OBJECTIVE: To estimate the effectiveness of nifedipine as a uterine relaxant during external cephalic version to correct breech presentation.
METHODS: In this randomized, double-blind, placebo-controlled trial, women with a singleton fetus in breech presentation and a gestational age of 36 weeks or more were eligible for enrollment. Participating women received two doses of either nifedipine 10 mg or placebo, 30 and 15 minutes before the external cephalic version attempt. The primary outcome was a cephalic-presenting fetus immediately after the procedure. Secondary outcome measures were cephalic presentation at delivery, mode of delivery, and adverse events. A sample size of 292 was calculated to provide 80% power to detect a 17% improvement of the external cephalic version success rate, assuming a placebo group rate of 40% and alpha of .05.
RESULTS: Outcome data for 310 of 320 randomly assigned participants revealed no significant difference in external cephalic version success rates between treatment (42%) and control group (37%) (relative risk 1.1, 95%; 95% confidence interval 0.85–1.5). The cesarean delivery rate was 51% in the treatment group and 46% in the control group (relative risk 1.1, 95% confidence interval 0.88–1.4).
CONCLUSION: Nifedipine did not significantly improve the success of external cephalic version. Future use of nifedipine to improve the outcome of external cephalic version should be limited to large clinical trials.
CLINICAL TRIAL REGISTRATION: Current Controlled Trials, http://isrctn.org, ISRCTN 28715121
LEVEL OF EVIDENCE: I
Nifedipine does not significantly improve the success of external cephalic version.
From the Departments of Obstetrics and Gynecology, 1Academic Medical Centre, Amsterdam; 2Medical Centre Alkmaar, Alkmaar; 3Onze Lieve Vrouwe Gasthuis, Amsterdam; 4Amphia Hospital, Breda; 5Flevo Hospital, Almere; 6Spaarne Hospital, Hoofddorp; and 7Zaans Medical Centre, Zaandam, the Netherlands.
For a list of the participants in the Dutch External Cephalic Version Trial and the trial coordinators, see the Appendix online at www.greenjournal.org/cgi/content/full/112/2/271/DC1.
Corresponding author: Marjolein Kok, MD, Academic Medical Centre, Department of Obstetrics and Gynecology, Meibergdreef 9, room H4-205, Amsterdam, 1105 AZ, the Netherlands; e-mail: email@example.com.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
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Breech presentation occurs in 3% to 4% of all term pregnancies.1 External cephalic version reduces the rate of breech presentation at term by an average of 40% and leads to a significant reduction in the risk of caesarean delivery (relative risk [RR] 0.55, 95% confidence interval [CI] 0.33–0.91) without a significant increased risk to the neonate.2 The actual caesarean delivery rate with breech presentation is approximately 80%,3 which is driven by the reported increase in perinatal risks for the vaginally delivered breech neonate.3,4 Because external cephalic version is a relatively simple procedure that carries minimal risk for mother and child,5,6 it is considered an important obstetric intervention.7,8
The use of uterine relaxant drugs is thought to improve the external cephalic version success rate. The majority of studies that evaluated the effectiveness of tocolysis have used β-agonists.9 These studies reported a beneficial effect of the use of β-agonists over placebo in external cephalic version from 40% to 57% (RR 0.74, 95% CI 0.64–0.87). However, β-agonists have known adverse maternal cardiovascular adverse effects in terms of flushing, chest pain, and palpitations,10 and adequate blinding for treatment allocation in placebo-controlled trials is therefore virtually impossible. Furthermore, although there is a higher success rate from external cephalic version with betamimetics compared with placebo, there is no significant reduction in noncephalic presentations at birth.9 In view of these issues, there is considerable interest in the evaluation of alternative uterine relaxants in external cephalic version.
The calcium antagonist nifedipine has relaxant effects on isolated, nonlabor, human myometrium, and is therefore used for tocolysis in obstetrics.11 In women with threatened preterm labor, it is more effective in delaying delivery, and it has considerably fewer adverse effects than β-agonists.12 Long-term neonatal follow-up showed no adverse effects.13 We performed an electronic search to identify all studies that reported on randomized controlled trials assessing the effectiveness of nifedipine in external cephalic version. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, and the ISRCTN Register for the period January 1975 to March 2007. There were no language restrictions. This search did not reveal any randomized controlled trials assessing the effectiveness of nifedipine in external cephalic version. Therefore, our objective was to compare the efficacy of the use of nifedipine as a uterine relaxant with placebo during external cephalic version.
MATERIALS AND METHODS
We performed a randomized, double-blind, placebo-controlled clinical trial in seven teaching hospitals in the Netherlands, together responsible for approximately 14,000 high-risk deliveries annually (annual hospital delivery rates ranging from 1,500 to 3,000). The study was approved by the institutional review board of the Academic Medical Centre, Amsterdam. The boards in each participating hospital granted local approval.
From a gestational age of 36 weeks onwards, women with singleton fetus in breech presentation were recruited for participation. Maternal exclusion criteria were any contraindication to labor or vaginal birth, a scarred uterus other than transverse in the lower segment, known uterine anomalies, placental abruption in the obstetric history, preeclampsia, maternal cardiac disease, and third-trimester bleeding. Fetal exclusion criteria were intrauterine growth restriction (estimated fetal weight less than 5th percentile for gestational age assessed by ultrasonography), fetal anomalies or an extended fetal head, oligohydramnios (defined as an amniotic fluid index of 5 cm or less), and nonreassuring signs of fetal well-being. Before randomization, each potential study participant had an ultrasound scan to assess fetal position, fetal growth, and amniotic fluid. All participants gave written consent before enrolment.
Randomization was controlled by the pharmacy of the Academic Medical Centre that prepared and distributed the containers with study medication. Randomization was stratified by center and by parity using computer-generated blocks of 10. The pharmacy prepared sealed opaque containers with study medication and kept an allocation list until completion of the study. Each container was labeled with the randomization number and medication expiration date.
Participants were enrolled by clinicians performing the external cephalic version procedure. Randomization assignment was performed by nurses handing out the consecutively numbered containers. The intervention group received a container with two nifedipine 10-mg capsules, the control group received a container with two placebo capsules. All participants, nurses, and doctors who performed the external cephalic version were blinded for the assignment.
The external cephalic version procedure was performed in all hospitals by experienced obstetricians, midwives, or by a resident supervised by experienced clinicians. Annual external cephalic version rates of the clinicians performing the external cephalic version ranged from 15 to 50. Fetal well-being was established by electronic fetal heart rate monitoring for at least 30 minutes preceding and after the procedure. The capsules with study medication were taken sublingually 30 and 15 minutes before the external cephalic version attempt. The fetal heart rate was monitored intermittently by ultrasound scanning during the procedure, followed by electronic fetal heart rate monitoring after the procedure. If fetal bradycardia would occur, the duration was registered. Nonsensitized Rhesus-negative women received anti-D immunoglobulin (1,000 international units intramuscularly) after the external cephalic version procedure. Crossmatch results of blood samples from each participant were available before an external cephalic version procedure was started. For the external cephalic version procedure a forward and a backward roll were allowed.
The primary outcome measure was a successful external cephalic version, defined as a fetus in cephalic position 30 minutes after the external cephalic version procedure. Secondary outcome measures were fetal presentation at delivery, mode of delivery, and adverse maternal and fetal events. Adverse maternal events were major side effects due to medication: hypotension with fetal consequences, anaphylactic shock due to the medication, and any adverse cardiac events due to medication intake. Furthermore, minor side effects were recorded: nausea, dizziness and flushing, and cessation of treatment because of side effects. Adverse neonatal events were defined as fetal death, emergency delivery, fetal bradycardia, premature rupture of the membranes, and placental abruption within 24 hours after the external cephalic version procedure.
All data were collected on Web-based electronic case record forms. Uploaded cases were stored in an Access (Microsoft Corp., Redmond, WA) database. For participants delivering outside the participating hospitals after successful external cephalic version, paper forms to register delivery outcome were supplied. A Data Safety and Monitoring Board, blinded to treatment allocation, followed the study for any adverse events.
This trial was designed to detect a 17% improvement of the external cephalic version success rate, based on the reported increase in success from 40% to 57% for tocolysis with β-agonists.9 A total sample size of 292 women (146 in each group) provided 80% power at the 5% significance level. During the study, adverse events were reported to the Data Safety and Monitoring Board.
Analysis was performed according to the intention-to-treat principle. The χ2 test was used to compare dichotomous variables, with Fisher exact test when appropriate. The Student t test was used to compare continuous variables. A difference was considered to be significant in cases where the P<.05 (two-tailed). Results are presented as RR with 95% CIs.
Between August 2004 and December 2006, 320 women were recruited, and 160 were allocated to each group (Fig. 1). Eight women (four in the treatment group and four in the placebo group) were not included in the analysis because an external cephalic version was attempted before 36 weeks of gestation (n=4) or because it was a repeat external cephalic version attempt (n=4). Two participants from the treatment group were excluded from the analysis due to being lost to follow-up. No adverse events occurred in any of these attempts. Thus, 310 women were included in the analysis (154 in the treatment group and 156 in the control group). Baseline characteristics are summarized in Table 1.
After external cephalic version with uterine relaxation with nifedipine, the number of women with a cephalic presentation was 64 (42%) as compared with 58 (37%) in the control group (RR 1.1, 95% CI 0.85–1.5) (Table 2). At delivery, there were 67 (44%) fetuses in cephalic position in the treatment group and 60 fetuses (39%) in the control group (RR 1.1, 95% CI 0.87–1.5). There were 79 (51%) caesarean deliveries in the treatment group, and 72 (46%) in the control group (RR 1.1, 95% CI 0.88–1.4). The other outcomes in the treatment and control group were also comparable (Table 2).
Except for fetal bradycardia, occurring in 12 (7.8%) in the treatment group and 11 (7.1%) in the control group (RR 1.1, 95% CI 0.5–2.4), no adverse fetal events occurred (Table 3). None of these bradycardias led to an emergency delivery. There were no maternal major side effects due to medication intake. There was, however, a significant difference between the minor side effects in the two groups, with 11 (7.1%) women complaining of flushes in the treatment group and no women complaining in the control group. Eight of the 11 participants with reported flushing had a successful version. There was no cessation of treatment because of side effects in either group.
This trial is the first to evaluate nifedipine for uterine relaxation during an external cephalic version procedure at term, and it is the largest single trial on uterine relaxation with external cephalic version thus far. We found no benefit of nifedipine compared with placebo.
The results of our trial are in contrast with studies evaluating the effectiveness of β-agonists for external cephalic version. These trials showed a beneficial effect of the use of β-agonists, with an improvement of the external cephalic version success rate from 40% without uterine relaxation to 57% with β-agonists.9
We anticipated that nifedipine would be at least as effective as β-agonists in external cephalic version. The calcium antagonist nifedipine is known for its superiority in inhibiting preterm labor compared with β-agonists. When compared with any other uterine relaxant, nifedipine significantly reduced the number of women giving birth within 7 days of receiving treatment (RR 0.76, 95% CI 0.60–0.97).12 In two randomized controlled trials in women with threatened preterm labor, nifedipine was found to be more effective than betamimetics for inhibiting preterm labor (RR 0.76, 95% CI 0.59–0.99), and discontinuation of treatment because of side effects occurred less frequently after nifedipine than after β-agonists (0.2% compared with 7%; RR 0.14, 95% CI 0.05–0.36).12 Long-term neonatal follow-up after tocolysis with nifedipine has not demonstrated particular side effects.13 Furthermore, there is one recently published retrospective cohort study that evaluated the efficacy of nifedipine as a uterine relaxant before external cephalic version compared with intravenous ritododrine.14 This study showed that oral nifedipine was equally effective as intravenous ritodrine (RR 1.1, 95% CI 0.8–1.5).
The fact that we found no treatment effect of nifedipine, whereas previous studies with β-agonists reported a beneficial effect might be due to the fact that adequate blinding in studies with β-agonists is virtually impossible. Because β-agonists generate clear and detectable side effects,10,15 this may have resulted in an overestimation of the success rate. Furthermore, only two of the six studies investigating the effectiveness of β-agonists for external cephalic version had adequate allocation concealment. Both inadequate allocation concealment and inadequate blinding could have resulted in an overestimation of the success of uterine relaxation with a magnitude of 10% to 30%.16 The opinion that the beneficial effect of uterine relaxants might not be as high as claimed is shared by Impey et al,17 who assessed the effectiveness of uterine relaxation in repeat external cephalic version.
To avoid the bias of inadequate blinding we chose to compare nifedipine with placebo rather than designing a trial comparing β-agonists with nifedipine. Only 11 (7%) participants in our trial reported minor side effects related to nifedipine. Eight of the 11 participants with reported flushing had a successful version where one would expect four on basis of the results of our trial. There is, however, little chance that this might have influenced our primary outcome.
The optimal dose of nifedipine was determined after simulations with the MW/Pharm 3.50 pharmacokinetic software (Mediware, Zuidlaren, the Netherlands), using population data on the drug.18,19 To obtain an effective serum concentration within one half hour, two 10-mg capsules should be taken sublingually. This nifedipine serum concentration is comparable to the nifedipine serum concentrations after the most commonly used tocolytic dose regimens. Therefore, we consider the dose regimen used to be adequate. Despite recent reports in literature concerning serious adverse effects of nifedipine used as a tocolytic, mostly in twin pregnancies,20 we did not find any adverse effect in this trial, probably because of the low dose used in a limited time frame. Fetal bradycardia occurred slightly more often than in a recent review from Collaris et al5 (7.1% compared with 5.7%).
The main goal of external cephalic version is preventing breech delivery, thus improving neonatal outcome and preventing a caesarean delivery. Cephalic presentation after external cephalic version in our study was not different from the success rates of the placebo groups described in other studies ranging from 28–68%.9 Therefore, we feel confident that the external cephalic version was carried out properly. In addition, the caesarean delivery rate for breech presentation in this trial was 68%. After external cephalic version in 310 women, 120 delivered vaginally in cephalic position. Thus, our study confirms the benefits of external cephalic version in the reduction of maternal and neonatal complications.
In conclusion, this trial did not show nifedipine to significantly improve the success of external cephalic version but shows nifedipine to be safe in external cephalic version. Given the fact that there is still a 20% chance nifedipine does improve the effectiveness of external cephalic version, considering the power of 80%, future use of nifedipine to improve the outcome of external cephalic version should be limited to the use in large clinical trials.
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