12, 2004; revised April 15, 2004; accepted April 29, 2004
KEY WORDS Nitroglycerin Terbutaline Breech External cephalic version
Objective: The purpose of this study was to compare the efficacy and safety of intravenous nitroglycerin with that of subcutaneous terbutaline as a tocolytic agent for external cephalic version at term. Study design: We performed a prospective randomized trial. Patients between 37 and 42 weeks of gestation were assigned randomly to receive either 200 mg of intravenous nitroglycerin therapy or 0.25 mg of subcutaneous terbutaline therapy for tocolysis during external cephalic version. The rate of successful external cephalic version and side effects were compared between groups. Results: Of 59 randomly assigned patients, 30 patients received intravenous nitroglycerin, and 29 patients received subcutaneous terbutaline. The overall success rate of external cephalic version in the study was 39%. The rate of successful external cephalic version was significantly higher in the terbutaline group (55% vs 23%; P Z .01). The incidence of palpitations was significantly higher in patients who received terbutaline therapy (17.2% vs 0%; P Z .02), as was the mean maternal heart rate at multiple time periods. Conclusion: Compared with intravenous nitroglycerin, subcutaneous terbutaline was associated with a significantly higher rate of successful external cephalic version at term. Ó 2004 Elsevier Inc. All rights reserved.
Breech presentation occurs in 3% to 4% of term pregnancies. Recent evidence suggests that a policy of planned cesarean delivery may be safer for the singleton fetus in breech presentation at term as compared with a policy of planned vaginal birth.1 In an effort to reduce * Reprint requests: Yasser Y. El-Sayed, MD, Department of Obstetrics and Gynecology, Stanford University, Room HH333, 300 Pasteur Dr, Stanford, CA 94305. E-mail: [email protected] 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.04.040
potential maternal complications of cesarean delivery, a trial of external cephalic version (ECV) is a reasonable option to offer a term patient with a breech fetal presentation.2 The reported success rates with ECV are quite broad, ranging from 24% to 86%.2,3 The most commonly used tocolytics for ECV have been the b-mimetics. Several randomized controlled trials have demonstrated enhanced ECV success rates with this category of tocolytics.4-7 More recently, investigators have studied nitroglycerin for use in ECV.
2052 Yanny et al8 performed a randomized controlled study that compared nitroglycerin spray to placebo for ECV. They found no differences in ECV success rates between groups. Bujold et al9 demonstrated a trend toward a lower success rate and higher rates of some side effects with sublingual nitroglycerin as compared with intravenous ritodrine for ECV. In another randomized trial, Bujold et al10 compared sublingual nitroglycerin to placebo for ECV in parous women and showed a higher incidence of headaches in the nitroglycerin group and a trend toward more ECV failures. We performed a prospective randomized study that compared the efficacy and safety of subcutaneous terbutaline therapy to intravenous nitroglycerin therapy for ECV.
Material and methods This randomized trial was conducted on labor and delivery at Stanford University Medical Center, after approval by the hospital Institutional Review Board. Eligible patients for this study included women between 37 and 42 weeks of gestation with a fetus in breech presentation. Maternal exclusion criteria included chronic hypertension, preeclampsia, placental abruption, placenta previa, maternal cardiac disease, chorioamnionitis, or previous uterine surgery. Fetal exclusion criteria included ruptured membranes, intrauterine growth restriction (estimated fetal weight, !10th percentile for gestational age by ultrasonography), decreased amniotic fluid or oligohydramnios (amniotic fluid index, !8 cm), fetal anomalies incompatible with life, or an extended fetal head. Before randomization, each potential study patient had a nonstress test and an ultrasound scan for position and amniotic fluid index measurement. In addition, a recent ultrasound examination (within the last 2 weeks) for estimated fetal weight and anatomy was required. After giving informed consent, 60 women were assigned randomly to intravenous nitroglycerin therapy or subcutaneous terbutaline therapy. Randomization was performed by a third party who was not involved in the conduct or analysis of the trial, who prepared 30 labels bearing the word nitroglycerin and 30 labels bearing the word terbutaline. The labels were placed in 60 unmarked, opaque envelopes that were sealed, shuffled thoroughly, and numbered sequentially. Terbutaline was administered as a 0.25 mg subcutaneous injection, and the ECV started approximately 5 minutes after drug administration. Because of its short serum half-life (approximately 3 minutes), 100 mg of nitroglycerin was administered intravenously immediately before and again just after beginning the ECV procedure, for a total of 200 mg of nitroglycerin. ECV was performed in the labor and delivery suite. Both a forward and backward roll was attempted before
El-Sayed et al the procedure was called unsuccessful. Attending obstetricians, maternal-fetal medicine fellows, and attending maternal-fetal medicine specialists performed the ECV procedures. Maternal blood pressures and heart rates were recorded before each ECV procedure, every minute after either nitroglycerin or terbutaline administration for 5 minutes, then every 5 minutes for 30 minutes. The fetal heart rate was monitored intermittently by ultrasound scanning during the procedure, followed by electronic fetal heart rate monitoring for at least 1 hour after the procedure. After successful ECV, the decision regarding immediate induction versus discharge to await labor was left to the discretion of the patient’s physician. Similarly, after a failed ECV procedure, further treatment that included a second ECV procedure with the alternate drug, discharge with scheduled cesarean delivery, or immediate cesarean delivery was left to the discretion of the patient’s physician. The primary outcome was the success or failure of the first ECV procedure with the use of either terbutaline or nitroglycerin. Assuming a 30% success rate with terbutaline therapy, we calculated that a total of at least 56 patients would be required to detect a 50% reduction in failed ECV with nitroglycerin therapy, with an a value of .05 and a power of 80%. Statistical analysis of the data was performed using Student t tests and c2 and Fisher exact tests where appropriate.
Results One patient was randomly assigned improperly to receive terbutaline therapy before the ultrasound that confirmed a breech presentation was performed. The fetus was in vertex presentation; therefore, the patient was removed from the study, which left 59 subjects. Thirty patients were assigned randomly to the nitroglycerin group, and 29 patients were assigned randomly to the terbutaline group. There were no statistically significant differences in pretreatment maternal or fetal characteristics (Table I). Successful initial ECV was achieved in 16 of 29 patients who received terbutaline therapy, compared with 7 of 30 patients who received nitroglycerin therapy (55% vs 23%; P Z .01; Table II). After successful initial ECV, 86% of patients who were assigned to nitroglycerin therapy had a vaginal delivery, compared with 69% of patients who were assigned to terbutaline therapy (P Z .6). The vaginal delivery rate for the entire group of patients was 36%. Two patients who were assigned randomly to nitroglycerin therapy had successful planned vaginal breech deliveries after unsuccessful ECV. Eight patients who were assigned randomly to
El-Sayed et al Table I
2053
Maternal and fetal characteristics
Characteristic
Nitroglycerin (n = 30)
Terbutaline (n = 29)
P value
Maternal age (y)* Gestational age at ECV (wk)* Multiparity (n) Estimated fetal weight (g)* Body mass index (kg/m2)*y Anterior placenta (n)y ECV by maternal-fetal medicine attending (n)
31.1 G 5.6 38.4 G 0.7 13 (43%) 3266 G 336 28.6 G 4 13 (46%) 21 (70%)
31.7 G 4.8 38.4 G 0.8 11 (38%) 3227 G 398 30.2 G 7 14 (40%) 24 (83%)
.66 .93 .67 .69 .3 .79 .36
* Data are represented as mean G SD. y Data were available on 56 of 59 cases.
Table II
Outcomes of pregnancies after attempted ECV
Outcome
Nitroglycerin (n = 30)
Terbutaline (n = 29)
P value
Successful ECV (n) Expectant treatment after ECV (n) Cesarean delivery (n) Indication for cesarean delivery Failed ECV Reversion Hand presentation Labor arrest Birth weight (g)*
7 (23%) 9 (30%) 20 (67%)
16 (55%) 16 (55%) 18 (62%)
.01 .05 .71
19 (95%) 1 (4.8%) 0 0 3325 G 349
13 (72%) 3 (17%) 1 (5.6%) 1 (5.6) 3501 G 386
.08 .32 .46 .46 .07
* Data are represented as mean G SD.
Table III
Characteristics of successful and failed ECV
Characteristic 2
Body mass index (kg/m )*y Anterior placenta (n)* ECV by maternal-fetal medicine attending (n) Multiparity (n)
Successful ECV (n = 23)
Failed ECV (n = 36)
P value
29 11 17 15
34 16 28 9
.65 .83 .73 .002
G4 (50%) (74%) (65%)
G6 (47%) (78%) (25%)
* Data were available on 56 of 59 cases. y Data are represented as mean G SD.
terbutaline therapy and 12 patients who were assigned randomly to nitroglycerin therapy underwent another ECV trial with the alternate drug after an initial failed attempt. Of these 20 women, only 2 women subsequently had a successful version, both with terbutaline therapy. Both patients had vaginal deliveries. One patient who was assigned to nitroglycerin therapy required an emergency cesarean delivery for placental abruption after unsuccessful nitroglycerin and terbutaline ECV procedures. Forty-one percent of our patients were nulliparous. There was no difference in the percentage of multiparous women between groups (Table I). ECV success was associated significantly with multiparity (65% vs 25%; P Z .002; Table III). Attending maternal-fetal medicine specialists performed 76% of the ECV procedures. ECV success was
not associated with whether the procedure was performed by an attending maternal-fetal medicine specialist or the presence of an anterior placenta or maternal BMI (Tables II and III). Table IV provides a comparison of the maternal cardiovascular changes, side effects, and fetal heart rate changes that were encountered with nitroglycerin and terbutaline therapy. There were significantly faster maternal heart rates among patients who received terbutaline therapy. In addition, maternal palpitations were significantly more frequent in the terbutaline group (17% vs 0%; P Z .02).
Comment Nitroglycerin, which is a nitric oxide donor and potent smooth muscle relaxant, acts on smooth muscle by
2054 Table IV
El-Sayed et al Vital signs and side effects during and after ECV
Effect Mean blood pressure (mm Hg)*y Baseline 2 min 5 min 10 min 15 min 20 min 25 min 30 min Mean heart rate (beats/min)*y Baseline 2 min 5 min 10 min* 15 min* 20 min* 25 min* 30 min* Flushing (n) Lightheadedness (n) Palpitations (n) Headache (n) Fetal heart rate decelerations (n)
Nitroglycerin (n = 30)
Terbutaline (n = 29)
88 86 81 79 80 79 78 78
87 86 83 84 84 84 81 82
G 10 G13 G 12 G9 G 10 G 11 G8 G 10
82 G 12 91 G 13 81 G 13 78 G 14 77 G 9 76 G 8 77 G 9 77 G 13 3 (10%) 2 (6.7%) 0 (0%) 2 (6.7) 8 (27%)
G G G G G G G G
11 12 13 13 16 13 12 12
81 G 12 87 G 17 90 G 16 91 G 15 94 G 16 95 G 18 93 G 18 89 G 13 6 (21%) 1 (3.4%) 5 (17%) 0 3 (10%)
P value .61 .89 .42 .09 .34 .14 .31 .32 .96 .36 .04 .003 ! .0001 ! .0001 .0002 .0011 .30 .99 .02 .49 .18
* For maternal vital signs, significance is at the probability value of !.006 (Bonferroni correction applied). y Data are represented as mean G SD.
elevating cyclic guanosine monophosphate.11 It has been used increasingly in obstetrics for preterm labor, ECV, internal podalic version, retained placenta, uterine inversion, and fetal extraction at cesarean delivery. Nitroglycerin’s ability to relax the uterus effectively in these and other clinical settings, however, remains a matter of debate.12-15 In our study, intravenous nitroglycerin was less effective than subcutaneous terbutaline as a tocolytic for ECV at term (23% vs 55%; P Z .01). Our findings are consistent with other studies of nitroglycerin for ECV. In the only published study that compared nitroglycerin (sublingual) to a b-mimetic (ritodrine), Bujold et al9 found a trend toward more successful ECV in nulliparous women with ritodrine therapy (45% vs 25%; P Z .075). In a subsequent study in parous women, Bujold et al noted a statistically nonsignificant trend toward more ECV failures with nitroglycerin therapy as compared with placebo (48% vs 63%; P Z .13). This study was stopped prematurely, after an interim analysis demonstrated a significantly higher rate of side effects (headache and hypotension) with nitroglycerin and the trend toward more ECV failures.10 In another study, Yanny et al8 found no significant difference in ECV success with sublingual nitroglycerin therapy compared with placebo in 57 women after the initial attempt at ECV without tocolysis had failed. Forty-one percent of our patients were multiparous, and ECV success was significantly associated with
multiparity (65% vs 25%; P Z .002). ECV success was not associated with maternal-fetal medicine specialty training, the presence of an anterior placenta, or maternal body mass index. Before randomization, all patients underwent a nonstress test and an amniotic fluid index. Aside from documenting the absence of oligohydramnios (amniotic fluid index, !8 cm), we did not record specific numeric values routinely for the amniotic fluid index. The performance of a cervical examination was left to the discretion of the attending physician. Maternal side effects of terbutaline and nitroglycerin have been described in various studies.9,10,12,13,16,17 Side effects of terbutaline include maternal tachycardia, cardiac arrhythmia, myocardial ischemia, hyperglycemia, and death. Nitroglycerin has been associated with headache and hypotension. In our study, the use of terbutaline was associated with significantly higher rates of palpitations than nitroglycerin (17% vs 0%; P Z .02) and a significantly more rapid maternal heart rate. No significant differences in the incidence of headache or in mean arterial pressures were noted between agents. Bujold et al9 did show a more rapid maternal heart rate with intravenous ritodrine compared with sublingual nitroglycerin during ECV. In contrast to our study, the incidence of headaches was significantly higher with nitroglycerin, and the incidence of palpitations was not different between groups. In that study, a lower mean
El-Sayed et al blood pressure at 10 minutes after sublingual nitroglycerin possibly is confounded by significantly different mean blood pressures between groups at admission.9 Transient changes in fetal heart rate patterns are common, regardless of tocolysis during an attempt at ECV. Several studies and case series on ECV have reported up to an 18% incidence of fetal heart rate decelerations.6,9,18-21 We did not find a significant difference in the incidence of fetal heart rate decelerations between nitroglycerin and terbutaline therapies (27% vs 10%; P Z .18). However, we cannot rule out a type II error. One patient required an emergency cesarean delivery for placental abruption after an unsuccessful initial ECV attempt with nitroglycerin and an unsuccessful second ECV attempt with terbutaline. Our overall cesarean delivery rate was 64%. After a successful ECV, the cesarean delivery rate was 14% for the nitroglycerin group and 31% for the terbutaline group (P Z .6), which is consistent with the reported 0 to 31% incidence of cesarean delivery after a successful ECV.22-24 In our study, subcutaneous terbutaline was more effective than intravenous nitroglycerin for ECV at term. However, ECV success rates, even with b-mimetic tocolysis, can still be as low as 26.5%.25 Further studies are needed to investigate the most effective dose, method of administration, and tocolytic agent for ECV, as well as the optimal candidates.
Acknowledgments Abbott Laboratories provided some of the nitroglycerin for this study.
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