Nifedipine Compared With Atosiban for Treating.11

Nifedipine Compared With Atosiban forTreating Preterm LaborA Randomized Controlled Trial

Raed Salim, MD, Gali Garmi, MD, Zohar Nachum, MD, Noah Zafran, MD, Shira Baram, MD,and Eliezer Shalev, MD

OBJECTIVE: To compare the tocolytic efficacy and tol-

erability of nifedipine with that of atosiban among

pregnant women with preterm labor.

METHODS: Pregnant women admitted with preterm

labor and intact membranes between 24 and 33 weeks

6 days of gestation, between January 2008 and December

2011, were randomly assigned to either atosiban or

nifedipine treatment. Assigned treatment was planned

for up to 48 hours. If progress was determined after 1

hour or more, a crossover of the study drugs was

performed. The primary outcome was to estimate the

tocolytic efficacy and tolerability profile that was as-

sessed in terms of the proportion of women who were

not delivered and did not require an alternate tocolytic

agent within 48 hours. Secondary outcomes were gesta-

tional age at delivery and neonatal morbidity.

RESULTS: Seventy-five women in the nifedipine group

and 70 in the atosiban group were included and

analyzed. Baseline demographic and obstetric character-

istics were comparable. Forty-eight (68.6%) women

allocated to atosiban and 39 (52%) to nifedipine did

not deliver and did not require an alternate agent at

48 hours respectively (P5.03). At 7 days from enrollment,

55 (78.6%) women allocated to atosiban and 67 (89.3%)

to nifedipine remained undelivered with or without

a rescue agent (P5.02). Mean gestational age at delivery

was 35.2 (63.0) and 36.4 (62.8) weeks among the atosi-

ban and nifedipine groups, respectively (P5.01). Mean

birth weight and neonatal morbidity were comparable.

CONCLUSIONS: Atosiban has fewer failures within 48

hours. Nifedipine may be associated with a longer post-

ponement of delivery.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov,

www.clinicaltrials.gov, NCT00599898.

(Obstet Gynecol 2012;120:1323–31)

DOI: http://10.1097/AOG.0b013e3182755dff

LEVEL OF EVIDENCE: I

Preterm birth is the leading cause of perinatal mor-bidity and mortality.1 Both morbidity and mortal-

ity rates are inversely related to gestational age atdelivery and each day of delay, particularly before28 weeks of gestation, increases the survival rate by3%.2 Spontaneous preterm labor with intact mem-branes is responsible for approximately one-third ofall cases of preterm birth.3 Between 24 and 33 weeksof gestation, the benefits of tocolytic therapy generallyoutweigh the risk of maternal, fetal, or both compli-cations and these agents should be initiated providedno contraindications exist.2

Comparison studies of the effectiveness of differ-ent tocolytic drugs showed comparable results. Allhave demonstrated a relative benefit that consistsmainly of prolonging the gestational age for at least48 hours, which may allow for the administration ofcorticosteroids and allow maternal transport to a ter-tiary care center.4 There is no clear first-line tocolyticdrug to manage preterm labor. The optimal agentwould combine the highest tolerability and the highestproportion of delayed deliveries.2 Most currentlyavailable tocolytic agents carry inherent risks of unde-sirable adverse effects caused by their nonselectivepharmacologic actions on maternal or fetal organs.

From the Department of Obstetrics and Gynecology, Emek Medical Center, Afula,and Rappaport Faculty of Medicine, Technion, Haifa, Israel.

Supported by the Department of Obstetrics and Gynecology, Emek Medical Cen-ter, Afula.

The authors thank Paula S. Herer, MSc, biostatistician, for assisting in thestatistical analysis.

Corresponding author: Raed Salim, MD, Department of Obstetrics andGynecology, Emek Medical Center, Afula, Israel 18101; e-mail: [email protected].

Financial DisclosureThe authors did not report any potential conflicts of interest.

© 2012 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/12

VOL. 120, NO. 6, DECEMBER 2012 OBSTETRICS & GYNECOLOGY 1323

Treatment with b-adrenergic receptor agonists maybe accompanied occasionally with severe adverseeffects.2 The efficacy of magnesium sulfate is uncer-tain,5,6 and concerns regarding adverse fetal effects ofcyclooxygenase inhibitors limited its use particularlyat a gestational age above 30–32 weeks.2 Comparedwith all of these agents, both nifedipine and atosibanwere found to be superior or comparable to b-adren-ergic receptor agonists for tocolysis. In addition, bothwere associated with fewer fetal and maternal adverseeffects.7,8 To determine the ideal first-line tocolyticagent, we aimed in this study to compare the tocolyticefficacy and tolerability of nifedipine with that of ato-siban among pregnant women with preterm labor.

PATIENTS AND METHODS

This randomized study was held at a single universityteaching medical center between January 2008 andDecember 2011. Women with preterm labor andintact membranes diagnosed between 24 weeks 0 daysand 33 weeks 6 days of gestation were included andrandomly assigned to either the atosiban group or thenifedipine group. Preterm labor was defined as thepresence of four or more uterine contractions, eachlasting 30 seconds or more within 30 minutes con-firmed by external tocography and accompanied withcervical effacement of at least 50% and cervicaldilatation of 0–4 cm among nulliparous women or1–4 cm among multiparous women. Gestational agewas confirmed by either a documented first-trimesterultrasound scan or by a reliable menstrual date con-firmed by ultrasonography performed before 20weeks of gestation. Exclusion criteria included ruptureof membranes, vaginal bleeding resulting fromplacenta previa or placental abruption, fever above38°C, severe preeclampsia, maternal cardiovascularor liver diseases, systolic blood pressure less than90 mm Hg, known uterine malformation, intrauterinegrowth restriction below the fifth percentile, nonreas-suring fetal status, antepartum diagnosis of major fetalmalformations, multiple gestations other than twins(triplets or greater), and fetal death.

After random allocation to a treatment group,women received atosiban or nifedipine as follows:

1. Atosiban was given as a single loading intrave-nous dose, 6.75 mg in 0.9% sodium chloridesolution, followed by an intravenous infusion of300 micrograms/min in 0.9% sodium chloridesolution for the first 3 hours and then 100 micro-grams/min for another 45 hours. The choice ofthe dose regimen for atosiban was consistent withthe recommendations of the product labeling.

2. Nifedipine was given as a loading dose of 20 mgorally followed by another two doses of 20 mg,20–30 minutes apart as needed. Maintenancewas started after 6 hours with 20–40 mg fourtimes a day for a total of 48 hours.Women were randomly assigned to receive

intravenous therapy with atosiban or oral nifedipinefor at least 1 hour. Assigned treatment was plannedfor up to 48 hours. Maintenance therapy after thefirst 48 hours was not provided. In addition, tocolyticdrugs were discontinued when progression to a cervi-cal dilatation of 5 cm or more or rupture ofmembranes occurred. Other tocolytic agents werenot permitted concomitantly. Labor was considered tohave progressed and the woman became eligible forrescue tocolysis if either of the following occurredafter at least 1 hour of observation during treatment:1. increase or no change in the frequency of thecontractions, or 2. an increase in cervical dilatation of1 cm or more. If progress was determined after 1 houror more, but before 48 hours, or if adverse effects ofthe drug were noted, a crossover of the study drugswas performed and the alternative tocolytic drug(rescue treatment) was initiated. In cases in whichboth drugs failed before 48 hours of admission, andthe gestational age was 28 weeks or less, indometha-cin, as a second rescue agent, was then initiated(two 100-mg per rectum tablets, 1 hour apart,followed by oral tablets of 25 mg four times a dayfor the rest of the 48 hours). Women with successfultocolysis but with a recurrence of preterm labor at anytime after the cessation of the study drug were treatedagain with the same assigned agent, provided thatall eligibility criteria were still met. Prophylacticantibiotics for group B streptococcus and cortico-steroids were administered according to standardclinical indications.

Uterine contractions were monitored continu-ously by an external tocodynamometer for 2–4 hoursafter initiation of the study drug followed by two tothree times a day for 30–60 minutes. The primaryoutcome was to estimate the tocolytic efficacy andtolerability profile that was assessed in terms of theproportion of women who were not delivered andwho did not require an alternate tocolytic agent within48 hours after initiation of the study drug. Secondaryoutcomes included the proportion of women who didnot deliver and did not require an alternate tocolyticagent at 7 days after initiation of therapy. In addition,tocolytic effectiveness was assessed in terms of thetotal number of women in the intent-to-treat popula-tion who had not been delivered at 48 hours and at7 days after starting treatment, number of preterm

1324 Salim et al Nifedipine or Atosiban for Preterm Labor OBSTETRICS & GYNECOLOGY

deliveries, and the latency period from enrollmentuntil delivery. Safety was assessed by assessing mater-nal adverse effects that included maternal tachycardiadefined as heart rate above 120 beats per minute,hypotension defined as systolic blood pressure lessthan 90 mm Hg, feeling of palpitations, headache,nausea, vomiting, itching, and rash. Other secondaryoutcomes examined were gestational age at deliveryand neonatal morbidity and mortality related to pre-maturity that were assessed until either discharge fromthe hospital or neonatal death.

Randomization of the groups was performed inblocks of 10 using a computer randomization sequencegeneration program and the randomization resultswere kept in the labor and delivery ward in a closedstudy box. The sequence was concealed until interven-tion was assigned, ie, just before administrating thetocolytic drug. Because the study drugs were adminis-tered by different roots, blinding of participants or careproviders was not performed. All authors took part inenrolling and assigning women to interventions.

The study was approved by the local institutionalreview board, Emek Medical Center, and theIsraeli ministry of health. Each woman signed aninformed consent.

An intent-to-treat analysis was performed. Toassess the difference in the two treatment groups’demographic and clinical data, the Wilcoxon rank-sum test was used for continuous data and the x2 orFisher’s exact tests where appropriate were used for thecategorical data. Adjusted odds ratio and 95% confi-dence interval were calculated for the tocolytic efficacyand tolerability and for the tocolytic effectiveness at48 hours and 7 days by multiple logistic regressionanalysis. The same calculations were performed for

other secondary outcomes. Adjustment was made fortwins, previous preterm delivery, progesterone treat-ment, closed cervix at presentation, and additional to-colytics. Kaplan-Meier survival analysis was alsoperformed for comparing gestational age at birth usingthe intent-to-treat protocol. Breslow’s test (Gehan’s gen-eralized Wilcoxon test) was used to compare the sur-vival time of the two treatments. This test gives greaterweight for differences in treatment at the beginning ofthe study than at the end of the study time.

Sample size was based on the results of a previousmulticenter study that our department took part in8

and which showed that the tocolytic efficacy and tol-erability of atosiban is 71.4% at 48 hours. Accordingly70 women per group were sufficient to show a differ-ence of 25% in the tocolytic efficacy and tolerability ofatosiban as compared with nifedipine (ie, 71.4% to46.4%) with a level of significance of 95% (a50.05)and a power of 80% (b50.2).

RESULTS

One hundred forty-nine women were randomizedduring the study period. Three women were excludedas a result of cervical progression beyond 4 cm beforethe study drug was initiated and one woman allocatedto atosiban withdrew her consent before therapy. Allother women were included and analyzed, 75 womenin the nifedipine group and 70 in the atosiban group(Fig. 1). Baseline demographic and obstetric charac-teristics were comparable between the groups(Table 1). None of the women had a cervical cerclage.

The tocolytic efficacy and tolerability profile at 48hours was significantly higher among women allo-cated to atosiban as compared with the nifedipine(Table 2). Of all women allocated to atosiban, 48

Assessed for eligibilityN=172

Excluded: n=23Not meeting inclusion criteria: 1Declined to participate: 22

Randomized n=149

Allocated to atosibann=72

Received atosibann=70

Did not receive atosiban: n=2Progressed beyond 4 cm: 1Elected to discontinue: 1

Allocated to nifedipinen=77

Received nifedipinen=75

Did not receive nifedipine: n=2Progressed beyond 4 cm: 2

Analyzedn=70

Analyzedn=75

Fig. 1. Randomization and analysisof women included in the study.

Salim. Nifedipine or Atosiban forPreterm Labor. Obstet Gynecol 2012.

VOL. 120, NO. 6, DECEMBER 2012 Salim et al Nifedipine or Atosiban for Preterm Labor 1325

(68.6%, 95% confidence interval [CI] 57.0–78.6) didnot deliver and did not require an alternate tocolyticagent at 48 hours as compared with 39 (52.0%, 95%CI 40.7–63.1) among the nifedipine group (P5.03).This difference was not significant at 7 days fromenrollment. Tocolytic effectiveness that was assessedin term of the proportions of women in the intent-to-treat population who had not been delivered at 48hours after treatment regardless of whether a crossoverwas made or not did not differ between the groupsirrespective of gestational age at enrollment or thenumber of fetuses (Table 2). Nevertheless, the propor-tion of women who remained undelivered at 7 dayshad a singleton and enrolled at 28 weeks of gestationor more was significantly higher among the nifedipinecompared with the atosiban group (P5.02) (Table 2).Of all women who had a crossover to the alternateagent within 48 hours from enrollment, only one wasthe result of adverse effects within the nifedipinegroup. Two women in each group required theuse of a third line, ie, indomethacin. Nine women

(12.9%, 95% CI 6.5–22.3) in the atosiban group and11 (14.7%, 95% CI 8.0–24.1) in the nifedipine groupreceived one or more additional treatments, 48 hoursor more after enrollment (P5.9). There was no differ-ence between the groups with any particular maternalmorbidity investigated (Table 3); however, the num-ber of women with any adverse effect was significantlyhigher among the nifedipine (22.7%, 95% CI 14.3–33.2) compared with the atosiban group (7.1%, 95%CI 2.7–15.1) (adjusted odds ratio [OR] 4.18, 95% CI1.38–12.68, P5.01). Women with any cardiovascularadverse effect (hypotension, tachycardia, or palpita-tion) was also significantly higher among the nifedi-pine (17.3%, 95% CI 14.3–33.2) compared with theatosiban group (4.3%, 95% CI 2.7–15.1) (adjusted OR5.14, 95% CI 1.23–21.40, P5.03).

Gestational age at delivery was significantly high-er among the nifedipine group compared with theatosiban group, regardless of whether labor wasinitiated spontaneously or not (Table 4). The numberof women delivered preterm, ie, less than 37 weeks of

Table 1. Baseline Maternal Demographic and Obstetric Characteristics According to Treatment Allocation

Nifedipine (n575) Atosiban (n570) P

Age (y) 27 (19–48) 28 (20–44) .88Body mass index (kg/m2) (pregestation) 21.4 (16.4–37.3) 22.6 (15.2–44.8) .21Ethnic group .16

Arab 32 (42.7) 38 (54.3)Jewish 43 (57.3) 32 (45.7)

Gravidity 2 (1–9) 2 (1–9) .10Parity .10

0 37 (49.3) 25 (35.7)1 or more 38 (50.7) 45 (64.3)

Past preterm delivery .400 63 (84.0) 55 (78.6)1 or more 12 (16.0) 15 (21.4)

Gestational age at randomization (wk) 31.8 (25.0–33.8) 31.1 (24.1–33.8) .24Gestational status according to no. of fetuses at randomization .97

Singletons at 28 wk of gestation or before 5 (6.7) 6 (8.6)Singletons after 28 wk of gestation 47 (62.7) 43 (61.4)Twins at 28 wk of gestation or before 5 (6.7) 4 (5.7)Twins after 28 wk of gestation 18 (24.0) 17 (24.3)

Progesterone treatment 17 (22.7) 16 (22.9) .98Past spontaneous preterm labor 7 (41.2) 8 (50.0)Short cervix 10 (58.8) 8 (50.0)

Maternal diseaseNone 53 (70.7) 44 (62.9) .38Gestational hypertensive disorders 3 (4.0) 6 (8.6) .31Diabetes in pregnancy 7 (9.3) 9 (12.9) .60Thrombophilia 3 (4.0) 2 (2.9) ..99Urinary tract infection 8 (10.7) 8 (11.4) ..99Thyroid disease 2 (2.7) 5 (7.1) .26Epilepsy 0 (0.0) 1 (1.4) .48

Contraction frequency/30 min 9 (4–16) 9 (4–18) .78Cervical dilatation (cm) 1.5 (0–3) 1.5 (0–4) .12Percentage of cervical effacement 70 (50–100) 70 (50–100) .36

Data are median (range) or n (%) unless otherwise specified.


gestation, was significantly higher among the atosibangroup (66.2%, 95% CI 54.4–76.6) as compared withthe nifedipine group (43.2%, 95% CI 32.0–54.7,P5.007). The incidence of deliveries at less than 34weeks of gestation did not differ significantly betweenthe groups (Table 4).

Among the nifedipine group, 40 (53.3%, 95% CI42.0–64.4) women used the assigned drug only (deliv-ery was delayed for more than 48 hours without a res-cue or dilatation progressed to more than 5 cm within1 hour from enrollment) compared with 54 (77.1%,95% CI 66.2–85.8) women among the atosiban group

Table 3. Maternal Morbidity According to Treatment Allocation

Nifedipine (n575) Atosiban (n570)Adjusted

Odds Ratio* 95% CI Adjusted P*

Hypotension 8 (10.7) 2 (2.9) 4.79 0.88–25.97 .07Tachycardia 4 (5.3) 1 (1.4) 3.84 0.42–35.47 .24Palpitation 1 (1.3) 0 (0.0) — —Headache 4 (5.3) 2 (2.9) 1.81 0.29–11.17 .52Nausea 1 (1.3) 0 (0.0) — —Vomiting 0 (0.0) 0 (0.0) — —Pruritus 1 (1.3) 0 (0.0) — —Local irritation 0 (0.0) 0 (0.0) — —Rush 0 (0.0) 0 (0.0) — —Women with any morbidity 17 (22.7) 5 (7.1) 4.18 1.38–12.68 .01Readmission before 34 wk of gestation 17 (22.7) 18 (25.7) 0.73 0.30–1.78 .49Mode of delivery .64

Vaginal 71 (94.7) 65 (92.9) 1.39 0.35–5.46Cesarean 4 (5.3) 5 (7.1) 0.72 0.18–2.83

CI, confidence interval.Data are n (%) unless otherwise specified.* Adjustment was made for twins, previous preterm delivery, progesterone treatment, closed cervix, and additional tocolytics.

Table 2. Tocolytic Efficacy and Tolerability and Tocolytic Effectiveness of Atosiban and Nifedipine at 48Hours and at 7 Days

Nifedipine (n575) Atosiban (n570)Adjusted

Odds Ratio* 95% CI Adjusted P*

Tocolytic efficacy and tolerabilityNo failure at 48 h 39 (52.0) 48 (68.6) 2.26 1.10–4.63 .03

At 28 wk of gestation or before 6/10 (60.0) 7/10 (70.0) 1.50 0.14–16.04 .74After 28 wk of gestation 33/65 (50.8) 41/60 (68.3) 2.27 1.06–4.84 .04

No failure at 7 d 37 (49.3) 44 (62.9) 1.89 0.94–3.80 .07At 28 wk of gestation or before 5/10 (50.0) 6/10 (60.0) 1.72 0.17–17.37 .65After 28 wk of gestation 32/65 (49.2) 38/60 (63.3) 1.94 0.92–4.10 .08

Tocolytic effectivenessNot yet delivered at 48 h 69 (92.0) 60 (85.7) 0.54 0.18–1.61 .27

At 28 wk of gestation or before 9/10 (90.0) 9/10 (90.0) 1.00 0.05–18.70 ..99After 28 wk of gestation 60/65 (92.3) 51/60 (85.0) 0.43 0.13–1.40 .16

Not yet delivered at 7 d 67 (89.3) 55 (78.6) 0.31 0.11–0.85 .02At 28 wk of gestation or before 9/10 (90.0) 8/10 (80.0) 0.46 0.03–6.28 .56After 28 wk of gestation 58/65 (89.2) 47/60 (78.3) 0.32 0.11–0.95 .04

Tocolytic effectivenessNot yet delivered at 48 h 69 (92.0) 60 (85.7) 0.54 0.18–1.61 .27

Singletons 47/52 (90.4) 43/49 (87.8) 0.66 0.18–2.42 .53Twins 22/23 (95.7) 17/21 (81.0) 0.20 0.02–2.00 .17

Not yet delivered at 7 d 67 (89.3) 55 (78.6) 0.31 0.11–0.85 .02Singletons 47/52 (90.4) 39/49 (79.6) 0.21 0.05–0.82 .02Twins 20/23 (87.0) 16/21 (76.2) 0.45 0.08–2.56 .37

CI, confidence interval.Data are n (%) or n/N (%) unless otherwise specified.* Adjustment was made for twins, previous preterm delivery, progesterone treatment, closed cervix, and additional tocolytics.


(OR 2.9, 95% CI 1.4–6.1, P5.003). Median gesta-tional age at delivery within these pure groups wasalso higher among the nifedipine group (37.6 weeks,range 28.9–41.0 weeks) compared with the atosibangroup (35.6 weeks, range 24.7–40.3 weeks, P5.02).

Kaplan-Meier survival analysis of the gestationalage at birth showed that there was a statisticallysignificant difference between the two treatmentgroups (Breslow P5.04). Median gestational age forwomen allocated to the nifedipine group was 37weeks (95% CI 36.2–37.4) and 35 weeks (95% CI34.1–35.6) for women allocated to the atosiban group(Fig. 2). Similar results were found when stratifying forgestational age at enrollment (P5.03).

The number of neonates admitted to the neonatalintensive care unit (NICU) and length of stay afterdelivery were significantly higher among the atosibangroup as compared with the nifedipine group(Table 4). Overall, neonatal morbidity related to pre-maturity was comparable between the groups,although the incidence of respiratory distress syn-drome and mechanical ventilation among singletonswas more than double within the atosiban group ascompared with the nifedipine group; however, this

Table 4. Perinatal Outcomes of Pregnancies According to Treatment Allocation

Nifedipine Atosiban

Adjusted Odds Ratioand Coefficient*

(95% CI) Adjusted P*

n575 women n570 womenGestational age atdelivery (wk)

36.462.8 (37, 28–41) 35.263.0(35, 24.7–40.3)

21.20 (22.14 to 20.27) .01

Gestational age ofspontaneous deliveries (wk)

36.562.8 (37.2, 28–41) 35.463.0(35.2, 24.7–40.3)

21.24 (22.18 to 20.30) .01

Days from enrollment tospontaneous delivery

37.4620.3 (35, 1–94) 31.7620.6 (32, 1–70) 25.44 (211.89 to 1.02) .1

Spontaneous deliveriesbefore 37 wk of gestation

31 (43.1) 45 (66.2) 2.78 (1.32—5.87) .007


12 (16.7) 19 (27.9) 2.12 (0.92–4.89) .08


1 (1.4) 2 (2.9) 3.40 (0.26–43.87) .35

n598 neonates n591 neonatesBirth weight (g) 2,4086658

(2,351, 920–3,800)2,3266627

(2,243, 750–3,600)288.6 (2249.4 to 72.2) .28

Neonates with birth weightsless than 2,500 g

54 (55.1) 60 (65.9) 2.50 (0.71–8.77) .15

Neonatal intensive careunit admission

29 (29.6) 46 (50.5) 2.81 (1.44–5.48) .002

Hospitalized days 11.1618.2 (2.0, 1–95) 16.5618.9(11.0; 2–97)

5.5 (0.2–10.8) .04

CI, confidence interval.Data are mean6standard deviation (median range) or n (%) unless otherwise specified.* Linear regression was performed on the continuous variables (beta coefficient is shown) and logistic regression for the binary variables

(odds ratio is shown). Adjustment was made for twins, previous preterm delivery, progesterone treatment, closed cervix, and additionaltocolytics.

Not

del

iver

ed (

%)

Gestational age at birth (weeks)25 27 29 31 33 35 37 39 41

1.0

0.8

0.6

0.4

0.2

0.0

NifedipineAtosiban

Fig. 2. Statistical curves for comparing gestational age atbirth using the intent-to-treat protocol. There was a statisti-cally significant difference between the two treatmentgroups (P5.04).

Salim. Nifedipine or Atosiban for Preterm Labor. ObstetGynecol 2012.


difference was not significant. There were no neonataldeaths in either study group (Table 5).

DISCUSSION

The present study was undertaken to compare thetocolytic efficacy and tolerability profile of nifedipineas compared with atosiban among pregnant womenadmitting with signs of preterm labor between 24 and34 weeks of gestation. Atosiban was found to besuperior to nifedipine in terms of the proportion ofwomen who did not give birth and who did not requirean alternate tocolytic agent within 48 hours from theinitiation of therapy. In addition, atosiban was bettertolerated by women compared with nifedipine. Bothdrugs were comparable in terms of the total number ofwomen, in the intent-to-treat analysis, who did notdeliver at 48 hours after enrollment. However, theproportion of women who had a singleton and enrolledat 28 weeks of gestation or more and who hadremained undelivered at 7 days was significantly higheramong the nifedipine compared with the atosibangroup. Additionally, women assigned to nifedipinehad a lower rate of preterm deliveries and delivered1 week more than women assigned to atosiban. Asa result, probably, more neonates in the atosiban groupwere hospitalized at the NICU and for a longer time.Furthermore, the incidence of respiratory distresssyndrome and mechanical ventilation among single-tons was more than two times greater within theatosiban group as compared with the nifedipine group,although this difference was not significant.

Preterm birth is responsible for approximately75% of all neonatal deaths and 50% of childhoodneurologic morbidities.9,10 It is also associated withboth high immediate and long-term costs after dis-

charge from the hospital.11 Postponing delivery for48 hours to administer corticosteroids or to gain crit-ical time to allow the transfer of women to a centerwith NICU facilities or both is the crucial goal toachieve with tocolytic drugs in cases of a threateningpreterm delivery. Several agents have been used toinhibit uterine contractility, but it remains unclearwhat is the first-line tocolytic agent. Betamimeticsreduce the rate of preterm delivery within 48 hours;however, maternal adverse effects are considerable.7

Magnesium sulfate has not been proven to be an effec-tive tocolytic agent at delaying birth, and its use hadbeen reported to be associated with an increasedincidence of adverse effects and risk of neonatalmortality.12 Concerns regarding adverse effects ofcyclooxygenase inhibitors on the fetal kidneys, ductusarteriosus, increased risk of neonatal intraventricularhemorrhage, and necrotizing enterocolitis have lim-ited its use, especially at a gestational age above30–32 weeks.2 Nifedipine and atosiban were foundto be comparable to betamimetics and both were asso-ciated with significantly fewer maternal adverse effectsas compared with betamimetics.7,8

Atosiban is currently licensed in Europe but notin the United States. As a result of its placebo-likematernal-fetal adverse effect profile, the Royal Collegeof Obstetricians and Gynecologists suggested consid-ering atosiban as a first-line tocolytic agent.2,8,13,14 Onthe other hand, several systematic reviews and meta-analysis confirmed that in addition to its comparableeffect to betamimetics in delaying delivery for morethan 48 hours, nifedipine reduced the incidence of pre-term delivery, and more notably reduced neonatalmorbidity, including respiratory distress syndromeand NICU admissions.7,15 Although nifedipine is not

Table 5. Neonatal Morbidity Among Singletons and Twins

Singletons Twins

Nifedipine (n552) Atosiban (n549) P Nifedipine (n546) Atosiban (n542) P

Apgar score less than 7 at 5 min 2 (3.8) 0 (0.0) .50 0 (0.0) 1 (2.4) .48Sepsis 1 (1.9) 1 (2.0) ..99 2 (4.3) 1 (2.4) ..99Respiratory distress syndrome 2 (3.8) 5 (10.2) .26 5 (10.9) 4 (9.5) ..99Mechanical ventilation 4 (7.8) 8 (16.3) .23 6 (13.0) 5 (11.9) ..99Apnea 0 (0.0) 1 (2.0) .49 1 (2.2) 0 (0.0) ..99Intraventricular hemorrhage 2 (3.8) 2 (4.1) ..99 0 (0.0) 2 (4.8) .23Necrotizing enterocolitis 0 (0.0) 1 (2.0) .49 0 (0.0) 3 (7.1) .11Retinal disorder 0 (0.0) 1 (2.0) .49 1 (2.2) 1 (2.4) ..99Bradycardia 0 (0.0) 0 (0.0) — 0 (0.0) 1 (2.4) .48No. of neonates with any morbidity* 4 (7.7) 9 (18.4) .11 9 (19.6) 9 (21.4) ..99Neonatal mortality 0 (0.0) 0 (0.0) — 0 (0.0) 0 (0.0) —

Data are n (%) unless otherwise specified.* Singleton, adjusted odds ratio (OR) 2.80, 95% confidence interval (CI) 0.79–9.98, P5.11; twins, adjusted OR 1.29, 95% CI 0.44–3.80,

P5.65. Adjustment made for twins, previous preterm delivery, progesterone treatment, closed cervix, and additional tocolytics.


licensed as a tocolytic agent, the results of these meta-analyses and others brought some authors to suggestthat nifedipine appears to meet several characteristicsof an ideal tocolytic agent and may be considereda first-line tocolytic agent.15,16

In view of this, the question of which agent shouldbe the first line, atosiban or nifedipine, is still a subjectof controversy in many articles. A meta-analysis withan indirect comparison of nifedipine and atosibanshowed that the former was associated with a non-significant increase in the number of women whosedelivery was delayed for at least 48 hours anda significant reduction in respiratory distress syn-drome compared with atosiban. Because biases maygo along with results of a meta-analysis with anindirect comparison, the authors strengthen the needfor better evidence from randomized trials directlycomparing nifedipine and atosiban.17 Following thepublication of this meta-analysis, two small, under-powered studies that compared the efficacy and safetyof atosiban and nifedipine in preventing or delayingpreterm labor were published. According to theresults of both studies, the efficacy of both medica-tions was the same, but adverse effects of nifedipinewere significantly more than atosiban.18,19

In this study, atosiban as compared with nifedi-pine was found to be superior in terms of theproportion of women who did not deliver and whodid not require an alternate agent within 48 hoursafter initiation of therapy. This effect was pronounced,particularly among women admitted at a gestationalage of 28 weeks or more. Similar results regarding theinferiority of atosiban at less than 28 weeks ofgestation were reported by others.1,19 This observa-tion may be attributed to the fact that lower concen-trations of oxytocin receptors are present at an earliergestational age.20 In addition, the onset of pretermuterine contractions, particularly the very preterm,may involve other pathways that do not bring intoplay oxytocin.21 On the other hand, nifedipine ascompared with atosiban was found to be associatedwith a higher mean gestational age at delivery, a lowerincidence of preterm deliveries, and, probably accord-ingly, lead to a lower incidence of respiratory distresssyndrome, NICU admissions, and a shorter length ofstay. This effect was valid among women assigned tonifedipine regardless of whether they received nifedi-pine only or needed a rescue agent. Although bothdrugs were discontinued at 48 hours from enrollment,these repeated observations regarding the superiorityof nifedipine may indicate that it probably has anadditional long-acting effect that may involve otherpathways in the pathophysiologic process of preterm

birth beyond that achieved by impeding acute uterinecontractions.

The limitations of the current study are worthmentioning. First, although we conducted a priorisample size calculation to ensure adequate power toexamine the efficacy and tolerability of the tocolyticdrugs, we may be underpowered to detect smalldifferences 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 thestudy drugs. The decision was based on medical andethical issues, because both study drugs are consid-ered to have the greatest maternal and fetal safetyprofile compared with other medications.

The choice of the first-line tocolytic agent in termsof safety profile, efficacy, and costs is a topic of debate.An ideal tocolytic agent is supposed to delay deliverywith minimal maternal and fetal adverse effects at lowcosts. None of the tocolytic medications availablefulfills all these criteria. According to the currentstudy, atosiban has fewer failures within 48 hours andprobably a better maternal safety profile, both ofwhich favor its use as a first line, particularly in casesin which maternal transport to a tertiary center isbeing planned or among women with cardiovasculardisorders. On the other hand, the overall low inci-dence of maternal adverse effects associated with theuse of nifedipine, the oral route of administration, lowcosts compared with atosiban, better effectiveness,and a possible efficacy in reducing neonatal morbidityfavor its use as a first line, ie, the first agent to startwith, among the remaining cases.

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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.

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8. Moutquin JM, Sherman D, Cohen H, Mohide PT, Hochner-Celnikier D, FejginM, 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 Gynecol2000;182:1191–9.

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11. Petrou S, Mehta Z, Hockley C, Cook-Mozaffari P, Henderson J,Goldacre M. The impact of preterm birth on hospital inpatientadmissions and costs during the first 5 years of life. Pediatrics2003;112:1290–7.

12. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate forpreventing preterm birth in threatened preterm labour. TheCochrane 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 man-agement of preterm birth: a review. Am J Perinatol 2011;28:449–60.

14. Petraglia F, Visser GH. Prevention and management of pretermlabour. 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 admin-istration 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. Effec-tiveness of nifedipine versus atosiban for tocolysis in pretermlabour: a meta-analysis with an indirect comparison of rando-mised trials. BJOG 2003;110:1045–9.

18. Kashanian M, Akbarian AR, Soltanzadeh M. Atosiban andnifedipin for the treatment of preterm labor. Int J GynaecolObstet 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 receptorsin the human uterus during pregnancy and parturition. Am JObstet Gynecol 1984;150:734–41.

21. Cole RM, Lamont RF. Current perspectives on drug treatmentfor preterm labour. J Obstet Gynaecol 1998;18:309–14.

Harold A. Kaminetzky AwardThe American College of Obstetricians and Gynecologists (the College) and Obstetrics & Gynecology haveestablished the Harold A. Kaminetzky Award to recognize the best paper from a non-U.S. researchereach year.

Dr. Harold A. Kaminetzky, former College Secretary and President, as well as Vice President, PracticeActivities, has had a long career as editor of major medical journals. His last editorship was as Editorof the International Journal of Gynecology and Obstetrics. Dr. Kaminetzky has also had a long interest in international activities.

The Harold A. Kaminetzky Award winner will be chosen by the editors and a special committee of former Editorial Board members. The recipient of the award will receive $2,000.

Read the journal online at www.greenjournal.org1/2010


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Nifedipine Compared With Atosiban for Treating.11