Atosiban and nifedipine in acute tocolysis: A comparative study

doi:10.1016/j.ejogrb.2005.12.010

European Journal of Obstetrics & Gynecology and Reproductive Biology

Volume 128, Issues 1–2, September–October 2006, Pages 129-134

https://doi.org/10.1016/j.ejogrb.2005.12.010 Get rights and content

Abstract

Objective

The objective was to compare the effectiveness, efficacy, and safety of atosiban and nifedipine in preventing or delaying premature labor.

Design

An interventional, randomized, controlled trial of 63 women experiencing preterm labor varying from 24 to 35 completed weeks of gestation. The women were randomized to receive either atosiban intravenously (group I, n = 31), or nifedipine orally (group II, n = 32).

Results

There were no significant differences in effectiveness and efficacy of tocolysis between the two groups. Women with a history of preterm labor responded significantly better to atosiban than those with no such history. Those at 28 weeks or less responded significantly better to nifedipine, while those at more than 28 weeks’ gestation showed an equal response in the two groups. Nifedipine achieved uterine quiescence in a significantly shorter time than atosiban. The maternal side effects were higher with nifedipine. Neonatal complications were comparable in both groups.

Conclusions

Both drugs are equally effective and efficacious in acute tocolysis. Subgrouping of patients according to gestational age and history of preterm labor may be applied in selecting the line of treatment. The maternal side effects were higher with nifedipine.

Introduction

Labor occurring prior to the completion of 36 weeks’ gestation is termed preterm labor (PTL) [1]. It is a continuing global obstetrical problem: 13 million babies are born prematurely each year [2]. This incidence remained static for many years and the explanation for this is that the management of PTL has changed very little over the past 30 years. It is the main cause of neonatal mortality and accounts for 69–83% of neonatal deaths [3], [4]. It also contributes to neonatal early-onset morbidity like respiratory distress syndrome (RDS), sepsis, jaundice, intraventricular hemorrhage, necrotizing colitis, as well as late-onset disabilities involving different nervous system abnormalities such as deafness, blindness, cerebral palsy, and low IQ [5].

The economic burden of PTL is tremendous. This comprises both immediate neonatal intensive care costs and the long term cost of the development of the infant through childhood and beyond [2], [4]. Neonatal mortality has declined, mostly due to improved management of very low birth weight babies rather than prevention of PTL, which has been largely unsuccessful so far. PTL still represents a major health care problem in both developed and developing countries [6].

As more information has become available about the exact biochemical steps taking place in uterine smooth muscle contractions, many tocolytic agents have been tried with variable tocolytic activity but for a short period of time and unfortunately disappointing results with regard to prevention of preterm labor.

Atosiban (Tractocil; Ferring Pharmacuticals, Copenhagen, Denmark) is an oxytocin antagonist, recently used in the treatment of PTL, it produces tocolysis by competing with oxytocin at its receptors without activation of those receptors. Nifedipine (Nippon; Kayako, Japan) on the other hand, is a calcium channel blocker inhibiting uterine contractions by preventing the influx of calcium ions inside the smooth muscle cells.

Section snippets

Patients and methods

Seventy-one pregnant women aged 18–35 years at 24–35 completed weeks’ gestation took part in the study. They all had preterm labor, as defined by Moutquin et al. (regular uterine contractions ≥4 per 20 min, each lasting 30 s, and cervical dilatation of 0–3 cm for nulliparous and 1–3 cm for multiparous with cervical effacement of 50%) [7]. All were singleton pregnancies with intact membranes.

Exclusion criteria were multiple pregnancy, ruptured membranes, medical and other obstetrical complications

Main outcome measurements

Efficacy and tolerability, which is the proportion of women who did not deliver and who did not require an alternative drug to achieve tocolysis or to avoid side effects 48 h and 7 days after the initiation of therapy. Effectiveness, which is the proportion of women who did not deliver 48 h and 7 days after initiation of tocolytic therapy, even when alternative therapy was used.

Maternal, fetal and neonatal side effects were recorded. Maternal and fetal tachycardia ≥120, ≥170 bpm, respectively [7],

Baseline characteristics

The baseline characteristics for the two groups were comparable, with no significant difference (Table 1).

Tocolytic outcome

There was no statistically significant differences between the two groups regarding tocolytic effectiveness and efficacy at 48 h and 7 days (Table 2).

The need for alternative drug (rescue treatment) was comparable in the two groups at 48 h and 7 days, although one woman from group II was lost to follow-up within the 7 days. Despite this, there was no statistically significant difference

Discussion

It is difficult to evaluate two tocolytic agents [13] for several reasons. Firstly, the diagnosis of preterm labor is difficult with different diagnostic criteria in different studies. The second difficulty is the variable etiology of PTL and that most PTL can only be partially explained. The third difficult point arises from the non-responders with rapid progression of labor [2], [14]. The fourth variable arises from patients with a partial or incomplete response who need an additional

Conclusion

Our results are encouraging for the continued use of atosiban and nifedipine in the treatment of PTL, as they were equally successful at arresting contractions in more than half of the cases. Maternal side effects, although not serious, were higher with nifedipine. Using clinical subgrouping criteria (history of PTL and gestational age), as suggested by this work, can help to select the line of treatment.

Acknowledgements

Thanks to all colleagues and nursing staff of the obstetric ward, labor room, and neonatal care unit of Baghdad Teaching Hospital for their generous help and cooperation with the research team. We are grateful to Ferring Pharmaceutical for supplying us with atosiban.

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Cited by (53)

Atosiban-induced acute pulmonary edema: A rare but severe complication of tocolysis
2023, Heliyon
Atosiban is commonly used to delay premature labor in pregnant women and is thought to have few side effects.
To report a case of acute pulmonary edema (APE) following administration of atosiban and conduct a systematic review to identify common characteristics and risk factors of atosiban-associated APE.
Searches were performed in Pubmed, Embase, and Web of Science using the keyword “Atosiban” combined with the terms “Pulmonary edema” or “Dyspnea” or “Hypoxia” on 9th July 2022. Only case reports of atosiban-associated APE were included without language restrictions. Data were extracted from the reports, and median, range, and percentages were calculated as applicable. The risk of bias was assessed using the Joanna Briggs Institute critical appraisal checklist for case reports.
Seven cases of atosiban-associated APE were included in the systematic review, including our case. APE occurred at a median gestational age of 32 + 6 weeks. Most patients were nulliparous (6/7, 85.7%) and were in multiple pregnancies (5/7, 71.4%). All patients were prescribed antenatal corticosteroids and tocolytics, with three (42.9%) receiving only atosiban and four (57.1%) receiving atosiban and other tocolytics. The median interval from starting atosiban administration to APE onset was about 40 h, and three patients (42.9%) showed symptoms 2–10 h after the end of atosiban treatment. Radiographic examinations (chest X-ray and/or computer tomography scan) confirmed APE in all patients and pleural effusion in four patients (57.1%). Five patients (71.4%) underwent emergency cesarean section, one patient (14.3%) with twin pregnancy had vaginal delivery with the help of suction cup and forceps, and another patient (14.3%) continued the pregnancy. All patients recovered well after administration of oxygen, diuresis, and other supportive therapy.
Atosiban may cause acute pulmonary edema in patients with underlying risk factors. This complication remains rare, but caution during tocolytic treatment using atosiban is recommended.
Tocolysis for preterm labor without premature preterm rupture of membranes
2016, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Analyser la littérature scientifique évaluant les bénéfices et risques des différentes molécules tocolytiques dans la menace d’accouchement prématuré, dans le but d’émettre des recommandations pour la pratique clinique.
Recherche bibliographique dans les bases de données Medline et Cochrane et les recommandations de sociétés savantes internationales. Il est important de noter que les études incluent généralement des femmes avec une menace d’accouchement prématuré avec et sans RPM.
Aucun tocolytique n’est associé à une diminution de la mortalité et de la morbidité néonatale par rapport au placebo (NP2). Comparée aux bêtamimétiques, la nifédipine est associée à une réduction significative du risque d’entérocolite ulcéronécrosante, d’hémorragie intraventriculaire et de syndrome de détresse respiratoire (NP2). Il n’y a pas de différence entre nifédipine et atosiban sur le pronostic néonatal, à l’exception d’une réduction modeste des transferts en néonatologie avec la nifédipine (NP2). Les bêtamimétiques, l’atosiban et la nifédipine ont une efficacité équivalente pour prolonger la grossesse au-delà de 48 heures (NP2). Comparée aux bêtamimétiques, la nifédipine réduit les accouchements avant 34 SA (NP2) et est associée à une prolongation de la grossesse plus longue (NP2). L’atosiban est équivalent à la nifédipine pour prolonger la grossesse de plus de 7 jours (NP2), mais en cas de menace d’accouchement prématuré sans rupture prématurée des membranes, la nifédipine réduit le risque d’accouchement avant 37 SA et est associée à une prolongation de la grossesse plus longue, sans toutefois de bénéfice néonatal démontré (NP2). Tous les tocolytiques peuvent engendrer des effets indésirables graves (NP4). Les effets indésirables maternels cardiopulmonaires décrits avec les bêtamimétiques entraînent des interruptions de traitement fréquentes (NP2) et sont parfois graves (décès maternels) (NP4). La tolérance maternelle de l’atosiban et de la nifédipine est supérieure à celle des bêtamimétiques (NP2). Les effets indésirables cardiovasculaires sont modérément augmentés avec la nifédipine comparée à l’atosiban (NP2), mais les taux d’interruption de traitement sont similaires (NP2). Compte tenu de leur bénéfice sur la prolongation de la grossesse et de leur bonne tolérance maternelle, l’atosiban et la nifédipine peuvent être utilisés à visée tocolytique (grade B) pour les grossesses monofœtales et multiples (accord professionnel). La nifédipine a l’avantage d’une administration per os et d’un coût peu élevé (accord professionnel). Il est recommandé de ne pas utiliser la nicardipine (accord professionnel), et de plus prescrire de bêtamimétiques à visée tocolytique (grade C). Il est recommandé de ne pas prescrire un traitement d’entretien à l’issue des 48 heures de tocolyse initiale (grade B). En cas d’échec du tocolytique de première intention, il est possible de tenter une tocolyse par la molécule non utilisée en première intention (accord professionnel). Il est recommandé de ne pas associer les molécules tocolytiques (grade C). En l’absence de données scientifiques, il n’est pas possible d’émettre de recommandation concernant la pertinence d’une deuxième tocolyse à distance d’une première chez une patiente de nouveau symptomatique et ayant reçu une cure complète de corticoïdes (accord professionnel). Il n’y a pas d’argument pour proposer une tocolyse à une dilatation avancée (grade C), ni pour prescrire une tocolyse au-delà de 34 SA (accord professionnel). Aucune donnée ne permet de définir un terme à partir duquel une tocolyse peut être réalisée (accord professionnel).
La nifédipine et l’atosiban peuvent être utilisés pour la tocolyse d’attaque (grade B), y compris pour les grossesses multiples (accord professionnel). Un traitement d’entretien est inutile (grade C) et potentiellement délétère (grade C). Les bêtamimétiques doivent être abandonnés dans cette indication (accord professionnel).
To propose guidelines for clinical practice for tocolysis in preterm labor without premature preterm rupture of the membranes (PPROM).
Bibliographic searches were performed in the Medline and Cochrane databases and gynecologist and obstetricians’ international society guidelines. It is important to note that most studies included women in preterm labour with and without PPROM.
Compared with placebo, tocolytics are not associated with a reduction in neonatal mortality or morbidity (LE2). Compared with betamimetics, nifedipine is associated with a reduction in necrotizing enterocolitis, intraventricular hemorrhage and respiratory distress syndrome (LE2). There is no difference between nifedipine and atosiban regarding neonatal prognosis, except a modest reduction in NICU transfer with nifedipine (LE2). Betamimetics, atosiban and nifedipine are equivalent to prolong pregnancy for more than 48 hours (LE2). Compared with betamimetics, nifedipine reduces delivery before 34 WG and is associated with a longer pregnancy (LE2). Atosiban and nifedipine are equivalent to prolong the pregnancy over 7 days (LE2), but in women with spontaneous preterm labour without PPROM, nifedipine reduces deliveries before 37 WG and pregnancy prolongation is longer, without improving neonatal prognosis (LE2). Maternal severe adverse effects may occur with all tocolytics (LE4). Betamimetics cardiovascular adverse effects are frequents (LE2) and may be serious (maternal death) (LE4). Nifedipine and atosiban reduce maternal adverse effect compared with placebo (LE2). Cardiovascular adverse effects are moderately increased with nifedipine compared with atosiban (LE2), without increasing treatment discontinuation (LE2). Regarding their benefits on pregnancy prolongation and good maternal tolerance, atosiban and nifedipine can be used for tocolysis in spontaneous preterm labour without PPROM (Grade B), for singleton and multiple pregnancies (Professional Consensus). Advantageously, nifedipine is orally taken and is inexpensive (Professional Consensus). Nicardipine should not be used for tocolysis (Professional Consensus) and betamimetics should not be prescribed anymore for tocolysis (Grade C). All tocolytic treatment should be prescribed for up to 48 hours (Grade B). In case of initial tocolysis failure, another treatment may be proposed with the other class of tocolytic (Professional Consensus). Different class of tocolytics should not be combined (Grade C). Scientific data are lacking to propose guidelines regarding a rescue tocolysis, after a first previous successful tocolysis with complete antenatal corticosteroid therapy (Professional Consensus). There is no scientific evidence to propose a tocolysis in women with advanced dilatation (Grade C), nor prescribe a tocolysis after 34 WG (Professional Consensus). There is no evidence to define a gestational age lower limit for tocolysis (Professional Consensus).
Nifedpine and atosiban can be used for tocolysis (Grade B), including for multiple pregnancies (Professional Consensus). Maintenance tocolysis is useless (Grade C) and potentially harmful (Grade C). Betamimetics should not be used for tocolysis (Professional Consensus).
Tocolysis and preterm labour
2016, The Lancet
Nifedipine versus atosiban for threatened preterm birth (APOSTEL III): A multicentre, randomised controlled trial
2016, The Lancet
Citation Excerpt :
The two other trials (n=80 and n=63) did not find a significant difference in the ability of either drug to delay delivery for 48 h.16,17 Salim and colleagues18 showed a shorter length of stay at the neonatal intensive care unit for babies from women in the nifedipine group as compared with those from women in the atosiban group. The two trials that reported on neonatal outcome did not show a significant difference, but were underpowered. 17,18 Evidence before this study
In women with threatened preterm birth, delay of delivery by 48 h allows antenatal corticosteroids to improve neonatal outcomes. For this reason, tocolytics are often administered for 48 h; however, there is no consensus about which drug results in the best maternal and neonatal outcomes. In the APOSTEL III trial we aimed to compare the effectiveness and safety of the calcium-channel blocker nifedipine and the oxytocin inhibitor atosiban in women with threatened preterm birth.
We did this multicentre, randomised controlled trial in ten tertiary and nine teaching hospitals in the Netherlands and Belgium. Women with threatened preterm birth (gestational age 25–34 weeks) were randomly assigned (1:1) to either oral nifedipine or intravenous atosiban for 48 h. An independent data manager used a web-based computerised programme to randomly assign women in permuted block sizes of four, with groups stratified by centre. Clinicians, outcome assessors, and women were not masked to treatment group. The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. Analysis was done in all women and babies with follow-up data. The study is registered at the Dutch Clinical Trial Registry, number NTR2947.
Between July 6, 2011, and July 7, 2014, we randomly assigned 254 women to nifedipine and 256 to atosiban. Primary outcome data were available for 248 women and 297 babies in the nifedipine group and 255 women and 294 babies in the atosiban group. The primary outcome occurred in 42 babies (14%) in the nifedipine group and in 45 (15%) in the atosiban group (relative risk [RR] 0·91, 95% CI 0·61–1·37). 16 (5%) babies died in the nifedipine group and seven (2%) died in the atosiban group (RR 2·20, 95% CI 0·91–5·33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups.
In women with threatened preterm birth, 48 h of tocolysis with nifedipine or atosiban results in similar perinatal outcomes. Future clinical research should focus on large placebo-controlled trials, powered for perinatal outcomes.
ZonMw (the Netherlands Organisation for Health Research and Development).
Adverse effects and hemodynamic effects of nifedipine as a tocolytic
2015, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Décrire les effets indésirables notamment cardiorespiratoires et les effets hémodynamiques de la tocolyse par nifédipine sur la mère et son fœtus.
Étude rétrospective évaluative descriptive analysant les dossiers des femmes traitées par nifédipine selon le protocole de tocolyse du CHU Sainte-Justine (Montréal, Canada) entre le 1^er janvier 2004 et le 1^er mars 2007. Les fréquences cardiaques maternelle et fœtale, la tension artérielle maternelle ainsi que les effets indésirables maternels répertoriés ont été colligés.
Des effets indésirables ont été retrouvés chez 61 % des 213 femmes traitées avec nifédipine et des effets indésirables cardiorespiratoires chez 32,4 %. Des effets indésirables cardiorespiratoires graves ont été notés chez 8,9 % des femmes, incluant 6 cas d’œdème aigu du poumon ou de surcharge pulmonaire. La moyenne des tensions artérielles maternelles systolique et diastolique était significativement diminuée et les moyennes des fréquences cardiaques maternelle et fœtale étaient significativement augmentées après la dose de charge de nifédipine. Des effets indésirables autres que cardiorespiratoires ont été observés chez 46,9 %.
La nifédipine est un tocolytique dont l’utilisation peut être associée à des effets indésirables cardiorespiratoires justifiant une surveillance étroite.
To describe maternal and fetal adverse effects, in particular cardiorespiratory, of nifedipine as tocolytic, as well as effects on hemodynamic parameters.
A retrospective evaluative study describing the use of nifedipine as tocolytic at CHU Sainte-Justine in Montreal. Demographic data as well as maternal blood pressure and adverse effects, and maternal and fetal heart rate were collected from medical records of women treated with nifedipine following our tocolysis protocol between January 1st 2004 and March 1st 2007.
The medical records of 213 pregnant women were included in the study. Cardiorespiratory adverse effects were noted in 69 (32.4%); of these, 19 (8.9%) had serious cardiorespiratory adverse events, including 6 acute pulmonary edema or overload. Mean maternal systolic and diastolic blood pressures were significantly decreased and mean maternal and fetal heart rates were significantly increased after the bolus dose. Other adverse effects were reported for 100 (46.9%) women.
Nifedipine may cause cardiorespiratory adverse effects warranting a close monitoring.
Efficiency and tolerance of calcium channel blockers as first-line tocolysis
2015, Journal de Gynecologie Obstetrique et Biologie de la Reproduction
Les inhibiteurs calciques sont largement utilisés à visée tocolytique en première intention, mais prescrits hors AMM dans cette indication. Cette revue de la littérature, dont l’objectif est d’évaluer l’efficacité et la tolérance des inhibiteurs calciques comparativement, d’une part, au placebo et, d’autre part, à tous les agents tocolytiques utilisés, concerne les essais randomisés, les études comparatives ainsi que les méta-analyses d’essais randomisés sur le sujet. La nifédipine est supérieure au placebo pour diminuer le risque d’accouchement dans les 48 h (RR = 0,3 ; IC95 % [0,21–0,43]) mais induit plus d’effets indésirables maternels (RR = 3,8 ; IC95 % [1,02–16,92]). L’efficacité de la nifédipine est supérieure à celle des bêtamimétiques pour prolonger la grossesse au-delà de 48 h (OR = 1,52 ; IC95 % [1,03–2,24]), et jusqu’à 34 SA (OR = 1,87 ; IC95 % [1,11–3,15]) avec une moindre incidence des effets indésirables nécessitant un arrêt du traitement en cas d’utilisation de la nifédipine (RR = 0,22 ; IC95 % [0,10–0,48]), mais sans différence significative sur la mortalité néonatale. L’efficacité de la nifédipine est similaire à celle des antagonistes de l’ocytocine pour prolonger la grossesse de 48 h (RR = 0,92 ; IC95 % [0,37–2,30]), mais entraîne plus d’effets indésirables maternels peu sévères (RR = 2,61 ; IC95 % [1,43–4,74]). La nicardipine est moins bien évaluée que la nifédipine en tant que traitement tocolytique. Elle semble aussi efficace que le salbutamol et semble présenter moins d’effets secondaires maternels que le salbutamol IV.
Calcium channel blockers are widely used as first-line tocolytic, but prescribed off-label for this indication. The primary objective of this review is to evaluate the efficiency and safety of calcium channel blockers compared to placebo and to all tocolytic agents used. This review concerns the randomized trials, comparative studies and meta-analyzes of randomized trials on the subject. Nifedipine is superior to placebo in reducing the risk of delivery within 48 hours (RR = 0.3; 95 % CI [0.21–0.43]), but induces more maternal side effects (RR = 3.8; 95 % CI [1.02–16.92]). The effectiveness of nifedipine is greater than that of betamimetics to prolong pregnancy beyond 48 hours (OR = 1.52; 95 % CI [1.03–2.24]), and up to 34 weeks (OR = 1.87; 95 % CI [1.11–3.15]), with a lower incidence of adverse events requiring discontinuation of treatment in case of use of nifedipine (RR = 0.22; 95 % CI [0.10–0.48]), but no significant difference in neonatal mortality. Efficacy of nifedipine is similar to that of oxytocin antagonists to prolong pregnancy beyond 48 hours (RR = 0.92; 95 % CI [0.37–2.30]), but causes more mild maternal adverse events (RR = 2.61, 95 % CI [1.43–4.74]). Nicardipine is not evaluated as nifedipine as a tocolytic treatment. It appears as effective as salbutamol and appears to have fewer maternal side effects than IV salbutamol.

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