Oxytocin receptor antagonists for inhibiting preterm
labour: a Cochrane systematic review
Responses to key questions
My understanding is that TRACTOCILE is more effective than placebo for
delaying preterm labour. Doesn’t this review contradict this?
The systematic review concludes that ‘…atosiban was shown to have similar tocolytic
efficacy to placebo.’ However, there are a number of problems with this statement:

This conclusion is based on the results of a single study, which had several
critical design limitations [Goodwin et al 1994]. Most importantly, women in the
study received a sub-therapeutic dose of TRACTOCILE (300 g/min for only
2 hours with no bolus loading dose). Secondly, the study was designed to
evaluate the effect of TRACTOCILE on preterm uterine activity, not efficacy.
Thirdly, the gestational ages varied considerably between the different centres
and went down as low as 20–23 weeks; which is both outside the current licence
for TRACTOCILE and outside limits of viability at the time. Lastly, ‘delivery within
48 hours of treatment’ is not the most clinically relevant indicator of efficacy. As
such, it is debatable whether the Goodwin et al 1994 study should have been
included in this review and this view was supported by a leading independent
expert in the field1

The much larger placebo-controlled trial [n = 501; Romero et al 2000] has been
omitted from the evaluation of efficacy in this review. This trial uses the much
more clinically relevant composite endpoint of non-delivery within 48 hours
without the need for an alternative tocolytic and demonstrates a significant
difference in favour of TRACTOCILE (P = 0.008).
1
Douglas Badenoch, Minervation Ltd, Oxford, UK.
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TRACTOCILE seems to be no better than -agonists so why should I use it?
This systematic review does conclude that ‘…atosiban has similar tocolytic efficacy to
-agonists.’ However, again there are a number of misrepresentations in this
statement:

TRACTOCILE is as effective as -agonists at 48 hours and more effective at
7 days [Moutquin et al 2001]

TRACTOCILE’s comparable or superior efficacy is accompanied by a significantly
superior side effects profile, particularly with respect to maternal cardiovascular
events [Moutquin et al 2001]

Whereas the three -agonist studies are appropriately included, the inclusion of
the Phase II dose ranging study by Goodwin et al in this evaluation is
questionable [Goodwin et al 1996] as women in three out of four of the
treatment arms received sub-therapeutic doses of TRACTOCILE. For the analysis
in the review, data from all four arms are pooled, which is scientifically flawed
I have always thought that TRACTOCILE is well tolerated but this review
suggests its use is associated with an increase in infant mortality
compared with placebo
This review does report that ‘…when compared with placebo, TRACTOCILE resulted
in an increase in infant deaths at 12 months of age’. Once again, however, this
statement is misleading for a number of reasons:

This conclusion is based on the results of only one trial [Romero et al 2000],
which is acknowledged to have an imbalance in the treatment groups caused at
randomisation. This resulted in a higher proportion of women at extremely early
gestational ages (p=0.008) and more advanced stages of PTL (higher risk
women), being treated with TRACTOCILE
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Gestational age at admission versus placebo
Gestational age at
Number
admission
Atosiban
Placebo
<26 weeks
24/246 (10%)
13/255 (5%)
26 to <28 weeks
19/246 (8%)
21/255 (8%)
28 to <32 weeks
107/246 (44%)
105/255 (41%)
32 weeks
96/246 (39%)
116/255 (45%)
P=0.008 overall vs placebo

In the Romero et al 2000 trial, the infant deaths were determined to be
associated with extreme prematurity and not study drug [Romero et al 2000],
with > three quarters occurring at <26 weeks gestation and in most cases with
infants weighing < 650 g. Babies born at 26 weeks are known to have a 1-year
survival rate of just 1% [insert reference].

The number of infant deaths in the Romero et al 2000 trial was not significantly
different from placebo – significance is only achieved in the 2-year follow-up
study [Goodwin et al 1998], that includes infant deaths up to 12 months

The real message from the Romero et al 2000 study should be that despite this
imbalance, the systematic review found no significant differences in any of the
safety data compared with placebo (including perinatal death, fetal death,
neonatal death)

It is also of note that this trial included women at very early gestational ages
(between 20–23 weeks), which is both outside the licence for TRACTOCILE and
outside the accepted limits of viability at the time the trials were performed

In more recent, larger and well-controlled trials perinatal mortality was no higher
in patients receiving TRACTOCILE [Moutquin et al 2001]; a finding that has been
confirmed in a study of more than 800 women receiving TRACTOCILE in every
day clinical practice [Husslein et al 2005]
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
The benefit of corticosteroid administration on infant outcome was not well
understood and was not routine when some of these trials were performed and
could have contributed to poorer infant outcomes
From this review it appears that TRACTOCILE is associated with lower
birth weights and more maternal adverse drug reactions than placebo
This review does state that ‘…TRACTOCILE resulted in lower birth weight and an
increase in maternal adverse drug reactions compared with placebo’ and ‘Compared
with -agonists, atosiban increased the numbers of infants born under 1500 g’. But
this does not tell the whole story:

The placebo-controlled trial of Romero et al 2000 demonstrated comparable birth
weights following TRACTOCILE and placebo

The statement on birth weight vs -agonists is based on two trials [Moutquin et
al 2000; Goodwin et al 1996]. Since all three arms of the CAP-001 trial had an
identical study protocol, and birth weight data are available from each, it is
unclear why data from the salbutamol [Cabrol et al 2001] and terbutaline [Maršál
et al 2001] arms have been excluded in this analysis

The largest randomised controlled tocolytic trials performed to date [Moutquin et
al 2001] have demonstrated comparable birth weights in infants born to mothers
given TRACTOCILE or -agonists (P = 0.58)

The results of these highly controlled studies have been confirmed in a clinical
use trial in more than 800 women, where significantly fewer maternal (P < 0.01)
and fetal (P < 0.03) treatment-emergent adverse events were reported with
TRACTOCILE compared with usual care2 [Husslein et al 2005].
From this review it doesn’t appear that TRACTOCILE is any better than agonists or placebo in terms of tocolytic efficacy or infant outcomes

In the largest tocolytic trials performed to date, the composite endpoint used
demonstrated the comparable efficacy and superior safety of TRACTOCILE
2
Usual care included -agonists, calcium channel blockers and bed rest
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compared with -agonists at 48 hours. At 7 days both efficacy and safety were
superior to -agonists

Recent RCOG guidelines have recommended the use of TRACTOCILE or
nifedipine based on their comparable efficacy and superior safety compared with
-agonists [RCOG, 2002]

In a large, placebo-controlled study, significantly more women receiving
TRACTOCILE remained undelivered and did not receive an alternative tocolytic
after 48 hours (P = 0.008) and 7 days (P = 0.003) [Romero et al 2000]

No tocolytic trials to date have been designed to show improved neonatal
outcome
Without a direct comparison of TRACTOCILE and calcium channel blockers,
what evidence is available to support the use of one drug over the other?
The review authors stress the need for a direct comparison of TRACTOCILE and
calcium channel blockers. However, two recent studies have compared the most
commonly used calcium channel blocker, nifedipine, and TRACTOCILE for the
treatment of preterm labour. The results of these studies are in agreement with each
other and demonstrate that:

Whereas
TRACTOCILE
and
nifedipine
demonstrated
similar
efficacies,
TRACTOCILE was associated with significantly fewer adverse events [Kashanian
et al 2005; Al-Omari et al 2004]

In particular, in one study [Kashanian et al 2005] most of the adverse events
(17/29; 58.6%) reported in women receiving nifedipine were cardiovascular
(hypotension [n = 11]; palpitation [n = 3]; tachycardia [n = 3]) compared with
none in women receiving TRACTOCILE
Recent systematic reviews and meta-analyses have suggested the use of
calcium channel blockers instead of other tocolytics based on superior
efficacy and safety

These recommendations have been based on meta-analyses and systematic
reviews of generally small, poorly-conducted studies [Lamont et al 2005]
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
More recently, a number of studies have been published documenting serious
maternal cardiovascular and pulmonary adverse events [Hodges et al 2004; Oei
et al 1999; Verhaert and van Acker 2004; Bal et al 2004; Vaast et al 2004]

A case of fetal death has also been reported following the tocolytic administration
of nifedipine [van Veen et al 2005]

Nifedipine remains unlicensed for use in pregnancy. Its efficacy and safety has
never been demonstrated in pregnant women within the context of licensing
trials. Indeed the authors of this systematic review state that there is ‘no
evidence that either of them [nifedipine and atosiban] are clinically superior to
placebo when it comes to important perinatal outcome including long-term safety
for babies’

Two recent studies have directly compared TRACTOCILE and nifedipine in a
clinical situation, and both demonstrated that the two drugs have comparable
efficacy in delaying PTL, but that TRACTOCILE is associated with significantly
fewer maternal adverse events in 71 and 80 women, respectively [Al-Omari et al
2004; Kashanian et al 2005].

Maternal adverse events in the Kashanian et al 2005 trial occurred in fewer
women receiving TRACTOCILE (17.5%) compared with nifedipine (40%;
P = 0.027). Most of the adverse events (17/29; 58.6%) reported in women
receiving nifedipine were cardiovascular (hypotension [n = 11]; palpitation
[n = 3]; tachycardia [n = 3]) compared with none in women receiving
TRACTOCILE

There has never been a trial of nifedipine vs placebo
Further well-designed randomised controlled trials should address the
relative risks and benefits of TRACTOCILE, nifedipine and placebo

The manufacturers of nifedipine have actively discouraged the use of nifedipine in
preterm labour and maintain that there never has been, and never will be, a
registration trial of nifedipine in tocolysis [Lamont, 2004]

Of the [new] tocolytics registered, TRACTOCILE has undergone the most
thorough pharmacological and methodological evaluation [Tsatsaris et al 2004]
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
Two recent studies have directly compared TRACTOCILE and nifedipine in a
clinical situation, and both demonstrated that the two drugs have comparable
efficacy in delaying PTL, but that TRACTOCILE is associated with significantly
fewer maternal adverse events in 71 and 80 women, respectively [Al-Omari et al
2004; Kashanian et al 2005].
This review points to a number of issues raised by the FDA surrounding the
use of TRACTOCILE. Should I be concerned?
During the early stages of the development of TRACTOCILE in the mid-1990s the
FDA did suggest that the gestation-dependent expression of myometrial oxytocin
receptors may make TRACTOCILE more appropriate for use at later gestational ages.
However:

There has never been any in-vitro or in-vivo evidence to support this concept and
the trial investigators dismissed this proposition at the time

A recent trial has demonstrated that TRACTOCILE is effective in the management
of preterm labour at low gestational ages (18–24 weeks) and exhibited its
established favourable side effects profile [Richter et al 2005]
The review also reports increased infant mortality and lower birth weight with
TRACTOCILE compared with placebo. The FDA has suggested that these adverse
infant outcomes could be due to fetal vasopressin receptor blockade by
TRACTOCILE. However:

This theory was largely discredited at the time as there was no evidence at all to
support it

A subsequent animal study investigated the potential anti-vasopressinergic
effects of TRACTOCILE on fetal sheep. The study demonstrated that
TRACTOCILE had no long-term effects on fetal oxygenation [Nathanieisz P, data
on file]

Animal studies have also demonstrated that fetal plasma levels of atosiban are at
or below the detection limit and that fetal blood pressure is not affected [Greig et
al 1993]
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
A much more plausible explanation for the increased infant mortality and lower
birth weight with TRACTOCILE is the imbalance in treatment groups in the study
by Romero et al 2000, which is acknowledged by the wider obstetric community

In fact it is noteworthy that despite this imbalance, most of the mortality data in
this trial (perinatal death, fetal death, neonatal death) were comparable with
placebo. Even the infant mortality rate is only significantly different in the followup study [Goodwin et al 1998], with the inclusion of infant deaths up to
12 months
Cochrane is a respected organisation well known for the publication of
evidence-based systematic reviews. The findings of this review must be
accurate.
Cochrane has justifiably earned its reputation in evidence-based medicine by the
publication of high quality science. However, as with all large organisations it is not
infallible.
In order to maintain the impartiality and independence for which the Cochrane
Library is respected, it is critical that there is balanced opinion among the authors of
every review. However, in this case, the independence of some of the authors might
be debatable. It is worth noting some key points:

The authors of this Cochrane review are self-appointed

Drs Papatsonis and Flenady have both published prolifically on calcium channel
blockers (including the recent Cochrane Systematic Review on calcium channel
blockers for use in preterm labour) and have very strongly advocated the use of
nifedipine in this indication

As there is no mention of TRACTOCILE in the previous Cochrane Systematic
Review on calcium channel blockers for use in preterm labour, it is unclear why
nifedipine data are specifically mentioned in this review. Again, it might be
argued by some readers that this is reflective of the authors’ own clinical
preferences
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References
1. Papatsonis D, Flenady V, Cole S and Liley H. Oxytocin receptor antagonists for inhibiting
preterm labour: a Cochrane systematic review. Cochrane Database Syst Rev 2005; Jul
20(3): CD004452.
2. Al-Omari WR. Atosiban and nifedipine in acute tocolysis, comparative study [abstract].
XVIII European Congress of Obstetrics and Gynaecology; 2004 May 12–15; Athens,
Greece. 2004: 103.
3. Bal L, Thierry S, Brocas E, Adam M, Van de Louw A, Tenaillon A. Pulmonary edema
induced by calcium-channel blockade for tocolysis. Anesth Analg 2004; 99(3): 910–911.
4. Cabrol D and the French/Australian Atosiban Investigators Group. Treatment of preterm
labor with the oxytocin antagonist atosiban: a double-blind, randomized, controlled
comparison with salbutamol. Eur J Obstet Gynecol Reprod Biol 2001; 98(2): 177–185.
5. Goodwin TM, Paul R, Silver H, Spellacy W, Parsons M, Chez R, Hayashi R, Valenzuela G,
Creasy GW, Merriman R. The effect of the oxytocin antagonist atosiban on preterm
uterine activity in the human. Am J Obstet Gynecol 1994; 170(2): 474–478.
6. Goodwin TM, Valenzuela GJ, Silver H, Creasy G. Dose ranging study of the oxytocin
antagonist atosiban in the treatment of preterm labor. Atosiban Study Group. Obstet
Gynecol 1996; 88(3): 331–336.
7. Goodwin TM, Randall H, Perry K, Menard MK, Bauer C, Shangold G et al. A report on
infant outcomes at 6 and 12 months after the use of atosiban in the management of
preterm labour. 46th ACOG Annual Meeting; 1998 May 9–13; New Orleans, Louisiana.
8. Greig PC, Massmann GA, Demarest KT, Weglein RC, Holland ML, Figueroa JP. Maternal
and fetal cardiovascular effects and placental transfer of the oxytocin antagonist atosiban
in late-gestation pregnant sheep. Am J Obstet Gynecol 1993; 169(4): 897–902.
9. Hodges R, Barkehall-Thomas A, Tippett C. Maternal hypoxia associated with nifedipine for
threatened preterm labour. BJOG 2004; 111(4): 380–381.
10. Husslein et al. Poster presented at COGI, Athens, Greece, 2005.
11. Kashanian M, Akbarian AR, Soltanzadeh M. Atosiban and nifedipin for the treatment of
preterm labor. Int J Gynaecol Obstet 2005; [epub before print].
12. Lamont RF. Reply to article by King et al. Aust N Z J Obstet Gynaecol 2004; 44(3): 275–
276.
13. Maršál K and the European Atosiban Study Group. The oxytocin antagonist atosiban
versus the beta-agonist terbutaline in the treatment of preterm labor. A randomized,
double-blind, controlled study. Acta Obstet Gynecol Scand 2001; 80(5): 413–422.
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14. Moutquin J-M, Sherman D, Cohen H, Mohide PT, Hochner-Celnikier D, Fejgin M, Liston
RM, Dansereau J, Mazor M, Shalev E, Boucher M, Glezerman M, Zimmer EZ, Rabinovici J.
Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of
preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol 2000;
182(5): 1191–1199.
15. Moutquin J-M and the Worldwide Atosiban versus Beta-agonists Study Group.
Effectiveness and safety of the oxytocin antagonist atosiban versus beta-adrenergic
agonists in the treatment of preterm labour. The Worldwide Atosiban versus Betaagonists Study Group. BJOG 2001; 108(2): 133–142.
16. Oei SG, Oei SK, Brolmann HA. Myocardial infarction during nifedipine therapy for preterm
labor. N Engl J Med 1999; 340(2):154.
17. Richter ON, Dorn C, van de Vondel P, Ulrich U, Schmolling J. Tocolysis with atosiban:
experience in the management of premature labor before 24 weeks of pregnancy. Arch
Gynecol Obstet 2005; 272(1): 26–30.
18. Romero R, Sibai BM, Sanchez-Ramos L, Valenzuela GJ, Veille JC, Tabor B, Perry KG,
Varner M, Goodwin TM, Lane R, Smith J, Shangold G, Creasy GW. An oxytocin receptor
antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind,
placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000; 182(5): 1173–
1183.
19. RCOG guidelines, 2002.
20. Tsatsaris V, Carbonne B, Cabrol D. Atosiban for preterm labour. Drugs 2004; 64(4):
375–382.
21. Vaast P, Dubreucq-Fossaert S, Houfflin-Debarge V, Provost-Helou N, Ducloy-Bouthors AS,
Puech F, Subtil D. Acute pulmonary oedema during nicardipine therapy for premature
labour; Report of five cases. Eur J Obstet Gynecol Reprod Biol 2004; 113(1): 98–99.
22. Valenzuela GJ, Sanchez-Ramos L, Romero R, Silver HM, Koltun WD, Millar L, Hobbins J,
Rayburn W, Shangold G, Wang J, Smith J, Creasy GW. Maintenance treatment of preterm
labor with the oxytocin antagonist atosiban. The Atosiban PTL-098 Study Group. Am J
Obstet Gynecol 2000; 182(5): 1184–1190.
23. Van Veen AJ, Pelinck MJ, Pampus MG, Erwich JJ. Severe hypotension and fetal death due
to tocolysis with nifedipine. BJOG 2005; 112(4): 509–510.
24. Verhaert D, Van Acker R. Acute myocardial infarction during pregnancy. Acta Cardiol
2004; 59(3): 331–339.
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Appendix
Summary of trials included in the Cochrane review of oxytocin antagonists
Trial
Description
Patients
Atosiban versus placebo
Goodwin et al 1994

Phase II study to assess effect of atosiban on preterm
120
uterine activity (not efficacy)

Atosiban administered at sub-therapeutic dose
–
300 g/min for only 2 hours, with no bolus loading
dose
Romero et al 2000

Women unlikely to be in true preterm labour

Phase III trial (PTL-096)

Imbalance of groups at randomisation; with more
501
women at lower gestational ages (P = 0.008) and more
advanced labour in the atosiban group
Atosiban versus -agonists
Goodwin et al 1996

Phase II dose ranging study of atosiban vs ritodrine

Four atosiban dosing arms pooled (6.5 mg bolus +
302
300 g/min; placebo bolus + 300 g/min; 2 mg bolus
+ 100 g/min; 0.6 mg bolus + 30 g/min) – but at
least three arms were sub-therapeutic
Moutquin et al 2000

Phase III trial – CAP-001; atosiban vs ritodrine
247
Cabrol et al 2001

Phase III trial – CAP-001; atosiban vs salbutamol
241
Maršál et al 2001

Phase III trial – CAP-001; atosiban vs terbutaline
249
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