Efficacy of Oxytocin Receptors Antagonist, Magnesium Sulfate and Calcium Channel Blockers in Treatment of Preterm Labour

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1 Med. J. Cairo Univ., Vol. 84, No. 1, June: , Efficacy of Oxytocin Receptors Antagonist, Magnesium Sulfate and Calcium Channel Blockers in Treatment of Preterm Labour SHERIN A. SHAZLY, M.D. The Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University, Egypt Abstract Objective: The purpose of this study is to compare between Atosiban acetate and magnesium sulphate and calcium channel blocker as short-term tocolytic agents for managing preterm labor. Study desine: Randomized comparative single-blinded trial. Methods: In this study, one hundred forty pregnant women were recruited. They were admitted with threatened preterm labor on attending the Obstetrics and Gynecology Emergency Department of Zagazig University Hospital (N=140). They divided into three groups, atosiban group 20 cases, nifedipine group 60 cases, magnesium sulfate group 60 cases, each group receive initial dose then maintenance dose till cessation of uterine contractions. We estimate pregnancy prolongation on 48 hours and 7 days and also the maternal and fetal side effects reported in each group. Results: The result of the current study showed no significant difference between the three groups as regard pregnancy prolongation but there is statistically significant difference between the three groups (p-value <0.05) as regards neonatal outcome except apnea and no statically difference as regard intrauterine fetal side effects and there is statistically significant difference between the three groups (p-value <0.05) for all maternal side effects except dyspnea and absence of symptoms. Conclusion: We concluded that atosiban, magnesium sulphate, and nifedipine had the same efficacy in preventing preterm laboure with better patient compliance to nifedipine as it is oral drug and it had the least fetal and neonatal adverse effect. Key Words: Preterm labour Atosiban acetate Magnesium sulphate Calcium channel blocker. Introduction PRETERM birth is the most important determinant of adverse infant outcome, in terms of both survival and quality of life. It is, defined as delivery occurring between 20 and 36 completed weeks gestation and it is a major cause of perinatal mortality and Correspondence to: Dr. Sherin A. Shazly, Sherinshazly73@gmail.com morbidity. The rate of preterm birth is increasing specially in developing countries, affecting 8.6% of births in developed countries and between 7.4% to 13.3% in developing countries [1]. Numerous possible adverse neonatal consequences of PTL include neonatal deaths, respiratory distress syndrome, chronic lung disease, sepsis, Intraventricular Hemorrhage (IVH), cerebral palsy and other forms of neuro-developmental impairment [2]. Hypothermia, hypoglycemia, patent ducts arteriosus, jaundice [3]. The costs to the parents, community and society as a whole, both economic and emotional, are substantial [4]. A variety of risk factors contribute to the occurrence of PLT; mainly infections. Others include uterine malformation, antepartum hemorrhage, fetal congenital anomalies, cervical incompetence, Premature Rupture of Membranes (PROM) and maternal medical problems [3]. While the cause of spontaneous preterm birth is often unclear, some risk factors have been identified including: Maternal age (adolescence and advanced age); history of preterm birth; multiple pregnancy, short interpregnancy interval; infections; medical conditions; poor nutrition; psychological factors and genetic predisposition [5]. Despite improvements in the standards in obstetric and neonatal care over recent years, no progress has been made over the last two decades in reducing the incidence of preterm birth in developed countries. In fact, rates of preterm birth are rising, in part due to increasing obstetric intervention [5,6]. Prevention and treatment of PTL is important as a means of reducing adverse neonatal outcome [7] short-term tocolytic therapy is commonly used to inhibit preterm labour and postpone preterm birth to diminish fetal morbidity and mortality [8]. The chief use of short term tocolysis is to suppress preterm labor for at least 48 hours as for allowance of corticosteroid therapy, thus promoting fetal lung maturity [9], to transfer to a centre with highly qualified neonatal intensive care 609

2 610 Oxytocin Receptor Antagonist, Calcium Channel Blocker, Magnesium Sulfate, Preterm Labour facilities [10] and magnesium sulphate administration to minimize the risk of cerebral palsy [11]. Acute tocolysis have been advocated for a variety of indications including in utero transfer, management of intrapartum fetal distress, and to facilitate external cephalic version at term. Wide varieties of agents have been advocated for suppressing uterine contractions. Those in current use include beta adrenergic receptor agonists (ritodrine, terbutaline, salbutamol), magnesium sulphate, calcium channel blocker (nifedipine), prostaglandin synthetase inhibitors (indomethacin, celoxib, hexoprenaline), nitric oxide donors (glyceryl trinitrate), and oxytocin receptor antagonists [3]. Cyclo-Oxygenase (COX) inhibitors [12] and progesterone [13], and their relative effects have been explored in a recent network meta-analysis [14]. The betamimetics, arguably the most commonly used tocolytics, have been shown to be effective in delaying delivery by seven days and longer, although no impact has yet been shown on perinatal mortality [15]. If a tocolytic drug is to be used, ritodrine no longer seems the best choice. Atosiban or nifedipine appear preferable as they have fewer adverse effects and seem to have comparable effectiveness [16]. Aim of the study: The purpose of this study is to compare between atosiban acetate and magnesium sulphate and calcium channel blocker as short term tocolytic agents for managing preterm labor. Patients and Methods Study design: Randomized comparative singleblinded trial. Method of randomization: Closed enveloped method. Sample size: Was detected according to salim et al., [ 17]. In this study one hundred forty pregnant women were recruited. They were admitted with threatened preterm labor on attending the Obstetrics and Gynecology Emergency Department of Zagazig University Hospital, from June 2013 to June Patient selection was based on fulfilling diagnostic and inclusion criteria. Target population: Pregnant women who attended the emergency delivery ward and who were diagnosed to have threatened preterm labor in the gestational age range of 24 to 34 completed weeks, with the following diagnostic criteria: Regular uterine contractions of at least 30 seconds duration at a rate of four or more per 30 minutes, cervical dilation of 1-3cm for multiparas, and 0-3cm for nulliparas, cervical effacement of 50 per cent or more, cervical length (from internal cervical os to external os) less than 2.5 centimeters. Inclusion criteria also included: Age years (child bearing period), gestational age from 24 until 34 completed weeks, normal fetal heart rate, singleton, cephalic pregnancies. Exclusion criteria: Inevitable preterm labor, gestational age below 24 or over 34 completed weeks, premature rupture of membranes or evidence of chorioamnionitis, abnormal fetal heart rate, intrauterine growth restriction or intrauterine fetal death, congenital anomalies, antepartum hemorrhage, eclampsia and severe pre-ecla-mpsia, known hypersensitivity to active substance, any other conditions concerning the mother or fetus, in which continuation of pregnancy was hazardous. All patients were subjected to the following: Written informed consent to participate in the study complete medical history, including personal, menstrual, obstetrical, present, past and family history, physical examination, including an initial general examination, obstetrical examination (fundal level and fundal grips) and a vital signs measurement on hourly basis, complete laboratory assessment, Including CBC, PT, and PTT, random blood sugar, liver enzymes (SGOT and SGPT), serum creatinine and LDH, urine analysis and culture if needed, Pelvi-abdominal ultrasound for assessment of gestational age, biophysical profile, and Doppler of umbilical artery. Trans-vaginal ultrasound for assessment of cervical length, fetal monitoring on hourly basis using cardio-tocography, participants were subdivided randomly in three groups: Group (A): Atosiban group, Group (B): Magnesium sulphate group, Group (C): Nifedipine group. In Group (A), 20 patients received Atosiban acetate (Tractocile) in three successive stages. An initial intravenous bolus dose (6.75mg) administered in one minute using tractocile 7.5mg/ml solution in a 0.9ml injection. This is was immediately followed by a continuous high dose infusion (2 X 5ml of tractocile 7.5mg/ml concentrate for solution for infusion) added to a 90ml ringer lactate solutiona total of 100ml in the infusion bottle-was received by the each patient over three hours utilizing a loading infusion micrometer at a rate of 300 µg/min. For patients who did not achieve complete cessation of uterine contractions by the end of the second stage, a lower dose of tractocile 7.5mg/ml concentrate for solution for infusion in a new 100ml infusion bottle was prepared as previously mentioned (subsequent infusion 100 µ g/min utilizing a micrometer), was employed and sustained for 2 hours after complete cessation of uterine contractions. Duration of treatment was assured not to

3 Sherin A. Shazly 611 exceed a total of 48 hours. The total dose given during a full course of therapy also did not exceed 330mg. Intravenous therapy using the initial bolus injection was started as soon as possible after the diagnosis of preterm labor. The intravenous treatment was maintained for 2 hours after cessation of contractions. Alternative therapy was considered in the case of persistent uterine contractions or treatment discontinuation due to intolerance of undesirable drug side effects. In Group (B), 60 patients received 4gm intravenous magnesium sulphate infusion in a 200ml ringer lactate solution over an initial phase of 20 minutes, with a dose of 0.20mg/minute. Maintenance dosage was 2g/hour until the desired result of tocolysis was obtained or a maximum total maintenance dose of 24g. The intravenous maintenance treatment was sustained for 2 hours after complete cessation of contractions. Alternative therapy was considered in the case of persistent uterine contractions or treatment discontinuation due to intolerance of undesirable drug side effects. In Group (C), 60 patients received CCB nifedipine. Initial dose of 10mg oral capsule. Additional 10mg dose oral capsule given with no subsidence of contractions after 20mins and repeated every 20mins until contractions subsided with a maximum dose of 40mg within the first hr. 20mg oral nifedipine administered every 4hrs after uterine activity subsided and continued up to 48hrs. Alternative therapy was considered in the case of persistent uterine contractions or treatment discontinuation due to intolerance of undesirable drug side effects. All patients were subjected to the following: Complete bed rest, prophylactic broad-spectrum antibiotic therapy; in order to prolong latency and as for a tryout to improve perinatal outcome [18], corticosteroids (dexamethasone sodium sulphate 12mg-intramuscular injection/12 hours for two doses) for enhancement of fetal lung maturation [19]. Comparative assessment between atosiban, magnesium sulphate, and nifedipine was done in terms of the following: Pregnancy prolongation (in 48 hours and in a 7 day interval), drug side effects (maternal, fetal, and neonatal). Statistical analysis: On statistical data processing, analyses was done using Microsoft Excel Software. Data were then imported into Statistical Package for the Social Sciences (SPSS version 20.0) software for analysis. According to the type of data qualitative represent as number and percentage, the chi square test was used to calculate p-value and was set at <0.05 for significant results and <0.001 for high significant result. Sample size: Was detected according to salim et al., 2012 [17]. Results A total of 140 pregnant women matching both the diagnostic and the inclusion criteria of PTL were enrolled in this study. The patients were allocated randomly into three groups: Atosiban group, magnesium sulphate group, and nifedipine group. As a primary endpoint; our comparative measurement was for the proportion of women undelivered without the use of alternate tocolytic after 48 hours and similarly for seven days. Secondary endpoints were maternal, fetal, and neonatal side effects of the three treatment arms encountered in this study. No statistical difference was obtained concerning the personal data between the three groups (Table 1). No statistically significant difference was evidenced concerning patients undelivered till 48 hours between the three groups and also no statistically significant difference was noted concerning patients undelivered till 7 days as for the three drug groups (Table 2). The relation between tocolytic administration and symptoms and signs of maternal side effects in the three drug groups. Chest pain showed statistically significant difference between the three groups ( p<0.01 and more in MgSo 4 group, nausea, and vomiting showed a high statistically significant difference which was found to be in favor of the nifedipine group p-values 0.000, headache and flushing more in nifedipine group with highly significance difference between the studied groups, while palpitation is less in atosiban group with the p-value <0.014, dyspnea as a complaint showed no statistically significant difference was found. Concerning absence of associated symptoms, no statistically significant difference was found. All the maternal signs, tachycardia, hypotension, hyperglycemia, hypokalemia and no signs showed highly significance difference between the studied groups which all in favor nifedipine group with p-value <0.000 except tachycardia which was less in atosiban group with the p-value <0.029 (Table 3). Regarding the fetal side effects there was no statistically significant difference between the three drug groups was documented concerning fetal side effects. But regarding the neonatal hypotension, and respiratory distress syndrome, neonatal bradycardia and incubation there were statistically significant among the three drug groups. The respective p-values were 0.051, 0.036, and And insignificant difference was found as regard neonatal apnea. Comparing the neonatal outcomes on commencing atosiban, MgSo 4, and nifedipine counterparts evidenced that in general; nifedipine significantly had the least neonatal side effects among the three drug arms of this study (Table 4).

4 612 Oxytocin Receptor Antagonist, Calcium Channel Blocker, Magnesium Sulfate, Preterm Labour Table (1): Frequency distribution of personal data of the studied patients in the atosiban, magnesium sulphate and nifedipine groups (n=140). Variables Maternal age: Atosiban (n=20) MgSo4 Nifedipine N % N % N % p- value Parity: PG MG Gestational age (weeks): Personal data Occupation: Working Housewife Adverse maternal lifestyle factors of medical importance: Tea or/and coffee Smoking None Table (1) showed No statistical difference was obtained concerning the personal data between the three groups. Table (2): Frequency distribution of the studied patients according to relation between tocolytic administration and pregnancy prolongation in the atosiban, magnesium Sulphate and nifedipin groups (n=140). Variables Pregnancy prolongation: Atosiban (n=20) MgSo4 Nifedipin N % N % N % p- value Delivered before 48 hours Undelivered till 48 hours Undelivered till 7 days *: There is no statistically significant difference between the three groups.

5 Sherin A. Shazly 613 Table (3): Frequency distribution of the studied patients according to relation between tocolytic administration and symptoms of maternal side effects in the atosiban, magnesium sulphate and nifedipin groups (n=140). Maternal side effects Atosiban (n=20) MgSo4 N % N % N % Nifedipin p- value Symptoms: Chest pain * Dyspnea Palpitation * Nausea * Vomiting * Headache * Flushing * None Signs: Tachycardia * Hypotension * Hyperglycemia * Hypokalemia * None * *: There is statistically significant difference between the three groups ( p-value <0.05) for all maternal side effects except dyspnea and absence of symptoms. Table (4): Frequency distribution of the studied patients according to relation between tocolytic administration and fetal side effects in the atosiban, magnesium sulphate and nifedipine groups (n=140). Fetal side effects Atosiban (n=20) MgSo4 N % N % N % Nifedipin p- value Fetal distress: Persistent bradycardia Persistent tachycardia Non-reactive cardiotocography Neonatal side effects: Apnea Bradycardia * Hypotension * RDS * Incubation * *: There is statistically significant difference between the three groups ( p-value <0.05) as regards neonatal outcome except apnea and no statically difference as regard intrauterine fetal side effects. Discussion No statistical significance was documented in our study regarding pregnancy prolongation. A good agreement is established with Coomarasamy et al. [20], who stated that oxytocin antagonists appear to be effective and safe for tocolysis in preterm labor. He added that meta-analysis in his study showed that atosiban when compared to with placebo-beta-agonists was used in his study-had increased the proportion of women undelivered by 48 hours, but, did not reach statistical significance. The British Journal of Obstetrics and Gynecology, [21] affirmed that the proportion of women neither delivered nor required alternative tocolytic therapy within 48 hours and 7 days of initiation of therapy with atosiban was 76.6% and 61.1% respectively. This again perfectly matches the 70% obtained in this study concerning withholding delivery for 48 hours. Coomarasamy et al. [22], concluded that nifedipine was associated with a significant reduction in respiratory distress syndrome compared with atosiban (OR 0.55, 95% CI ). It also increased the number of women whose delivery was delayed by 48 hours (OR 1.20, 95% CI ), although this result was not statistically

6 614 Oxytocin Receptor Antagonist, Calcium Channel Blocker, Magnesium Sulfate, Preterm Labour significant and this not with our results. Veronica et al. [23], stated in his study that patients who commenced atosiban showed a significant difference in the proportion of patients that had not delivered nor had required an alternative drug 7 days after treatment in (64.3%). However, these figures concerning the seven days delay were significantly different from that in our study, where no statistically significant difference was observed in patients undelivered till 7 days as that for atosiban was only (20%), that for MgSo 4 were (23.3%), and that for nifedipine was (40%). The ACOG [24], stated that from their systematic review, there were no statistically significant differences between magnesium sulphate and a placebo to prolong pregnancy. The disagreement with this statement is evident as for the 48 hours delay according to the former magnesium sulphate results in our study. On the other hand, our results in relation to the seven days delay agree with this ACOG statement concerning the statistical insignificance. There was no difference between the groups over the course of the study done by Sedigheh and Fatemeh [25], in demographic characteristics, cervical examination and amniotic fluid index. Labor was arrested for 48 hours in 42 (81%) and 45 (87%) of the patients in the celecoxib and magnesium sulfate groups respectively ( p-0.298). He concluded that celecoxib is as effective as magnesium sulfate for primary tocolysis. In 15 comparative trials, magnesium sulfate was neither more nor less effective than other tocolytics Mercer and Merlino [26], for delivery within 48 hours of initiation of treatment, summary risk ratios were: Magnesium versus beta-adrenergic agonists (RR 1.23, 95% CI ), versus calcium channel blockers (RR 1.06, 95% CI ), versus cyclooxygenase inhibitors (RR 0.84, 95% CI ), and versus any control (active or placebo) (RR 0.90, 95% CI ). These comparative trials must be interpreted with caution since they were not designed as equivalence trials, and thus, are inadequately powered to evaluate the equivalence of magnesium sulfate to other tocolytics. No statistically significant difference was found. Atosiban has been shown to have similar efficacy in preventing preterm labor when compared to betamimetics but with reduced maternal side effects in a multiple centre, double-blind, placebo controlled trial (Moutquin et al., [27] ). Dwight et al. [28], stated that adverse events, such as flushing or sweating, were more frequent in the magnesium sulfate group than the placebo group. However, there were no life-threatening events or maternal deaths in either group. Magnesium sulfate causes fewer minor maternal side effects than beta- adrenergic agonists, but the risk of major adverse risk events is comparable. Macones et al. [29], found that diaphoresis and flushing are the most common side effects; magnesium toxicity is related to serum concentration. Husslein et al. [30], supported the use of atosiban to delay preterm birth and are consistent with previously conducted, randomized, controlled trials. Atosiban was associated with fewer maternal and fetal adverse events compared with other tocolytics, and presented no safety concerns for either the mother or the unborn baby. Husslein [31], found that 88.9% of the patients given atosiban as a tocolytic in his study suffered no maternal and fetal adverse events. He concluded that atosiban is effective for the delay of spontaneous preterm labor and presents no safety concerns irrespective of the time it is administered. Results of this study demonstrate a good agreement with Richter et al. [32], who stated that atosiban is better tolerated than the beta2-agonists, particularly with regard to the cardiovascular side effects. He added that in clinical studies, significantly more patients initially randomized to beta2-agonists required an alternative tocolytic due to adverse effects (mainly cardiovascular) than those patients initially randomized to atosiban. Moutquin et al. [33], stated that maternal cardiovascular side effects was substantially lower in the atosiban group (4.0% versus 84.3%, p<.001). In addition, intravenous therapy was terminated more frequently as a result of maternal adverse events in the ritodrine group (29.8%) than in the atosiban group (0.8%). Adverse events occurred in 7.9% of atosiban users versus 70.8% of ritodrine users (Sandra,) [34]. The ACOG practice bulletin [24], declared that if tocolytic drugs are used, the choice of drug should be individualized and based on maternal condition, potential drug side effects, and gestational age. Additionally, beta-mimetics, magnesium sulphate, and calcium channel blockers are all associated with an increased risk of pulmonary edema. Our results agree with Lumbiganon [35], who stated in his report that there were higher rates of minor maternal side-effects in the magnesium sulfate groups, but no significant increase in maternal complications was observed. However, nifedipine was associated with fewer maternal adverse effects than magnesium sulphate (Deirdre et al., [36] ) magnesium sulfate is safe only within a narrow dosage range and overdose can cause serious complications, including respiratory depression and cardiac arrest in the mother. One large study performed by Altman et al. [37], has reported that administration of magnesium sulfate using a strict protocol did not lead to a greater frequency of

7 Sherin A. Shazly 615 complications compared with placebo, even in under-resourced settings. In our study no statistically significant difference between the three drug groups was documented concerning fetal side effects. This was opposing to the U.S. Food and drug administration approval for atosiban use to arrest PTL was denied because of concerns regarding efficacy and fetal-newborn safety (Kenneth et al. [38]). The nil score recorded in our results concerning fetal mortalities in association to tocolytic administration disagree with the study of Romero et al. [39], was not intended to demonstrate an effect on neonatal morbidity or mortality but there was a higher fetal-infant death rate in the atosiban with or without rescue group (13/288) than in the placebo with or without rescue group (5/295). The reason for this may have been the higher rate of very early preterm labor patients allocated to atosiban (24 and 13 women <26 weeks in the atosiban and placebo groups, respectively). It is perhaps surprising that only around 50% of patients entered into the trial received corticosteroids and this may have reduced the benefits of tocolysis. The tocolytic efficacy (determined as the time from study drug administration to delivery or therapeutic failure) was not significantly different in the placebo and atosiban groups but this could be explained by the availability of tocolytic rescue in the placebo group. In this study, our resultsconcerning fetal demise rates only-agree with Moutquin et al. [27], who stated that fetal and neonatal effects were also determined in his comparative study, however, clinically important differences were not demonstrated. There were no fetal deaths and a total of three neonatal deaths, two of which occurred in the atosiban group. These were judged by the investigators to be unrelated to study drug and all were under 26 week's gestation. The United States Food and Drug Administration declined to approve the use of atosiban for tocolysis because of concerns about the drug's safety when used in fetuses of less than 28 weeks of gestation ( [40]. It is available for clinical use in Europe. According to our results, we disagree with these concerns. Maternal therapy with magnesium sulphate causes a slight decrease in baseline fetal heart rate and fetal heart rate variability, which are not clinically significant (Twickler et al. [41]). Antenatal fetal assessment test results (e.g., biophysical profile score and nonstress test reactivity) are not significantly altered. The insignificance recorded in our results matches this saying. Our results concerning match that of a Cochrane review six trials in 2005 (Papatsonis et al. [42] ) showed that atosiban did not improve the neonatal outcome as compared with placebo. Moutquin et al. [33], confirmed that neonatal morbidity was similar between the two treatment arms atosiban and ritodrine. It was apparently related to the gestational age of the infant rather than to the exposure to either tocolytic agent. Moreover, the risk of total pediatric mortality was significantly higher for infants exposed to magnesium sulfate (relative risk 2.8; 95% confidence interval ) (David et al. [43]). Patients who received magnesium sulfate achieved the primary outcome more frequently than nifedipine. However, delay of delivery, gestational age at delivery, and neonatal outcomes were similar between groups (Deirdre et al. [36] ). In Cochrane meta-analysis by Flenady V. et al. [44], this update includes 26 additional trials involving 2511 women, giving a total of 38 included trials (3550 women). Thirty-five trials used nifedipine as the CCB and three trials used nicardipine. Blinding of intervention and outcome assessment was undertaken in only one of the trials (a placebo controlled trial). However, objective outcomes defined according to timing of birth and perinatal mortality were considered to have low risk of detection bias. Authors' conclusions in this metaanalysis was that Calcium channel blockers (mainly nifedipine) for women in preterm birth have advantage, over placebo or no treatment in terms of postponement of birth thus, theoretically, allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer-term outcomes were limited. Our results agreed with this review in some results and in contrary with other results. Another review update by Flenady V. et al. [45], includes eight additional studies (790 women), giving a total of 14 studies involving 2485 women concerning oxytocin receptor blokers. Authors' concluded that This review did not demonstrate superiority of ORA (largely atosiban) as a tocolytic agent compared with placebo, betamimetics or CCB (largely nifedipine) in terms of pregnancy prolongation or neonatal outcomes, although ORA was associated with less maternal adverse effects than treatment with the CCB or betamimetics. The finding of an increase in infant deaths and more births before completion of 28 week of gestation in one placebo-controlled

8 616 Oxytocin Receptor Antagonist, Calcium Channel Blocker, Magnesium Sulfate, Preterm Labour study warrants caution. However, the number of women enrolled at very low gestations was small. Due to limitations of small numbers studied and methodological quality, further well-designed randomised controlled trials are needed. Further comparisons of ORA versus CCB (which has a better side-effect profile than betamimetics) are needed. Consideration of further placebo-controlled studies seems warranted. Future studies of tocolytic agents should measure all important short-and long-term outcomes for women and infants, and costs. The balance of evidence indicates that atosiban is as effective as nifedipine and more effective than beta-agonists and is significantly safer than both. Atosiban was developed specifically to treat preterm labor, so the cost is higher than nifedipine or ritodrine. However, the cost of a course of atosiban (approximately 200 pounds) should not only be considered in comparison with other tocolytic agents but to other medical budgets (e.g., oncology, fertility, cardiology and psychiatry) and to the huge healthcare costs associated with the morbidity and mortality caused by preterm birth. Atosiban is a new advance in the management of spontaneous preterm labor (Jens and Ronald) [46]. The Royal College of Obstetricians and Gynaecologists "Green Top Guidelines" in 2002 stated that when a tocolytic is required, nifedipine or atosiban (an oxytocin receptor antagonist) should be used as the preferred first line tocolytic agent, in preference to betamimetics (clinical guideline No. 1 (B), 2002). If a tocolytic drug is to be used, ritodrine no longer seems the best choice. Atosiban or nifedipine appear preferable as they have fewer adverse effects and seem to have comparable effectiveness. Atosiban is licensed for this usage in UK but nifedipine is not (RCOG Clinical Guideline 1B) [16]. Conclusions: We concluded that atosiban, magnesium sulphate, and nifedipine had the same efficacy in preventing preterm laboure with better patient compliance to nifedipine as it is oral drug and it had the least fetal and neonatal adverse effect. Conflict of interest: No conflict of interest. References 1- WHO: Eds. HOWSON C.P., KINNEY M.V. and LAWN J.E.: Born Too Soon: The Global Action Report on Preterm Birth. Geneva: World Health Organization, GLADSTONE M., NEILSON J.P., WHITE S., KAFU- LAFULA G. and VAN DEN BROEK N.: Post-neonatal mortality, morbidity, and developmental outcome after ultrasound-dated preterm birth in rural Malawi: A com- munity-based cohort study. PLoS Medicine, 8: E , KENNETH J.L., F. GARY C., NORMAN F.G. and James M.A.: Williams Manual of Obstetrics. McGraw-Hill Companies, Inc. 21 st Edition. "Preterm birth: definitions, consequences, and causes" 36: p. (856). 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