Nifedipine as a safe and effective tocolytic agent in

the treatment of preterm labor

To theEditors: We read with interest the article by Carr et
al (Carr DB, Clark AL, Kernek K, Spinnato JA. Mainte-
nance oral nifedipine for preterm labor: A randomized
clinical trial. Am J Obstet Gynecol 1999;181:822-7). The
data of only 74 patients were shown in the original arti-
cles Tables I through I I I , although there were 86 patients
randomly assigned. This opens the questions of whether
the 12 patients were equally divided between the two
groups and whether the characteristics of Tables I
through I I I were similar.
We agree with the conclusion of Carr et al that adju-
vant tocolytic therapy with nifedipine in this group of pa-
tients after initial intravenous magnesium sulfate tocoly-
sis showed no beneficial value. The question remains,
however, as to whether the patients that were selected by
this enrollment procedure were the patients who nor-
mally would require maintenance therapy. Patients were
enrolled in the study after uterine quiescence had been
achieved. I n how many cases could uterine quiescence
not be achieved with intravenous magnesium sulfate, and
therefore the patient could not be enrolled in the study,
and how many of these patients were delivered preterm?
Again, patients who can be successfully managed with in-
travenous magnesium sulfate and antibiotics may repre-
sent a group not in need of any further therapy. The only
correct way to perform such a trial is to randomly assign
patients on admission, rather than studying only the pa-
tients in whom uterine quiescence could be achieved
with intravenous magnesium sulfate.
There have been some questions lately about the effi-
cacy and safety of calcium-channel blockers in the treat-
ment of preterm labor. I n our study
1
that compared the
tocolytic efficacies of nifedipine and ritodrine we had to
discontinue ritodrine medication in 12 cases because of
severe maternal side effects. These patients were given
nifedipine instead. Because we were primarily interested
in the tocolytic efficacies of both drugs, we decided to in-
clude in the analysis only patients who actually only re-
ceived the tocolytic agent to which they had been ran-
domly assigned. To avoid a bias including these 12
patients (that is, there could be a beneficial effect of
nifedipine in this group of 12 patients), we decided to ex-
clude them from the analysis. Table I shows the results of
delay of delivery of that study
1
according to an intent-to-
treat analysis. There was a statistically significant differ-
ence in favor of nifedipine as compared with ritodrine in
delay of delivery for 24 hours, 48 hours, 1 week, and 2
weeks after starting tocolysis. When the data for delay of
delivery for 48 hours as mentioned in Table I were added
to the data of the meta-analysis of Ray,
2
meta-analysis
showed that there was a pooled odds ratio in favor of
American Journal of Obstetrics and Gynecology August 2000 513
nifedipine for delaying delivery compared with -agonists
of 1.54, with a 95% confidence interval from 1.06 to 2.24,
which is statistically significant (P = .03).
We agree with Carr et al that the incidence of mater-
nal side effects with nifedipine is significantly lower than
with -agonists.
1, 2
I n contrast to suggestions from some
animal studies, studies in human beings did not show any
significant alterations in uterine blood flow.
3
I n the late 1980s and early 1990s there were some re-
ported cases of profound hypotension, maternal death,
and neuromuscular blockade resulting from the combi-
nation of nifedipine and magnesium sulfate. The risk of
severe hypotension can be explained by the fact that both
drugs are effective calcium antagonists. However, the
clinical experience during the last decade has shown that
the actual risk of this combination is probably limited. We
recommend caution when using high tocolytic doses of
nifedipine in combination with a bolus of intravenous
magnesium sulfate. I n our opinion, nifedipine could be
used as a safe, well-tolerated and effective tocolytic agent.
D.N.M. Papatsonis, MD, H.P. van Geijn, MD, PhD, and
G.A. Dekker, MD, PhD
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gy-
necology, Free University Hospital, De Boelelaan 1117, 1081 HV
Amsterdam, TheNetherlands
REFERENCES
1. Papatsonis DN, Van Geijn HP, Adr HJ, Lange FM, Bleker OP,
Dekker GA. Nifedipine versus ritodrine in the management of
preterm labor: a randomized multicenter trial. Obstet Gynecol
1997;90:230-4.
2. Ray JG. Meta-analysis of nifedipine versus beta-sympathomimetic
agents for tocolysis during preterm labor. J Soc Obstet Gynaecol
Can 1998;20:259-69.
3. Hanretty KP, Whittle JM, Howie CA, Rubin PC. Effects of
nifedipine on Doppler flow velocity waveforms in severe pre-
eclampsia. BMJ 1989;299:1205-6.
6/ 8/ 105047
doi:10.1067/ mob.2000.105047
LETTERS TO THE EDITORS
Table I. Comparison of delay of delivery after tocolysis
between nifedipine and ritodrine
Nifedipine Ritodrine
(n =95) (n =90)
Statistical
Deliverytiming No. % No. % significance*
Within 24 h 11 12 23 26 P = .02
Within 48 h 21 22 33 37 P = .04
Within 1 wk 36 38 52 58 P = .008
Within 2 wk 43 45 59 66 P = .008
<34 wk 53 56 66 73 P = .01
<37 wk 66 69 72 80 P = .13
*P < .05, statistically significant.