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Nifedipine versus ritodrine for suppression of preterm labor
European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 204–208 www.elsevier.com/locate/ejogrb
Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects Vicenc¸ Cararach a, Montse Palacio a,*, Sergi Martı´nez a, Pere Deulofeu b, Myriam Sa´nchez a, Teresa Cobo a, Oriol Coll a a
Institut Clı´nic de Ginecologia, Obstetrı´cia i Neonatologia, Hospital Clı´nic de Barcelona, Sabino de Arana 1, 08028 Barcelona, Catalonia, Spain b Hospital Municipal de Badalona, Badalona, Spain
Received 4 November 2004; received in revised form 11 October 2005; accepted 18 October 2005
Abstract Objectives: To compare the efficacy of nifedipine and ritodrine in prolonging pregnancy beyond 48 h, 1 week and 36.0 weeks and to evaluate maternal side effects and adverse perinatal outcome. Study design: Non-blinded, randomized controlled trial. Eighty patients with singleton pregnancies admitted for preterm labor with intact membranes between 22 and 35 weeks of gestation were included in the study. Preterm labor was defined as the persistence of at least two symptomatic uterine contractions within a 10 min period during 60 min after admission and despite bed rest. Results: Forty women received oral nifedipine and forty intravenous ritodrine. Two patients, one from each group, were excluded because of loss to follow-up after discharge. Therefore, 39 women in the nifedipine and the ritodrine groups, respectively, were evaluable for the final analysis. Baseline characteristics were comparable in both groups. The percentage of initial response, the speed of onset of action and the rate of successful treatment within 48 h were significantly better in the ritodrine group. However, prolongation of pregnancy beyond 7 days and 36 weeks of pregnancy was similar with a significantly lower rate of side effects in the nifedipine group. Conclusions: In this small trial, ritodrine provided more effective tocolysis within the first 48 h than nifedipine at the doses used in this study, although with a significantly higher rate of side effects. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Preterm labor; Tocolytics; Nifedipine; Ritodrine
1. Introduction Preterm delivery occurs in 7–9% of all births and has even increased recently [1]. Moreover, the most frequently associated condition with neonatal mortality and morbidity, excluding congenital malformations, is also preterm delivery. Neurological and sensorial deficiency rates are especially high in newborns of less than 31–32 weeks [2,3]. Although primary prevention would be ideal, the efforts in this direction have not been successful so far, probably because of multifactorial social, behavioral and biological etiology [4]. * Corresponding author. Tel.: +34 93 227 56 00; fax: +34 93 227 56 05. E-mail address: [email protected] (M. Palacio).
When preterm uterine contractions are present, but especially when cervical conditions are modified, it is essential to start treatment to postpone delivery unless there are signs of intrauterine infection or fetal distress. The most commonly used tocolytic agents are beta-adrenergic agonists. Meta-analyses have shown that beta-adrenergic agents, especially ritodrine, are associated with a postponement of delivery of 24, 48 h and 7 days. However, such a delay has not been associated with a significant reduction in either perinatal mortality or morbidity [5,6]. The great incidence of usually mild but potentially severe side effects of beta-sympathicomimetics has led to the search for better drugs. The oxytocin receptor antagonist, atosiban, appeared in the tocolytic scenario in the year 2000. Nonetheless, despite the clear advantage in the lack of relevant side effects
0301-2115/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2005.10.020
V. Cararach et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 204–208
with its use, perinatal mortality and morbidity have not been modified with this new agent [7] and the high cost of this antagonist limits its widespread use. Therefore, financial costs must be taken into account, thereby restricting the use of atosiban to hemodynamic high risk patients and thus, justifying the wise use of other tocolytics. Nifedipine is a calcium-channel blocker drug (type II calcium blockers). It acts by reducing the intracellular entrance of calcium through the slow channel (or L type) producing an inhibition of contractile activity of nonpregnant, pregnant and postpartum myometrium. Nifedipine reduces the amplitude and frequency of contractions and the basal myometrial tone and is more active in pregnant than in non-pregnant women. The mean half-life in pregnant women is short (81 min) and, therefore, its effect is reversible. It was introduced as an antihypertensive drug but its hypotensive effect is mild in normotensive pregnant patients [8,9]. In the last 20 years many reports have evaluated the use and efficacy of nifedipine as a tocolytic agent. The latest systematic review includes 12 randomized controlled trials with a total of 1029 participating women. Ten compared its efficacy with ritodrine and all found nifedipine to be more effective than ritodrine in prolonging pregnancy beyond 7 days and much less likely to cause maternal side effects [10].
2. Materials and methods Pregnant women with singleton pregnancies admitted for preterm labor with intact membranes between 22 and 35 weeks of gestation were eligible for the study. Preterm labor was defined as the persistence of at least two symptomatic uterine contractions within a 10 min period during 60 min after admission and despite bed rest. Exclusion criteria were: cervix dilatation greater than 5 cm, polyhydramnios, fetal anomalies, signs of fetal distress, suspected intrauterine infection or growth restriction, contraindication for the use of beta-sympathomimetic drugs and previous treatment with tocolytics in the present gestation. Biochemical and hematological blood tests and an electrocardiogram were performed. Patients with a clinical contraindication for the use of beta-adrenergic drugs or nifedipine were excluded. Informed consent was obtained before randomization from eligible subjects. The study protocol was approved by the hospital’s Ethics and Research Committee. Women were allocated into two groups by opening a series of sealed, opaque, consecutively numbered envelopes that were sequentially selected. There was a 1:1 randomization ratio. Women were randomly assigned to receive either ritodrine or nifedipine. Clinicians were not blinded to the study group in which the women were allocated. Women assigned to the nifedipine group received an initial oral loading dose of 30 mg (10 sublingual and 20 mg
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oral) and a maintenance oral dose of 20 mg every 6 h. Treatment was discontinued if no uterine contractions occurred within a 48 h period [11]. Women allocated to the ritodrine group received an intravenous infusion at a rate of 100 mcg/min. The initial dose was increased 50 mcg every 20 min until uterine contractions were suppressed or intolerable side effects appeared or a limit dose of 350 mcg/min was achieved. The lowest effective tocolytic dose was maintained during 2 days, followed by oral therapy with a dose of 10 mg/6 h. After discharge, no maintenance tocolytic treatment was indicated. If uterine contractions reappeared, relapse was diagnosed and treatment was repeated as indicated above. Initial response was defined if uterine contractions were suppressed within 2 h of tocolytic treatment. Otherwise, treatment failure was considered and women received the drug indicated in the other study arm. If the second tocolytic was not effective, the woman was excluded from the analysis and indometacin was added. An ‘‘escape phenomenon’’ was considered on relapse of uterine contractions after their suppression before discontinuation of the treatment. In this case, an extra dose of 10 mg of sublingual nifedipine was added or ritodrine was increased as previously indicated. If contractions were not suppressed, a failure of treatment was considered and the patient was changed to the other treatment arm as referred above. Maternal blood pressure and heart rate were monitored every 20 min until a stable dose was achieved and every 4 h thereafter. Daily hydric balance was performed and blood parameters (cell blood count, glycemia, ionogram) and hepatic and renal function) were monitored every 24 h. Clinical signs and symptoms of intolerance to the drugs used were assessed every 6 h. Continuous fetal heart rate and uterine contraction monitoring was carried out during the first 12 h and until uterine contractions disappeared. Afterwards, fetal heart rate and uterine contractions were monitored every 12 h during hospital admission. At delivery, several neonatal parameters, such as weight, Apgar’s score, umbilical arterial and vein pH values and presence of hyperbilirrubinemia were determined. Neonatal complications such as hemorrhage or infections were recorded. Outcome measurements were successful tocolysis at 2 h, at 48 h and at 7 days. Prolongation of gestation from admission to hospital to delivery and the number of preterm deliveries before 36 weeks (252 days) of gestation were also assessed. The data collected were processed with Filemaker pro II for Macintosh database. Statistical analysis was performed using Stat View 512 for Macintosh. Differences were considered statistically significant when the p value was <0.05. For comparison of categorical variables the Chisquare test was used with Yate’s correction when appropriate. For comparison of mean values, the Student’s t-test for independent samples was used.
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Table 1 Characteristics of the study population
Maternal age (years) (mean (S.D.)) Parity (median (range)) Previous preterm delivery (n (%)) Gestational age (weeks.days) (mean (S.D.)) Bishop score (mean (S.D.))
Ritodrine, n = 39
Nifedipine, n = 39
p
26.2 (6.5)
26.9 (6.1)
NS
1 (0–3) 5 (12.8)
1 (0–3) 4 (10.3)
NS NS
32.1 (2.1)
32.2 (2.2)
NS
2.9 (1.9)
2.7 (1.8)
NS
3. Results Eighty patients were included in the study, 40 in each treatment group. Two patients were excluded, one from each group, because of loss to follow-up after hospital discharge. Therefore, 39 women in the nifedipine and the ritodrine groups, respectively, were evaluable for the final analysis. The excluded patients underwent successful tocolysis within 2 h. The characteristics of the two groups on admission are summarized in Table 1, with no significant differences being observed. The ‘‘escape phenomenon’’ was twice higher in the ritodrine group although differences did not reach statistical significance. The percentage of initial response, the speed of the onset of action (Table 2) and the rate of successful treatment within the first 2 days was better in the ritodrine group. However, the efficacy beyond 1 week and 36 weeks of gestation did not reach statistical significance (Fig. 1). The rate of adverse perinatal outcomes was similar, Table 2 Efficacy and perinatal outcome
Initial response (n (%)) Speed of onset of action (min) (mean (S.D.)) Escape phenomenon (n (%)) Overall response (n (%)) Gestational age at delivery (weeks.days) (mean (S.D.)) Prolongation of gestation (days) (mean (S.D.)) Birthweight (g) (mean (S.D.)) <2500 g (n (%)) Apgar score <7 at 5 min (n (%)) Respiratory distress syndrome (n (%)) Perinatal mortality (n (%)) Fetal death (n (%)) Neonatal death (n (%)) a
although the lack of power of the study does not allow strong conclusions on perinatal results to be drawn. There were no neonatal complications such as neonatal sepsis, necrotising enterocolitis or grade III or IV intraventricular hemorrhage. Two perinatal deaths were recorded in the ritodrine group: one was an antepartum fetal death at term of unknown origin and another was a neonatal death secondary to complications of an intracraneal teratoma non-diagnosed prenatally (Table 2). Most of the women receiving ritodrine reported side effects (76.9%) with severe tachycardia (>120 bpm) in 20% of all treated cases. Other side effects with a potential perinatal impact were hyperglycemia and hypokalemia observed in 30 and 20% of the cases, respectively. On the contrary, a lower rate of side effects was observed in the nifedipine group (20.5%, p < 0.001), being headache (10.3%), mild malleolar edema or rash and mild tachycardia or nausea the only relevant side effects (Table 3). Treatment was discontinued due to side effects in four patients in the ritodrine group but in no case in the nifedipine group.
Ritodrine, n = 39
Nifedipine, n = 39
p
37 (94.9) 35 (21)
29 (74.4) 62 (28.2)
0.012 0.002
9 (23.1) 28 (71.8) 36.1 (2.4)
6 (15.4) 25 (64.1) 36.2 (2.4)
NS NS NS
Table 3 Side effects observed with ritodrine and nifedipine
28 (21.6)
29.4 (25.1)
NS
2722 (676)
2870 (475)
NS
12 (30.8) 3 (7.7)
11 (28.2) 2 (5.1)
NS NS
3 (7.7)
2 (5.1)
NS
2 (5.1) 1 (2.6)a 1 (2.6)b
– – –
NS NS NS
Tachycardia Mild Severe Hyperglycemia Hypokalemia GPT elevation Nausea Anxiety Dyspnea Thoracic pain Edema Headache Rash or edema in lower limbs One or more side effects
Antepartum fetal death of unknown origin at term. Death after neonatal complications due to a prenatally non-diagnosed intracranial teratoma. b
Fig. 1. Prolongation of pregnancy beyond 48 h, 1 week and 36 weeks of gestation.
*
p < 0.001.
Ritodrine, n = 39, n (%)
Nifedipine, n = 39, n (%)
28 20 8 12 8 – 6 6 2 1 1 1 – 30
2 2 – – 1 1 2 – – – – 4 2 8
(71.8) (51.3) (20.5) (30.8) (20.5) (15.4) (15.4) (5.1) (2.6) (2.6) (2.6) (76.9) *
(5.1) (5.1)
(2.6) (2.6) (5.1)
(10.3) (5.1) (20.5)*
V. Cararach et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 204–208
4. Discussion The results obtained in our small study showed that ritodrine was more effective in the treatment of preterm labor than nifedipine during the first 2 days but the differences were not significant at 1 week and beyond 36 weeks. The better tocolytic effect of ritodrine within the first 48 h is apparently in contrast with the results observed in previous studies in which nifedipine showed a similar or even better efficacy than ritodrine. This may be explained by different reasons. Firstly, women with different baseline characteristics were included among different studies, which may explain some differences in the results. Four previous studies included patients with preterm premature rupture of membranes [12–15] and another included twin pregnancies [14,16] or patients who had previously received tocolysis [14]. In the present study, inclusion criteria were more restrictive and included only women with singleton pregnancies and intact membranes. Moreover, in our study the rate for preterm delivery before 36 weeks was 33 and 37% for the ritodrine and the nifedipine groups, respectively. In contrast, other authors [14,15] have reported a rate of preterm delivery before 34 weeks of between 44 and 77%, which is much higher, despite cervical conditions being comparable. These differences could be attributable to the fact that the population selected in our study was at a lower risk for preterm delivery before admission. The efficacy of nifedipine or ritodrine may be lower in women at high risk for preterm delivery. Secondly, the dosing used in the two arms of the study differed from that in other studies. The ritodrine regimen in the current study was, in general, higher than that reported in other studies. As expected, ritodrine produced a much higher incidence of side effects, and in four cases the medication had to be discontinued, whereas no patient in the nifedipine group required withdrawal. Our institution has lengthy experience in the use of ritodrine and in the monitoring of maternal hemodynamics. Early signs of pulmonary edema have usually been presented only in high-risk patients such as women with multiple pregnancies or pregestational diabetes. Since its introduction, we have used atosiban as the drug of choice for initial treatment in such cases. On the other hand, nifedipine was used at a much lower dose (maximum 80 mg/day) than that suggested by King et al. [10] (maximum of 160 mg/day) which has been used in other studies [14–17]. Dosing was chosen following available literature at the time the study was designed. Koks et al. [14] used an initial dose of 30 mg and later changed to 40 mg, Garcia-Velasco and Gonzalez [17] also used 30 mg as a loading dose and Papatsonis et al. [15] and Weerakul et al. [19] administered a maximum of 40 mg in the first hour. Because we had no experience with the use of nifedipine to treat preterm labor, we were cautious and we chose a maximum of 30 mg within the first hour. Well after our study was designed, in 2003 King et al. published a
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protocol recommending an initial dose of 20 mg plus 20 mg more after 30 min if tocolysis was not achieved and another 20 mg after 1 h if contractions were still present. This different dosage in our study may account for the greater effect observed within the first 48 h in the ritodrine group. However, the speed of onset of action would probably not change substantially because we were using a higher initial dose (30 mg). Compared with Papatsonis’ regimen of nifedipine [15], moderate doses were implemented in the design of our study with no possibility to increase the dosage when tocolysis was not effective enough or uterine contractions relapsed. We observed an increase in transaminases in one case in the nifedipine group while in none in the ritodrine group, detected by systematic control but without any clinical signs of hepatic disease. Indeed, the analytical abnormalities returned to the normal values after discontinuation of the treatment. Lastly, the possibility of submission or even publication bias must be taken into account. Considering that ritodrine has been widely used before the introduction of nifedipine as a tocolytic, the lack of studies on this issue is remarkable. Many clinical trials with drugs are not submitted because of negative or contrary to the expected results. This submission or publication bias may overestimate the beneficial effect of a drug if these effects are evaluated only considering published studies [18]. Interestingly, other studies with a similar number of patients have also observed that betaadrenergic drugs were more effective than nifedipine in postponing delivery beyond 48 h but the differences were not statistically significant [14,17,19]. The small number of patients included in these studies or a higher basal risk for preterm delivery of the women included (i.e. rupture of membranes or multiple gestation) which may limit the efficacy of tocolysis, may have prevented differences from being significant. Furthermore, the reduced number of cases also included in our study, may have limited the power to detect significant differences in prolonging pregnancy beyond 1 week. Since ritodrine may cause more side effects than nifedipine, it should be more effective than nifedipine to be recommended as a first-line tocolytic. Postponement of delivery beyond 48 h to allow corticosteroid treatment to be effective in order to improve neonatal morbimortality may be considered a valuable or significant benefit [20]. Indeed, the advantage of immediate response to the drug to allow an in utero transfer to a tertiary center has also been considered as relevant in the final outcome as outlined by King et al. [10]. In our study, the initial response and speed of the onset of action were significantly higher in the ritodrine group with an efficacy greater than 90% of the cases in the first 48 h. However, the ‘‘escape phenomenon’’ was also much higher in the ritodrine group. Although differences compared to the nifedipine group did not reach statistical significance, this may be due to the small number of patients included in the study. After 48 h of treatment, the ‘‘escape phenomenon’’ is increased due to a saturation of the
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myometrial receptors requiring progressive increase in the dosage leading to more severe secondary effects. In our study design, when the treatment was not effective in one arm or intolerable side effects appeared, the alternative drug was started despite the continued action of the other. Although this may be considered a limitation of the study because the treatment was not blinded and personal bias may have influenced the decision to change the drug, a potentiation of side effects was not observed, suggesting different mechanisms of action. This may also suggest the possibility of a combined regimen of these two drugs. The association of ritodrine with nifedipine may be of special interest because it allows the treatment to be maintained after 2 days with the same efficacy and fewer side effects. Although maintenance therapy with oral ritodrine has failed to demonstrate a significant prolongation of pregnancy [21,22], the role of maintenance therapy with calcium channel blockers is still not clear. More studies are needed to determine the efficiency and the safety of this association [23–25], especially in countries where the elevated cost of atosiban limits its use. However, the association of potential adverse effects must be taken into account. A final fact to be considered is that despite many reports on the use of nifedipine in pregnancy, this drug has never been licenced for its use in pregnancy. In the present worldwide context of legal litigation, this fact should also be kept in mind [26]. In conclusion, ritodrine provides more effective tocolysis within the first 48 h of preterm labor than nifedipine. This fact may support the use of this drug despite its side effects and thus, allow antenatal corticosteroids to be effective or an in utero transfer to a tertiary center to be made. However, close hemodynamic control is mandatory and it is necessary to exclude contraindications to the beta-adrenergic drugs. Although nifedipine was initially less effective than ritodrine in the first 2 days, similar perinatal results were obtained with a significantly lower rate of secondary effects than with ritodrine treatment. The possibility of combined therapy with these two drugs should to be evaluated.
Acknowledgment Supported by the FIS of Spanish Ministry of Health.
References [1] Goldenberg RL, Rouse DJ. Prevention of premature birth. N Engl J Med 1998;339:313–20. [2] McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985;312:82–90. [3] Woods NS, Marlow M, Costeloe K, Gibson AT, Wilkinson AR. Neurologic and developmental disability after extremely preterm birth. N Engl J Med 2000;343:378–84.
[4] Assessment of risk factors for preterm birth. ACOG Practice Bulletin 31. Obstet Gynecol 2001;98:709–16. [5] The Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic antagonist ritodrine. N Engl J Med 1992;327:308–12. [6] Gyetvai K, Hannah ME, Hodnett ED, Ohlsson A. Tocolytics for preterm labor: a systematic review. Obstet Gynecol 1999;94:869–77. [7] The Worldwide Atosiban versus Beta-agonists Study Group. Effectiveness and safety of the oxytocin antagonist atosiban versus betaadrenergic agonists in the treatment of preterm labour. Br J Obstet Gynaecol 2001;108:133–42. [8] Ulmsten U, Andersson KR, Wingerup L. Treatment of premature labor with the calcium antagonist nifedipine. Arch Gynecol 1980;229:1–5. [9] Fenakel K, Lurie S. The use of calcium channel blockers in obstetrics and gynecology: a review. Eur J Obstet Gynecol Reprod Biol 1990; 37:199–203. [10] King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B. Calcium channel blockers for inhibiting preterm labour: a systematic review of the evidence and a protocol for administration of nifedipine. Aust N Z J Obstet Gynaecol 2003;43:192–8. [11] Deulofeu P, Carmona F, Martinez S, et al. Tratamiento tocolı´tico con nifedipina en la amenaza de parto prete´rmino. Prog Obst Gin 1992; 35:74–81. [12] Ferguson 2nd JE, Dyson DC, Schutz T, Stevenson DK. A comparison of tocolysis with nifedipine or ritodrine: Analysis of efficacy and maternal, fetal, and neonatal outcome. Am J Obstet Gynecol 1990; 163:105–11. [13] Janky E, Leng JJ, Cormier PH, Salamon R, Meynard J. A randomized study of the treatment of threatened premature labor Nifedipine versus ritodrine. J Gynecol Obstet Biol Reprod (Paris) 1990;19:478–82. [14] Koks CAM, Bro¨lmann HAM, de Kleine MJK, Manger PA. A randomized comparison of nifedipine and ritodrine for suppression of preterm labor. Eur J Obstet Gynecol Reprod Biol 1998;77:171–6. [15] Papatsonis DNM, 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. [16] Kupfermic M, Lessing JB, Yaron Y, Peyser MR. Nifedipine versus ritodrine for suppression of preterm labour. Br J Obstet Gynaecol 1993;100:1090–4. [17] Garcia Velasco JA, Gonzalez AG. A prospective randomized trial of nifedipine versus ritodrine in threatened preterm labor. Int J Gynecol Obstet 1998;61:239–44. [18] Antes G, Chalmers I. Lancet 2003;361:978–9. [19] Weerakul W, Chittacharoen S, Suthutvoravut S. Nifedipine versus terbutaline in management of preterm labor. Int J Gynecol Obstet 2002;311–3. [20] NIH Consensus Development Panel on the Effect of Corticosteroids for Fetal Maturation on Perinatal Outcomes. JAMA 1995;273:413–8. [21] Macones GA, Berlin M, Berlin JA. Efficacy of oral beta-agonist maintenance therapy in preterm labor: a meta-analysis. Obstet Gynecol 1995;85:313–7. [22] Sa´nchez-Ramos L, Kaunitz AM, Gaudier FL, Delke I. Efficacy of maintenance therapy after acute tocolysis: a meta-analysis. Am J Obstet Gynecol 1999;181:484–90. [23] Carr DB, Clark AL, Kernek K, Spinnato JA. Maintenance oral nifedipine for preterm labor:A randomized clinical trial. Am J Obstet Gynecol 1999;181:822–7. [24] Sayin NC, Varol FG, Balkanli-kaplan P, Sayin M. Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor. J Perinat Med 2004;32:220–4. [25] Gaunekar NN, Crowther CA. Maintenance therapy with calcium channel blockers for preventing preterm birth after threatened preterm labour. The Cochrane Library )2004;(3). [26] Lamont RF. Reply to King JF et al. Aust N Z J Obstet Gynaecol 2004; 44:275–6.
Nifedipine versus ritodrine for suppression of preterm labor Comparison of their efficacy and secondary effects Vicenc¸ Cararach a, Montse Palacio a,*, Sergi Martı´nez a, Pere Deulofeu b, Myriam Sa´nchez a, Teresa Cobo a, Oriol Coll a a
Institut Clı´nic de Ginecologia, Obstetrı´cia i Neonatologia, Hospital Clı´nic de Barcelona, Sabino de Arana 1, 08028 Barcelona, Catalonia, Spain b Hospital Municipal de Badalona, Badalona, Spain
Received 4 November 2004; received in revised form 11 October 2005; accepted 18 October 2005
Abstract Objectives: To compare the efficacy of nifedipine and ritodrine in prolonging pregnancy beyond 48 h, 1 week and 36.0 weeks and to evaluate maternal side effects and adverse perinatal outcome. Study design: Non-blinded, randomized controlled trial. Eighty patients with singleton pregnancies admitted for preterm labor with intact membranes between 22 and 35 weeks of gestation were included in the study. Preterm labor was defined as the persistence of at least two symptomatic uterine contractions within a 10 min period during 60 min after admission and despite bed rest. Results: Forty women received oral nifedipine and forty intravenous ritodrine. Two patients, one from each group, were excluded because of loss to follow-up after discharge. Therefore, 39 women in the nifedipine and the ritodrine groups, respectively, were evaluable for the final analysis. Baseline characteristics were comparable in both groups. The percentage of initial response, the speed of onset of action and the rate of successful treatment within 48 h were significantly better in the ritodrine group. However, prolongation of pregnancy beyond 7 days and 36 weeks of pregnancy was similar with a significantly lower rate of side effects in the nifedipine group. Conclusions: In this small trial, ritodrine provided more effective tocolysis within the first 48 h than nifedipine at the doses used in this study, although with a significantly higher rate of side effects. # 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Preterm labor; Tocolytics; Nifedipine; Ritodrine
1. Introduction Preterm delivery occurs in 7–9% of all births and has even increased recently [1]. Moreover, the most frequently associated condition with neonatal mortality and morbidity, excluding congenital malformations, is also preterm delivery. Neurological and sensorial deficiency rates are especially high in newborns of less than 31–32 weeks [2,3]. Although primary prevention would be ideal, the efforts in this direction have not been successful so far, probably because of multifactorial social, behavioral and biological etiology [4]. * Corresponding author. Tel.: +34 93 227 56 00; fax: +34 93 227 56 05. E-mail address: [email protected] (M. Palacio).
When preterm uterine contractions are present, but especially when cervical conditions are modified, it is essential to start treatment to postpone delivery unless there are signs of intrauterine infection or fetal distress. The most commonly used tocolytic agents are beta-adrenergic agonists. Meta-analyses have shown that beta-adrenergic agents, especially ritodrine, are associated with a postponement of delivery of 24, 48 h and 7 days. However, such a delay has not been associated with a significant reduction in either perinatal mortality or morbidity [5,6]. The great incidence of usually mild but potentially severe side effects of beta-sympathicomimetics has led to the search for better drugs. The oxytocin receptor antagonist, atosiban, appeared in the tocolytic scenario in the year 2000. Nonetheless, despite the clear advantage in the lack of relevant side effects
0301-2115/$ – see front matter # 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejogrb.2005.10.020
V. Cararach et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 127 (2006) 204–208
with its use, perinatal mortality and morbidity have not been modified with this new agent [7] and the high cost of this antagonist limits its widespread use. Therefore, financial costs must be taken into account, thereby restricting the use of atosiban to hemodynamic high risk patients and thus, justifying the wise use of other tocolytics. Nifedipine is a calcium-channel blocker drug (type II calcium blockers). It acts by reducing the intracellular entrance of calcium through the slow channel (or L type) producing an inhibition of contractile activity of nonpregnant, pregnant and postpartum myometrium. Nifedipine reduces the amplitude and frequency of contractions and the basal myometrial tone and is more active in pregnant than in non-pregnant women. The mean half-life in pregnant women is short (81 min) and, therefore, its effect is reversible. It was introduced as an antihypertensive drug but its hypotensive effect is mild in normotensive pregnant patients [8,9]. In the last 20 years many reports have evaluated the use and efficacy of nifedipine as a tocolytic agent. The latest systematic review includes 12 randomized controlled trials with a total of 1029 participating women. Ten compared its efficacy with ritodrine and all found nifedipine to be more effective than ritodrine in prolonging pregnancy beyond 7 days and much less likely to cause maternal side effects [10].
2. Materials and methods Pregnant women with singleton pregnancies admitted for preterm labor with intact membranes between 22 and 35 weeks of gestation were eligible for the study. Preterm labor was defined as the persistence of at least two symptomatic uterine contractions within a 10 min period during 60 min after admission and despite bed rest. Exclusion criteria were: cervix dilatation greater than 5 cm, polyhydramnios, fetal anomalies, signs of fetal distress, suspected intrauterine infection or growth restriction, contraindication for the use of beta-sympathomimetic drugs and previous treatment with tocolytics in the present gestation. Biochemical and hematological blood tests and an electrocardiogram were performed. Patients with a clinical contraindication for the use of beta-adrenergic drugs or nifedipine were excluded. Informed consent was obtained before randomization from eligible subjects. The study protocol was approved by the hospital’s Ethics and Research Committee. Women were allocated into two groups by opening a series of sealed, opaque, consecutively numbered envelopes that were sequentially selected. There was a 1:1 randomization ratio. Women were randomly assigned to receive either ritodrine or nifedipine. Clinicians were not blinded to the study group in which the women were allocated. Women assigned to the nifedipine group received an initial oral loading dose of 30 mg (10 sublingual and 20 mg
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oral) and a maintenance oral dose of 20 mg every 6 h. Treatment was discontinued if no uterine contractions occurred within a 48 h period [11]. Women allocated to the ritodrine group received an intravenous infusion at a rate of 100 mcg/min. The initial dose was increased 50 mcg every 20 min until uterine contractions were suppressed or intolerable side effects appeared or a limit dose of 350 mcg/min was achieved. The lowest effective tocolytic dose was maintained during 2 days, followed by oral therapy with a dose of 10 mg/6 h. After discharge, no maintenance tocolytic treatment was indicated. If uterine contractions reappeared, relapse was diagnosed and treatment was repeated as indicated above. Initial response was defined if uterine contractions were suppressed within 2 h of tocolytic treatment. Otherwise, treatment failure was considered and women received the drug indicated in the other study arm. If the second tocolytic was not effective, the woman was excluded from the analysis and indometacin was added. An ‘‘escape phenomenon’’ was considered on relapse of uterine contractions after their suppression before discontinuation of the treatment. In this case, an extra dose of 10 mg of sublingual nifedipine was added or ritodrine was increased as previously indicated. If contractions were not suppressed, a failure of treatment was considered and the patient was changed to the other treatment arm as referred above. Maternal blood pressure and heart rate were monitored every 20 min until a stable dose was achieved and every 4 h thereafter. Daily hydric balance was performed and blood parameters (cell blood count, glycemia, ionogram) and hepatic and renal function) were monitored every 24 h. Clinical signs and symptoms of intolerance to the drugs used were assessed every 6 h. Continuous fetal heart rate and uterine contraction monitoring was carried out during the first 12 h and until uterine contractions disappeared. Afterwards, fetal heart rate and uterine contractions were monitored every 12 h during hospital admission. At delivery, several neonatal parameters, such as weight, Apgar’s score, umbilical arterial and vein pH values and presence of hyperbilirrubinemia were determined. Neonatal complications such as hemorrhage or infections were recorded. Outcome measurements were successful tocolysis at 2 h, at 48 h and at 7 days. Prolongation of gestation from admission to hospital to delivery and the number of preterm deliveries before 36 weeks (252 days) of gestation were also assessed. The data collected were processed with Filemaker pro II for Macintosh database. Statistical analysis was performed using Stat View 512 for Macintosh. Differences were considered statistically significant when the p value was <0.05. For comparison of categorical variables the Chisquare test was used with Yate’s correction when appropriate. For comparison of mean values, the Student’s t-test for independent samples was used.
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Table 1 Characteristics of the study population
Maternal age (years) (mean (S.D.)) Parity (median (range)) Previous preterm delivery (n (%)) Gestational age (weeks.days) (mean (S.D.)) Bishop score (mean (S.D.))
Ritodrine, n = 39
Nifedipine, n = 39
p
26.2 (6.5)
26.9 (6.1)
NS
1 (0–3) 5 (12.8)
1 (0–3) 4 (10.3)
NS NS
32.1 (2.1)
32.2 (2.2)
NS
2.9 (1.9)
2.7 (1.8)
NS
3. Results Eighty patients were included in the study, 40 in each treatment group. Two patients were excluded, one from each group, because of loss to follow-up after hospital discharge. Therefore, 39 women in the nifedipine and the ritodrine groups, respectively, were evaluable for the final analysis. The excluded patients underwent successful tocolysis within 2 h. The characteristics of the two groups on admission are summarized in Table 1, with no significant differences being observed. The ‘‘escape phenomenon’’ was twice higher in the ritodrine group although differences did not reach statistical significance. The percentage of initial response, the speed of the onset of action (Table 2) and the rate of successful treatment within the first 2 days was better in the ritodrine group. However, the efficacy beyond 1 week and 36 weeks of gestation did not reach statistical significance (Fig. 1). The rate of adverse perinatal outcomes was similar, Table 2 Efficacy and perinatal outcome
Initial response (n (%)) Speed of onset of action (min) (mean (S.D.)) Escape phenomenon (n (%)) Overall response (n (%)) Gestational age at delivery (weeks.days) (mean (S.D.)) Prolongation of gestation (days) (mean (S.D.)) Birthweight (g) (mean (S.D.)) <2500 g (n (%)) Apgar score <7 at 5 min (n (%)) Respiratory distress syndrome (n (%)) Perinatal mortality (n (%)) Fetal death (n (%)) Neonatal death (n (%)) a
although the lack of power of the study does not allow strong conclusions on perinatal results to be drawn. There were no neonatal complications such as neonatal sepsis, necrotising enterocolitis or grade III or IV intraventricular hemorrhage. Two perinatal deaths were recorded in the ritodrine group: one was an antepartum fetal death at term of unknown origin and another was a neonatal death secondary to complications of an intracraneal teratoma non-diagnosed prenatally (Table 2). Most of the women receiving ritodrine reported side effects (76.9%) with severe tachycardia (>120 bpm) in 20% of all treated cases. Other side effects with a potential perinatal impact were hyperglycemia and hypokalemia observed in 30 and 20% of the cases, respectively. On the contrary, a lower rate of side effects was observed in the nifedipine group (20.5%, p < 0.001), being headache (10.3%), mild malleolar edema or rash and mild tachycardia or nausea the only relevant side effects (Table 3). Treatment was discontinued due to side effects in four patients in the ritodrine group but in no case in the nifedipine group.
Ritodrine, n = 39
Nifedipine, n = 39
p
37 (94.9) 35 (21)
29 (74.4) 62 (28.2)
0.012 0.002
9 (23.1) 28 (71.8) 36.1 (2.4)
6 (15.4) 25 (64.1) 36.2 (2.4)
NS NS NS
Table 3 Side effects observed with ritodrine and nifedipine
28 (21.6)
29.4 (25.1)
NS
2722 (676)
2870 (475)
NS
12 (30.8) 3 (7.7)
11 (28.2) 2 (5.1)
NS NS
3 (7.7)
2 (5.1)
NS
2 (5.1) 1 (2.6)a 1 (2.6)b
– – –
NS NS NS
Tachycardia Mild Severe Hyperglycemia Hypokalemia GPT elevation Nausea Anxiety Dyspnea Thoracic pain Edema Headache Rash or edema in lower limbs One or more side effects
Antepartum fetal death of unknown origin at term. Death after neonatal complications due to a prenatally non-diagnosed intracranial teratoma. b
Fig. 1. Prolongation of pregnancy beyond 48 h, 1 week and 36 weeks of gestation.
*
p < 0.001.
Ritodrine, n = 39, n (%)
Nifedipine, n = 39, n (%)
28 20 8 12 8 – 6 6 2 1 1 1 – 30
2 2 – – 1 1 2 – – – – 4 2 8
(71.8) (51.3) (20.5) (30.8) (20.5) (15.4) (15.4) (5.1) (2.6) (2.6) (2.6) (76.9) *
(5.1) (5.1)
(2.6) (2.6) (5.1)
(10.3) (5.1) (20.5)*
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4. Discussion The results obtained in our small study showed that ritodrine was more effective in the treatment of preterm labor than nifedipine during the first 2 days but the differences were not significant at 1 week and beyond 36 weeks. The better tocolytic effect of ritodrine within the first 48 h is apparently in contrast with the results observed in previous studies in which nifedipine showed a similar or even better efficacy than ritodrine. This may be explained by different reasons. Firstly, women with different baseline characteristics were included among different studies, which may explain some differences in the results. Four previous studies included patients with preterm premature rupture of membranes [12–15] and another included twin pregnancies [14,16] or patients who had previously received tocolysis [14]. In the present study, inclusion criteria were more restrictive and included only women with singleton pregnancies and intact membranes. Moreover, in our study the rate for preterm delivery before 36 weeks was 33 and 37% for the ritodrine and the nifedipine groups, respectively. In contrast, other authors [14,15] have reported a rate of preterm delivery before 34 weeks of between 44 and 77%, which is much higher, despite cervical conditions being comparable. These differences could be attributable to the fact that the population selected in our study was at a lower risk for preterm delivery before admission. The efficacy of nifedipine or ritodrine may be lower in women at high risk for preterm delivery. Secondly, the dosing used in the two arms of the study differed from that in other studies. The ritodrine regimen in the current study was, in general, higher than that reported in other studies. As expected, ritodrine produced a much higher incidence of side effects, and in four cases the medication had to be discontinued, whereas no patient in the nifedipine group required withdrawal. Our institution has lengthy experience in the use of ritodrine and in the monitoring of maternal hemodynamics. Early signs of pulmonary edema have usually been presented only in high-risk patients such as women with multiple pregnancies or pregestational diabetes. Since its introduction, we have used atosiban as the drug of choice for initial treatment in such cases. On the other hand, nifedipine was used at a much lower dose (maximum 80 mg/day) than that suggested by King et al. [10] (maximum of 160 mg/day) which has been used in other studies [14–17]. Dosing was chosen following available literature at the time the study was designed. Koks et al. [14] used an initial dose of 30 mg and later changed to 40 mg, Garcia-Velasco and Gonzalez [17] also used 30 mg as a loading dose and Papatsonis et al. [15] and Weerakul et al. [19] administered a maximum of 40 mg in the first hour. Because we had no experience with the use of nifedipine to treat preterm labor, we were cautious and we chose a maximum of 30 mg within the first hour. Well after our study was designed, in 2003 King et al. published a
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protocol recommending an initial dose of 20 mg plus 20 mg more after 30 min if tocolysis was not achieved and another 20 mg after 1 h if contractions were still present. This different dosage in our study may account for the greater effect observed within the first 48 h in the ritodrine group. However, the speed of onset of action would probably not change substantially because we were using a higher initial dose (30 mg). Compared with Papatsonis’ regimen of nifedipine [15], moderate doses were implemented in the design of our study with no possibility to increase the dosage when tocolysis was not effective enough or uterine contractions relapsed. We observed an increase in transaminases in one case in the nifedipine group while in none in the ritodrine group, detected by systematic control but without any clinical signs of hepatic disease. Indeed, the analytical abnormalities returned to the normal values after discontinuation of the treatment. Lastly, the possibility of submission or even publication bias must be taken into account. Considering that ritodrine has been widely used before the introduction of nifedipine as a tocolytic, the lack of studies on this issue is remarkable. Many clinical trials with drugs are not submitted because of negative or contrary to the expected results. This submission or publication bias may overestimate the beneficial effect of a drug if these effects are evaluated only considering published studies [18]. Interestingly, other studies with a similar number of patients have also observed that betaadrenergic drugs were more effective than nifedipine in postponing delivery beyond 48 h but the differences were not statistically significant [14,17,19]. The small number of patients included in these studies or a higher basal risk for preterm delivery of the women included (i.e. rupture of membranes or multiple gestation) which may limit the efficacy of tocolysis, may have prevented differences from being significant. Furthermore, the reduced number of cases also included in our study, may have limited the power to detect significant differences in prolonging pregnancy beyond 1 week. Since ritodrine may cause more side effects than nifedipine, it should be more effective than nifedipine to be recommended as a first-line tocolytic. Postponement of delivery beyond 48 h to allow corticosteroid treatment to be effective in order to improve neonatal morbimortality may be considered a valuable or significant benefit [20]. Indeed, the advantage of immediate response to the drug to allow an in utero transfer to a tertiary center has also been considered as relevant in the final outcome as outlined by King et al. [10]. In our study, the initial response and speed of the onset of action were significantly higher in the ritodrine group with an efficacy greater than 90% of the cases in the first 48 h. However, the ‘‘escape phenomenon’’ was also much higher in the ritodrine group. Although differences compared to the nifedipine group did not reach statistical significance, this may be due to the small number of patients included in the study. After 48 h of treatment, the ‘‘escape phenomenon’’ is increased due to a saturation of the
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myometrial receptors requiring progressive increase in the dosage leading to more severe secondary effects. In our study design, when the treatment was not effective in one arm or intolerable side effects appeared, the alternative drug was started despite the continued action of the other. Although this may be considered a limitation of the study because the treatment was not blinded and personal bias may have influenced the decision to change the drug, a potentiation of side effects was not observed, suggesting different mechanisms of action. This may also suggest the possibility of a combined regimen of these two drugs. The association of ritodrine with nifedipine may be of special interest because it allows the treatment to be maintained after 2 days with the same efficacy and fewer side effects. Although maintenance therapy with oral ritodrine has failed to demonstrate a significant prolongation of pregnancy [21,22], the role of maintenance therapy with calcium channel blockers is still not clear. More studies are needed to determine the efficiency and the safety of this association [23–25], especially in countries where the elevated cost of atosiban limits its use. However, the association of potential adverse effects must be taken into account. A final fact to be considered is that despite many reports on the use of nifedipine in pregnancy, this drug has never been licenced for its use in pregnancy. In the present worldwide context of legal litigation, this fact should also be kept in mind [26]. In conclusion, ritodrine provides more effective tocolysis within the first 48 h of preterm labor than nifedipine. This fact may support the use of this drug despite its side effects and thus, allow antenatal corticosteroids to be effective or an in utero transfer to a tertiary center to be made. However, close hemodynamic control is mandatory and it is necessary to exclude contraindications to the beta-adrenergic drugs. Although nifedipine was initially less effective than ritodrine in the first 2 days, similar perinatal results were obtained with a significantly lower rate of secondary effects than with ritodrine treatment. The possibility of combined therapy with these two drugs should to be evaluated.
Acknowledgment Supported by the FIS of Spanish Ministry of Health.
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