Gestational age at delivery was significantly higher among the nifedipine group compared with the atosiban group, regardless of whether labor was initiated spontaneously or not (Table 4). The number of women delivered preterm, ie, less than 37 weeks of gestation, was significantly higher among the atosiban group (66.2%, 95% CI 54.4–76.6) as compared with the nifedipine group (43.2%, 95% CI 32.0–54.7, P=.007). The incidence of deliveries at less than 34 weeks of gestation did not differ significantly between the groups (Table 4).
Among the nifedipine group, 40 (53.3%, 95% CI 42.0–64.4) women used the assigned drug only (delivery was delayed for more than 48 hours without a rescue or dilatation progressed to more than 5 cm within 1 hour from enrollment) compared with 54 (77.1%, 95% CI 66.2–85.8) women among the atosiban group (OR 2.9, 95% CI 1.4–6.1, P=.003). Median gestational age at delivery within these pure groups was also higher among the nifedipine group (37.6 weeks, range 28.9–41.0 weeks) compared with the atosiban group (35.6 weeks, range 24.7–40.3 weeks, P=.02).
Kaplan-Meier survival analysis of the gestational age at birth showed that there was a statistically significant difference between the two treatment groups (Breslow P=.04). Median gestational age for women allocated to the nifedipine group was 37 weeks (95% CI 36.2–37.4) and 35 weeks (95% CI 34.1–35.6) for women allocated to the atosiban group (Fig. 2). Similar results were found when stratifying for gestational age at enrollment (P=.03).
The number of neonates admitted to the neonatal intensive care unit (NICU) and length of stay after delivery were significantly higher among the atosiban group as compared with the nifedipine group (Table 4). Overall, neonatal morbidity related to prematurity was comparable between the groups, although the incidence of respiratory distress syndrome and mechanical ventilation among singletons was more than double within the atosiban group as compared with the nifedipine group; however, this difference was not significant. There were no neonatal deaths in either study group (Table 5).
The present study was undertaken to compare the tocolytic efficacy and tolerability profile of nifedipine as compared with atosiban among pregnant women admitting with signs of preterm labor between 24 and 34 weeks of gestation. Atosiban was found to be superior to nifedipine in terms of the proportion of women who did not give birth and who did not require an alternate tocolytic agent within 48 hours from the initiation of therapy. In addition, atosiban was better tolerated by women compared with nifedipine. Both drugs were comparable in terms of the total number of women, in the intent-to-treat analysis, who did not deliver at 48 hours after enrollment. However, the proportion of women who had a singleton and enrolled at 28 weeks of gestation or more and who had remained undelivered at 7 days was significantly higher among the nifedipine compared with the atosiban group. Additionally, women assigned to nifedipine had a lower rate of preterm deliveries and delivered 1 week more than women assigned to atosiban. As a result, probably, more neonates in the atosiban group were hospitalized at the NICU and for a longer time. Furthermore, the incidence of respiratory distress syndrome and mechanical ventilation among singletons was more than two times greater within the atosiban group as compared with the nifedipine group, although this difference was not significant.
Preterm birth is responsible for approximately 75% of all neonatal deaths and 50% of childhood neurologic morbidities.9,10 It is also associated with both high immediate and long-term costs after discharge from the hospital.11 Postponing delivery for 48 hours to administer corticosteroids or to gain critical time to allow the transfer of women to a center with NICU facilities or both is the crucial goal to achieve with tocolytic drugs in cases of a threatening preterm delivery. Several agents have been used to inhibit uterine contractility, but it remains unclear what is the first-line tocolytic agent. Betamimetics reduce the rate of preterm delivery within 48 hours; however, maternal adverse effects are considerable.7 Magnesium sulfate has not been proven to be an effective tocolytic agent at delaying birth, and its use had been reported to be associated with an increased incidence of adverse effects and risk of neonatal mortality.12 Concerns regarding adverse effects of cyclooxygenase inhibitors on the fetal kidneys, ductus arteriosus, increased risk of neonatal intraventricular hemorrhage, and necrotizing enterocolitis have limited its use, especially at a gestational age above 30–32 weeks.2 Nifedipine and atosiban were found to be comparable to betamimetics and both were associated with significantly fewer maternal adverse effects as compared with betamimetics.7,8
Atosiban is currently licensed in Europe but not in the United States. As a result of its placebo-like maternal-fetal adverse effect profile, the Royal College of Obstetricians and Gynecologists suggested considering atosiban as a first-line tocolytic agent.2,8,13,14 On the other hand, several systematic reviews and meta-analysis confirmed that in addition to its comparable effect to betamimetics in delaying delivery for more than 48 hours, nifedipine reduced the incidence of preterm delivery, and more notably reduced neonatal morbidity, including respiratory distress syndrome and NICU admissions.7,15 Although nifedipine is not licensed as a tocolytic agent, the results of these meta-analyses and others brought some authors to suggest that nifedipine appears to meet several characteristics of an ideal tocolytic agent and may be considered a first-line tocolytic agent.15,16
In view of this, the question of which agent should be the first line, atosiban or nifedipine, is still a subject of controversy in many articles. A meta-analysis with an indirect comparison of nifedipine and atosiban showed that the former was associated with a nonsignificant increase in the number of women whose delivery was delayed for at least 48 hours and a significant reduction in respiratory distress syndrome compared with atosiban. Because biases may go along with results of a meta-analysis with an indirect comparison, the authors strengthen the need for better evidence from randomized trials directly comparing nifedipine and atosiban.17 Following the publication of this meta-analysis, two small, underpowered studies that compared the efficacy and safety of atosiban and nifedipine in preventing or delaying preterm labor were published. According to the results of both studies, the efficacy of both medications was the same, but adverse effects of nifedipine were significantly more than atosiban.18,19
In this study, atosiban as compared with nifedipine was found to be superior in terms of the proportion of women who did not deliver and who did not require an alternate agent within 48 hours after initiation of therapy. This effect was pronounced, particularly among women admitted at a gestational age of 28 weeks or more. Similar results regarding the inferiority of atosiban at less than 28 weeks of gestation were reported by others.1,19 This observation may be attributed to the fact that lower concentrations of oxytocin receptors are present at an earlier gestational age.20 In addition, the onset of preterm uterine contractions, particularly the very preterm, may involve other pathways that do not bring into play oxytocin.21 On the other hand, nifedipine as compared with atosiban was found to be associated with a higher mean gestational age at delivery, a lower incidence of preterm deliveries, and, probably accordingly, lead to a lower incidence of respiratory distress syndrome, NICU admissions, and a shorter length of stay. This effect was valid among women assigned to nifedipine regardless of whether they received nifedipine only or needed a rescue agent. Although both drugs were discontinued at 48 hours from enrollment, these repeated observations regarding the superiority of nifedipine may indicate that it probably has an additional long-acting effect that may involve other pathways in the pathophysiologic process of preterm birth beyond that achieved by impeding acute uterine contractions.
The limitations of the current study are worth mentioning. First, although we conducted a priori sample size calculation to ensure adequate power to examine the efficacy and tolerability of the tocolytic drugs, we may be underpowered to detect small differences in terms of secondary outcomes. Second, we did not use a third agent as a first rescue drug; rather, we chose to make a crossover between the study drugs. The decision was based on medical and ethical issues, because both study drugs are considered to have the greatest maternal and fetal safety profile compared with other medications.
The choice of the first-line tocolytic agent in terms of safety profile, efficacy, and costs is a topic of debate. An ideal tocolytic agent is supposed to delay delivery with minimal maternal and fetal adverse effects at low costs. None of the tocolytic medications available fulfills all these criteria. According to the current study, atosiban has fewer failures within 48 hours and probably a better maternal safety profile, both of which favor its use as a first line, particularly in cases in which maternal transport to a tertiary center is being planned or among women with cardiovascular disorders. On the other hand, the overall low incidence of maternal adverse effects associated with the use of nifedipine, the oral route of administration, low costs compared with atosiban, better effectiveness, and a possible efficacy in reducing neonatal morbidity favor its use as a first line, ie, the first agent to start with, among the remaining cases.
1. Romero R, Sibai BM, Sanchez-Ramos L, Valenzuela GJ, Veille JC, Tabor B, et al.. 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;182:1173–83.
2. Meloni A, Melis M, Alba E, Deiana S, Atzei A, Paoletti AM, et al.. Medical therapy in the management of preterm birth. J Matern Fetal Neonatal Med 2009;22(suppl):72–6.
3. Arias F, Tomich P. Etiology and outcome of low birth weight and preterm infants. Obstet Gynecol 1982;60:277–81.
4. Management of preterm labor. Practice Bulletin No. 127. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;119:1308–17.
5. Grimes DA, Nanda K. Magnesium sulfate tocolysis: time to quit. Obstet Gynecol 2006;108:986–9.
6. Mittendorf R, Pryde PG. A review of the role for magnesium sulphate in preterm labour. BJOG 2005;112(suppl):84–8.
7. Conde-Agudelo A, Romero R, Kusanovic JP. Nifedipine in the management of preterm labor: a systematic review and metaanalysis. Am J Obstet Gynecol 2011;204:134.e1–20.
8. Moutquin JM, Sherman D, Cohen H, Mohide PT, Hochner-Celnikier D, Fejgin M, et al.. 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;182:1191–9.
9. Slattery MM, Morrison JJ. Preterm delivery. Lancet 2002;360:1489–97.
10. Hack M, Dandruff AA. Outcomes of children of extremely low birthweight and gestational age in the 1990’s. Early Hum Dev 1999;53:193–218.
11. Petrou S, Mehta Z, Hockley C, Cook-Mozaffari P, Henderson J, Goldacre M. The impact of preterm birth on hospital inpatient admissions and costs during the first 5 years of life. Pediatrics 2003;112:1290–7.
12. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. The Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD001060. DOI: 10.1002/14651858.CD001060.
13. Usta IM, Khalil A, Nassar AH. Oxytocin antagonists for the management of preterm birth: a review. Am J Perinatol 2011;28:449–60.
14. Petraglia F, Visser GH. Prevention and management of preterm labour. J Matern Fetal Neonatal Med 2009;22(suppl):24–30.
15. 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.
16. Tsatsaris V, Papatsonis D, Goffinet F, Dekker G, Carbonne B. Tocolysis with nifedipine or beta-adrenergic agonists: a meta-analysis. Obstet Gynecol 2001;97:840–7.
17. Coomarasamy A, Knox EM, Gee H, Song F, Khan KS. Effectiveness of nifedipine versus atosiban for tocolysis in preterm labour: a meta-analysis with an indirect comparison of randomised trials. BJOG 2003;110:1045–9.
18. Kashanian M, Akbarian AR, Soltanzadeh M. Atosiban and nifedipin for the treatment of preterm labor. Int J Gynaecol Obstet 2005;91:10–4.
19. 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;128:129–34.
20. Fuchs AR, Fuchs F, Husslein P, Soloff MS. Oxytocin receptors in the human uterus during pregnancy and parturition. Am J Obstet Gynecol 1984;150:734–41.
© 2012 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
21. Cole RM, Lamont RF. Current perspectives on drug treatment for preterm labour. J Obstet Gynaecol 1998;18:309–14.