Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b744 (Published 06 March 2009) Cite this as: BMJ 2009;338:b744
All rapid responses
We read with great intrest the study by de Heus et al. (1) on
adverse drug reactions to tocolytic treatment for preterm labour. In their
conclusion the authors point to the need for a direct comparison between
oxytocin antagonists and calcium channel blockers in terms of tocolytic
efficiency and side effects. Actually 2 (small)randomized controlled
trials comparing atosiban and nifedipine have been published (2,3).
Pooling data from these trials for tocolysis before 35 weeks gestation
results in 71 women in the atosiban and 72 in the nifedipin group.
Delivery could be postponed in 57 (80.3%) with atosiban and 56 (77.7%),
the difference not being significant ( p in Chi square test = 0.713, odds
ratio 1.08; 95% confidence interval 0.71-1.65). Both studies also mention
side effects such as arterial hypotension, 1 (1.4%) versus 25 (34.7%)in
the atosiban and nifedipine group respectively ( p< 0.001, odds ratio
16.7, 95% confidence interval 2.43-115.9.
1.De Heus R, Mol BW, Erwich JJ, van Geijn HP, Gyselaers WJ, Hanssens
M, Härmark L, van Holsbeke CD, Duvekot JJ, Schobben FF, Wolf H, Visser GH.
Adverse drug reactions to tocolytic treatment for preterm labour:
prospective cohort study. BMJ. 2009: 338:b744.doi 10.1136/bmj.b744
2.Kashanian M, Aklbarian AR, Soltanzadeh M. Atosiban and nifedipine for
the treatment of preterm labor. Int J Gynaecol Obstet 2005; 91: 10-14
3. Al-Omari WR, Al-Shammaa HB, Al-Tikriti EM, Ahmed KW. Atosiban and
nifedipine in acute tocolysis: a comparative study. Eur J Obstet Gynecol
Reprod Biol 2006; 128: 129-134
Competing interests:
None declared
Competing interests: No competing interests
Roel de Heus et al. (1) report that the tocolysis by beta-adrenergic
agonists is associated with high incidence of serious adverse drug
reactions contrary to the atosiban and the indometacin.
Nevertheless, it is surprising that beta adrenoreceptor agonists were
still used for tocolysis in this recent study (2006-2007) given their
potentially serious side effects for the maternal cardiovascular functions
previously known. Indeed, the calcium channel blockers and the atosiban
are at least as effective as the beta-adrenergic agonists with fewer
severe side effects (2).
In addition, antenatal indometacin described in the study as having no
severe maternal side effects may be associated with severe neonatal
outcomes such as periventricular leukomalacia and necrotising
enterocolitis that limit its indications (3).
References
1. De Heus R, Mol BW, Erwich JJ, van Geijn HP, Gyselaers WJ, Hanssens
M, Härmark L, van Holsbeke CD, Duvekot JJ, Schobben FF, Wolf H, Visser GH.
Adverse drug reactions to tocolytic treatment for preterm labour:
prospective cohort study. BMJ. 2009;338:b744.
2. 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. BJOG.
2001;108:133-42.
3. Amin SB, Sinkin RA, Glantz JC. Metaanalysis of the effect of
antenatal indomethacin on neonatal outcomes. Am J Obstet Gynecol.
2007;197:486.e1-10.
Competing interests:
None declared
Competing interests: No competing interests
We read the article by de Heus1 with interest. They have studied
prospectively, 1920 women in 28 hospitals and have come up with
interesting conclusions. We feel that in India ritodrine, terbutaline and
isoxsuprine remains to be the major tocolytics. Hundreds of thousands of
women in preterm labour are given these drugs on daily basis. Though,
obstetricians using these drugs say that "theoretically, there are many
side effects; but practically we do not see many side effects". The side
effects which many obstetricians feel are palpitations, restlessness but
are not of ‘serious’ nature etc. Routine monitoring of potassium levels is
not done. Hypotension, arrhythmias and worsening of ischemic heart disease
are rarely seen. Indeed, few studies have reported no significant adverse
effects of ritodrine, a beta-2 agonist used for premature labour2. This
makes a fit case to initiate the intensive monitoring of side effects of
tocolytics in India. We feel that we need to look at the side effect
profile of tocolytics in india more closely.
References
1. de Heus R, Mol BW, Erwich JJ, van Geijn HP, Gyselaers WJ, Hanssens
M, Härmark L, van Holsbeke CD, Duvekot JJ, Schobben FF, Wolf H, Visser GH.
2. Sharma A, Suri V, Gupta I. Tocolytic therapy in conservative management
of symptomatic placenta previa. Int J Gynaecol Obstet. 2004;84(2):109-13.
Competing interests:
None declared
Competing interests: No competing interests
Nifedipine adverse reactions exaggerated
So ritodrine use in preterm labour produces a lot more adverse
reactions to mother and fetus than atosiban or nifedipine.
All 3 are equally effective.
Nifedipine reduces uterine contractions, as does atosiban.
Nifedipine presents a more favorable safety profile for the fetus,
compared to atosiban.
But atosiban presents a more favorable safety profile for the mother,
compared to nifedipine, this study concludes.
I believe that this last conclusion is biased, because the only
serious adverse reaction of nifedipine observed, hypotension, could have
been completely absent!
Administering nifedipine sublingually, every 15 minutes, or per os,
every 4 hours, is known to cause hypotension.
That is why 60mg controlled release tablets of nifedipine have been
produced and exist on the market!
If this formulation had been used during this, and other, studies,
the adverse reactions of the nifedipine group of patients would be
similar, or fewer, compared to those of the atosiban group of patients.
Future studies should only compare 60mg controlled release tablets of
nifedipine to i.v. atosiban.
All other aspects favor nifedipine use (cost, route of
administration, effects on fetuses).
If future studies compare mother safety profiles of atosiban and
nifedipine and find them similar, then only nifedipine should be
recommended for the management of preterm labour.
Competing interests: No competing interests