Research proposal The Terbutaline-Nifedipine ECV-trial

 1.      Title:

External Cephalic version in breech presentation. Randomised double blind controlled trial with use of nifedipine as a tocolyticum compared to ECV with “conventional” terbutaline.

 

2.      Main investigator:

Dr. Ron R.J. Collaris

Medical Officer

Department Obstetrics & Gynaecology

 

3.      Other investigators:

Dr. P.C. Tan

Consultant

Department Obstetrics & Gynaecology

 

4.      Project status:

New project

 

5.      Background & literature:

The steadily rising caesarean rate for breech after publication of the Term Breech Trial (1-3) has made ECV an increasingly attractive procedure in an effort to lower the number of caesareans for this indication. For this reason both RCOG & ACOG recommend the use of ECV in their most recent guidelines (4,5).

External cephalic version has been used for more than 100 years. Its efficacy has been well established (6). In the past 15 years increasing standardisation of ECV have made it to a procedure that seems safe for both mother and child (7). The role of (the nowadays almost universal use of) tocolysis in ECV is still unclear. Previous studies have shown a significant increase of successful ECV with tocolysis, though the eventual number of children in a cephalic position at time of delivery did not differ significantly from the control group. However, there was a significantly lower incidence of caesareans in the tocolysis group (8).

In UMMC ECV’s are performed on a regular basis. If tocolysis is used, it is usually a bolus of Terbutaline, administered subcutaneously or intravenously. Disadvan-tages of using this or other sympathomimetics is the mode of administration, difficulty in titrating the appropriate dose and the side effects that sometimes can be so severe that the procedure has to be stopped. Also the foetal heart rate will be influenced, making it more difficult to interpret the CTG after the procedure.

The widespread use of Nifedipine as both a tocolytic and an antihypertensive agent in the obstetric field is relatively new. Its tocolytic effect is at least equal to the “traditional tocolytics”, whilst the side effect profile is much milder, combined with an easier mode of administration (9). The increasing experience with Nifedipine in absence of evidence for short term adverse side effects for mother or foetus on a obstetrics seems to support its widening usage (10,11).

Since Nifedipine has already been proven to be an effective tocolytic in preterm labour, it would be interesting to investigate its usefulness in ECV-procedures.

 

References:

1.       Hutton EK, Hannah ME, Barret J. Use of external cephalic version for breech pregnancy and mode of delivery for breech and twin  pregnancy: a survey of Canadian practitioners. J Obstet Gynaecol Can 2002; 24: 804–10.

2.       Siddiqui D, Stiller RJ, Collins J, Laifer SA. Pregnancy outcome after successful external version. Am J Obstet Gynecol 1999; 181: 1092–5.

3.       James M, Hunt K, Burr R, Johanson R. A decision analytical cost analysis of offering ECV in a UK district general hospital. BMC Health Serv Res 2001; 1: 6.

4.       Royal College of Obstetricians and Gynaecologists. The management of breech presentation. Guideline No. 20. RCOG Clinical Green Top Guidelines, 2001.

5.       Committee on Obstetric Practice. ACOG committee opinion. Mode of term singleton breech delivery. No. 265, December 2001. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet 2002; 77: 65–6.

6.       Hofmeyr GJ, Kulier R. External cephalic version for breech presentation at term (Cochrane Review). In: The Cochrane Library, Issue 2, Oxford: Update Software, 2002.

7.       Collaris RRJ, Oei SG. External cephalic version: a safe procedure? A systematic review of version-related risks. Acta Obstet Gynecol Scand 2004; 83: 511–518.

8.       Hofmeyr GJ. Interventions to help external cephalic version for breech presentation at term (Cochrane Review). In: The Cochrane Library, Issue 2, Oxford: Update Software, 2002.

9.       King JF, Flenady VJ, Papatsonis DNM, Dekker GA, Carbonne B. Calcium channel blockers for inhibiting preterm labour. Cochrane database syst. Rev. 2004.

10.    Smith P, Anthony J, Johanson R. Nifedipine in pregnancy. Br J Obstet Gynaecol 2000; 10: 299-307.

11.    Bortolus R, Ricci E, Chatenoud L, Parazzini F. Nifedipine administered in pregnancy: effect on the development of children at 18 months. Br J Obstet Gynaecol 2000; 107: 792-4.

12.    Royal College of Obstetricians and Gynaecologists. The management of breech presentation. Guideline No. 1B. RCOG Clinical Green Top Guidelines, 2002.

13.    Papatsonis DN, van Geijn HP, Ader HJ, Lange FM, Bleker OP, Dekker GA. Nifedipine and ritodrine in the management of preterm labor: a randomized multicenter trial. Obstet Gynecol 1997;90:230–4.

14.    Fernandez CO, Bloom SL, Smulian JC, Ananth CV, Wendel GD Jr. A randomized placebo-controlled evaluation of terbutaline for external cephalic version. Obstet Gynecol 1997; 90: 775–9.

15.    El-Sayed YY, Pullen K, Riley ET, Lyell D, Druzin ML, Cohen SE, Chitkara U. Randomized comparison of intravenous nitroglycerin and subcutaneous terbutaline for external cephalic version under tocolysis. Am J Obstet Gynecol 2004 Dec; 19: 2051-5.

16.    Royal College of Obstetricians and Gynaecologists. The use of electronic foetal monitoring. Evidence-based Clinical Guideline Number 8, May 2001.

17.    Stine LE, Phelan JP, Wallace R, Eglinton GS, van Dorsten JP, Schifrin B. Update on external cephalic version performed at term. Obstet Gynecol 1985; 65: 642-6.

 

6.      Primary objective:

Investigate if there is a difference (advantage) in use of Nifedipine as opposed to other tocolytics (terbutaline) in ECV in terms of side-effects and success rate.

Secondary objective:

Number & sort of complications in Nifedipine-group as compared to the control-group, number of vaginal deliveries in successful ECV, confirm if foetomaternal transfusion is indeed as rare as is suggested by previous studies. Patient preference for route of medication and satisfaction of procedure.

 

7.      Expected outcome:

·         The success rate of Nifedipine is expected to be at least as good as the success rate of terbutaline.

·         The side effects in Nifedipine are expected to be less than those of terbutaline.

·         The complications are expected to be according to the complications as mentioned in the recent literature (7).

·         The caesarean rate of the successful versions is expected not to differ significantly from the caesarean rate of a comparable population

 

8.      Significance

If found to be equally effective or even better, a change in practice from use of Terbutaline to the use of Nifedipine, which is cheaper, easier to administer and more patient-friendly, leading to overall better patient satisfaction.

 

9.      Method:

Double blind randomised trial with analysis based on intention to treat. Patients eligible for ECV will be stratified for parity (nulliparous vs. parous) after inclusion. The patient will be allocated in one of 2 groups, receiving either Nifedipine or terbutaline. Neither patient, researcher nor the clinician performing the ECV will know which of both groups the patient was allocated to. For this purpose packages will be made containing either the combination of an ampulla terbutaline and a placebo tablet or an ampulla NaCl with a Nifedipine tablet. Every package will have its own lot number, corresponding with a coded list identifying the exact content of the package. The packages starting with lot number “A” will be used for the nulliparous, the packages starting with lot number “B” will be given to the (multi)parous. The ECV’s will preferably be done by a smaller group of clinicians who are reasonably experienced in the procedure. Assuming there will be a 50% success rate in terbutaline, 90 subjects will be needed to produce data with a power of 80% and an alpha of 0.05. For purposes of comparison a control group will be created by taking 1 random patient, matched for parity and term, who delivered in the 24 hours before and 1 who delivered after the delivery of the ECV-patient. The same inclusion- & exclusion criteria will be applied.

 

1. Patients in which breech is identified after 36 weeks of gestation will get an ultrasound, preferably the same day; contra-indications and congenital anomalies will have to be ruled out (see further).
2. Patient (if eligible) will be given information on the trial and if willing to be included, will sign a consent form.
3. A date will be set and patient will report fasted @ the “ECV-clinic”
4. The “ECV-clinic” will be @ the delivery ward; a new ultrasound will be done to re-assess the position of the foetus.
5. An i.v. access will be set and blood will be taken for Hb, Ht, blood group & cross match.
6. Informed consent will be taken from the patient.
7. The nurse will randomly choose a package, prepare the contents and administer them to the patient out of sight of the performing clinician. From that moment on the patient is “in the trial”.
8. A CTG-recording of minimal 30 minutes will be done to assess foetal condition. Maternal pulse & blood pressure will be recorded prior to CTG.
9. Patient receives 20-30 minutes prior to the ECV-procedure either a 10 mg in accordance to current literature (12,13) Nifedipine capsule or a placebo, together with respectively a s.c. injection of placebo or 250 mcg terbutaline (14,15,16).

 

If the foetal condition is good the ECV-procedure will be started;

An attempt to turn the foetus will last up to a maximum of 5 minutes and in one session not more than 2 attempts will be undertaken.

 

10. Regardless the result of the procedure another CTG-recording of 30-60 minutes will be performed, or at least till a reassuring pattern is seen. In a sub optimal CTG monitoring will be continued and the patient will be admitted to the antenatal ward, or in suspected foetal distress or grossly abnormal CTG (e.g. bradycardia >5 minutes) an emergency caesarean will be done.
11. During CTG monitoring and at the end the blood pressure & pulse will be measured manually (ca. 15 & 30 minutes after medication)
12. All Rhesus-negative patients will receive 1250 IU anti-D.
13. Patients will be seen again in ANC the next day for another CTG-recording, after which – if reassuring – weekly controls will be resumed.

 

14. Follow-up for all patients will be done to obtain the outcome parameters
15. The outcome of labour for patients in the group of successful ECV will be compared with the outcome of patients of a control group, derived from the nearest preceding delivery of a patient comparable in gestation and parity in an otherwise uncomplicated pregnancy.

 

Inclusion criteria are;

• Healthy pregnant women with a gestational age from 36 to 41 weeks
• Singleton pregnancy with child in breech

 

Exclusion criteria (conform to ACOG-guidelines)

• Previous caesarean or uterine surgery
• Uterine anomaly
• (Severe) hypertensive disease of pregnancy (pre-eclampsia, HELLP)
• Antepartum haemorrhage
• PROM
• Established labour
• Intra-uterine growth restriction (AC <10^th percentile)
• Foetal anomalies
• Oligohydramnion (AFI <5 cm)
• Placenta praevia
• Any indication for an elective primary caesarean

 

Outcome parameters are:

 

1. Number of foetuses with cephalic presentation following version
2. Number of foetuses with cephalic presentation at time of early labour
3. Number of successful vaginal deliveries after successful ECV-procedure
4. Number of caesareans after successful ECV-procedure and indications
5. Occurrence of abnormal / pathological CTG-readings following ECV (according to clear definitions)
6. Occurrence of vaginal blood loss in the week following ECV
7. Number of interventions (caesareans) clearly and directly related to the ECV procedure, e.g. because of pathological CTG-readings or suspicion of (partial) placental abruption
8. Neonatal outcome; Apgar & arterial + venous umbilical cord-pH
9. Occurrence of other complications, e.g. PROM, cord prolapse
10. patient (dis)comfort with either procedure

 

Resources needed:

• The packages with 1 placebo & 1 active medicine need to be prepared.
• Patient information folders necessary for consent need to be printed.
• Forms to note down the results need to be printed.

 

10. Time frame

The project is scheduled to be carried out over a period of 2 years or until the  number of 90 patients has been included, whichever comes first. It is to start as soon as the project is approved of and the necessary packages have been arranged. Ideally it would start by October 2005 and finish by October 2007. After this a period of 6 months will be taken to process the results and submit minimal 1 article for international publication. Depending on the results there might be enough material for 3 articles.

 

11. Other information:

Attached are a short CV, the patient information folder, the short questionnaire and the data sheet.