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Meta-Analysis
. 2014 Jun 5;2014(6):CD002255.
doi: 10.1002/14651858.CD002255.pub2.

Calcium channel blockers for inhibiting preterm labour and birth

Vicki Flenady  1 , Aleena M Wojcieszek, Dimitri N M Papatsonis, Owen M Stock, Linda Murray, Luke A Jardine, Bruno Carbonne
Affiliations
Meta-Analysis

Calcium channel blockers for inhibiting preterm labour and birth

Vicki Flenady et al. Cochrane Database Syst Rev. .

Abstract

Background: Preterm birth is a major contributor to perinatal mortality and morbidity, affecting around 9% of births in high-income countries and an estimated 13% of births in low- and middle-income countries. Tocolytics are drugs used to suppress uterine contractions for women in preterm labour. The most widely used tocolytic are the betamimetics, however, these are associated with a high frequency of unpleasant and sometimes severe maternal side effects. Calcium channel blockers (CCBs) (such as nifedipine) may have similar tocolytic efficacy with less side effects than betamimetics. Oxytocin receptor antagonists (ORAs) (e.g. atosiban) also have a low side-effect profile.

Objectives: To assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour.

Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 November 2013).

Selection criteria: All published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation.

Data collection and analysis: Two review authors independently assessed trial eligibility, undertook quality assessment and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with the 95% confidence interval (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) were calculated for categorical outcomes that were statistically significantly different.

Main results: 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.Two small trials comparing CCBs with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02, one trial of 89 women). Due to substantial heterogeneity, outcome data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported.Comparing CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.Comparing CCBs with ORA, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and reductions in preterm birth (RR 0.64, 95% CI 0.47 to 0.89); admissions to the NICU (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the NICU (MD -5.40 days,95% CI -10.84 to 0.04). Maternal adverse effects were increased in the CCB group (average RR 2.61, 95% CI 1.43 to 4.74).Comparing CCBs with magnesium sulphate, maternal adverse effects were reduced (average RR 0.52, 95% CI 0.40 to 0.68), as was duration of stay in the NICU (days) (MD -4.55, 95% CI -8.17 to -0.92). No differences were shown in the comparisons with GTN patch or NSAID, although numbers were small.No differences in outcomes were shown in trials comparing nicardipine with other tocolytics, although with limited data no strong conclusions can be drawn. No differences were evident in a small trial that compared higher- versus lower-dose nifedipine, though findings tended to favour a high dose on some measures of neonatal morbidity.

Authors' conclusions: Calcium channel blockers (mainly nifedipine) for women in preterm labour have benefits 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. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well-designed tocolytic trials are required to determine short- and longer-term infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence) and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer-term effects into early childhood, and also costs.

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Conflict of interest statement

Vicki Flenady: nothing to declare.

Aleena M Wojcieszek: nothing to declare.

Dimitri NM Papatsonis: D Papatsonis is a co‐author on a non‐Cochrane systematic review of nifedipine and beta‐agonists (Tsatsaris 2001) and was a co‐author of a randomised trial of nifedipine and ritodrine for preterm labour (Papatsonis 1997).

Owen M Stock: I am supported by an NHMRC Medical/Dental Postgraduate Scholarship as I am currently undertaking a PhD.

Linda Murray: nothing to declare.

Luke A Jardine: nothing to declare.

Bruno Carbonne: B Carbonne is a co‐author on a non‐Cochrane systematic review of nifedipine and beta‐agonists (Tsatsaris 2001). B Carbonne assisted in the organisation of a symposium with Ferring laboratories and has also participated as a speaker in meetings/symposia organised by Ferring. Funds in relation to these activities were provided by Ferring to B Carbonne’s institution.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Funnel plot of comparison: 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), outcome: 2.1 Birth less than 48 hours after trial entry.
4
4
Funnel plot of comparison: 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by agent), outcome: 2.3 Perinatal mortality.
5
5
Funnel plot of comparison: 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), outcome: 2.9 Preterm birth (before completion of 37 weeks of gestation).
1.1
1.1. Analysis
Comparison 1 Calcium channel blockers compared with placebo or no treatment, Outcome 1 Birth within 48 hours after trial entry.
1.2
1.2. Analysis
Comparison 1 Calcium channel blockers compared with placebo or no treatment, Outcome 2 Preterm birth (before completion of 37 weeks of gestation).
1.3
1.3. Analysis
Comparison 1 Calcium channel blockers compared with placebo or no treatment, Outcome 3 Maternal adverse effects.
2.1
2.1. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 1 Birth less than 48 hours after trial entry.
2.2
2.2. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).
2.3
2.3. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 3 Perinatal mortality (stillbirth and neonatal death up to 28 days).
2.4
2.4. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 4 Stillbirth.
2.5
2.5. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 5 Neonatal death.
2.6
2.6. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 6 Maternal death.
2.7
2.7. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 7 Interval between trial entry and birth (days).
2.8
2.8. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 8 Gestational age at birth (completed weeks).
2.9
2.9. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 9 Preterm birth (before completion of 37 weeks of gestation).
2.10
2.10. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 10 Extremely preterm birth (before completion of 28 weeks of gestation).
2.11
2.11. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 11 Apgar score < 7 at 5 minutes.
2.12
2.12. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 12 Admission to NICU.
2.13
2.13. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 13 Respiratory distress syndrome.
2.14
2.14. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 14 Chronic lung disease.
2.15
2.15. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 15 Necrotising enterocolitis.
2.16
2.16. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 16 Neonatal sepsis.
2.17
2.17. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 17 Neonatal jaundice.
2.18
2.18. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 18 Intraventricular haemorrhage.
2.19
2.19. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 19 Intraventricular haemorrhage grades 3 or 4.
2.20
2.20. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 20 Periventricular leukomalacia (PVL).
2.21
2.21. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 21 Retinopathy of prematurity.
2.22
2.22. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 22 Maternal adverse effects.
2.23
2.23. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 23 Discontinuation of therapy for maternal adverse effects.
2.24
2.24. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 24 Caesarean section.
2.25
2.25. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 25 Duration of stay in NICU (days).
2.26
2.26. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 26 Duration of maternal hospital stay (days).
2.27
2.27. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 27 Behavioural‐emotional problems at 9‐12 years.
2.28
2.28. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 28 Special education at 9‐12 years.
2.29
2.29. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 29 Motor quality at 9‐12 years.
2.30
2.30. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 30 Quality of life at 9‐12 years: physical.
2.31
2.31. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 31 Quality of life at 9‐12 years: motor.
2.32
2.32. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 32 Quality of life at 9‐12 years: autonomy.
2.33
2.33. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 33 Quality of life at 9‐12 years: cognitive.
2.34
2.34. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 34 Quality of life at 9‐12 years: social.
2.35
2.35. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 35 Quality of life at 9‐12 years: positive emotion.
2.36
2.36. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 36 Quality of life at 9‐12 years: negative emotion.
2.37
2.37. Analysis
Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 37 Parent distress scores at 9‐12 years.
3.1
3.1. Analysis
Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 1 Birth within 48 hours after trial entry.
3.2
3.2. Analysis
Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).
3.3
3.3. Analysis
Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 3 Perinatal mortality (fetal death and neonatal death up to 28 days).
3.4
3.4. Analysis
Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 4 Interval between trial entry and birth (days).
3.5
3.5. Analysis
Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 5 Respiratory distress syndrome.
3.6
3.6. Analysis
Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 6 Discontinuation of therapy for maternal adverse effects.
4.1
4.1. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 1 Birth within 48 hours after trial entry.
4.2
4.2. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).
4.3
4.3. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 3 Perinatal mortality (fetal death and neonatal death up to 28 days).
4.4
4.4. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 4 Maternal death.
4.5
4.5. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 5 Interval between trial entry and birth (days).
4.6
4.6. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 6 Respiratory distress syndrome.
4.7
4.7. Analysis
Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 7 Discontinuation of therapy for maternal adverse effects.
5.1
5.1. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 1 Birth within 48 hours after trial entry.
5.2
5.2. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).
5.3
5.3. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 3 Extremely preterm birth (before completion of 28 weeks of gestation).
5.4
5.4. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 4 Perinatal mortality (stillbirth and neonatal death up to 28 days).
5.5
5.5. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 5 Stillbirth.
5.6
5.6. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 6 Neonatal death.
5.7
5.7. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 7 Maternal death.
5.8
5.8. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 8 Interval between trial entry and birth (days).
5.9
5.9. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 9 Gestational age at birth (completed weeks).
5.10
5.10. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 10 Preterm birth (before completion of 37 weeks of gestation).
5.11
5.11. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 11 Apgar score < 7 at 5 minutes.
5.12
5.12. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 12 Admission to NICU.
5.13
5.13. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 13 Respiratory distress syndrome.
5.14
5.14. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 14 Necrotising enterocolitis.
5.15
5.15. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 15 Neonatal sepsis.
5.16
5.16. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 16 Neonatal jaundice.
5.17
5.17. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 17 Intraventricular haemorrhage.
5.18
5.18. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 18 Maternal adverse effects.
5.19
5.19. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 19 Discontinuation of therapy for maternal adverse effects.
5.20
5.20. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 20 Duration of stay in NICU (days).
5.21
5.21. Analysis
Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 21 Duration of maternal hospital stay (days).
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Update of

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References

References to studies included in this review

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Laohapojanart 2007 {published data only}
    1. Laohapojanart N, Soorapan S, Wacharaprechanont T, Ratanajamit C. Safety and efficacy of oral nifedipine versus terbutaline injection in preterm labour. Journal of the Medical Association of Thailand 2007;90(11):2462‐7. - PubMed
Larmon 1999 {published and unpublished data}
    1. Larmon J, Ross B, May W, Dickerson G, Fischer R, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. American Journal of Obstetrics and Gynecology 1999;181:1432‐7. - PubMed
    1. Ross E, Ross B, Dickerson G, Fischer R, Morrison J. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. American Journal of Obstetrics and Gynecology 1998;178(1):181. - PubMed
Lyell 2007 {published data only}
    1. Lyell D, Penn A, Caughey A, Kogut E, McClellan L, Adams B, et al. Neonatal outcomes following antenatal magnesium sulfate exposure: follow up from a magnesium vs. nifedipine tocolysis RCT. American Journal of Obstetrics and Gynecology 2009;201(6 Suppl 1):S180‐1.
    1. Lyell DJ, Pullen K, Campbell L, Ching S, Druzin ML, Chitkara U, et al. Magnesium sulfate compared with nifedipine for acute tocolysis of preterm labor. Obstetrics & Gynecology 2007;110(1):61‐7. - PubMed
Mawaldi 2008 {published data only}
    1. Mawaldi L, Duminy P, Tamim H. Terbutaline versus nifedipine for prolongation of pregnancy in patients with preterm labor. International Journal of Gynecology and Obstetrics 2008;100:65‐8. - PubMed
Nassar 2009 {published and unpublished data}
    1. Nassar A, Khalil A, Awwad J, Abu Musa A, Tabbara J, Usta I. A randomized trial of two dose regimens of nifedipine for management of preterm labor. American Journal of Obstetrics and Gynecology 2007;197(6 Suppl 1):S206. - PubMed
    1. Nassar AH, Abu‐Musa AA, Awwad J, Khalii A, Tabbara J, Usta IM. Two dose regimens of nifedipine for management of preterm labor: a randomized controlled trial. American Journal of Perinatology 2009;26(8):575‐81. - PubMed
Padovani 2012 {published data only}
    1. Padovani TR, Lopes LC. Nifedipine and terbutaline: comparative study of effectiveness and safety in preventing preterm labor. International Journal of Gynecology and Obstetrics 2012;119(Suppl 3):S761.
Papatsonis 1997 {published and unpublished data}
    1. Houtzager BA, Hogendoorn S, Samson JF, Papatsonis D, Wassenaer AG. Nine years' follow up of children born from mothers who participated in a RCT of nifedipine versus ritodrine for threatened preterm labor [abstract]. Pediatric Academic Societies Annual Meeting; 2005 May 14‐17; Washington DC, USA. 2005:Abstract no: 2100.
    1. Houtzager BA, Hogendoorn SM, Papatsonis DNM, Samsom JF, Geijn HP, Bleker OP, et al. Long‐term follow up of children exposed in utero to nifedipine or ritodrine for the management of preterm labour. BJOG: an international journal of obstetrics and gynecology 2005;113:324‐31. - PubMed
    1. Papatsonis DM, Hogendoorn SM, Houtzager BA, Wassenaer AG, Samsom JF. Long‐term follow‐up of children exposed in utero to nifedipine or ritodrine in the management of preterm labor [abstract]. American Journal of Obstetrics and Gynecology 2004; Vol. 191, issue 6 Suppl 1:S106. - PubMed
    1. Papatsonis DN, Kok JH, Geijn HP, Bleker OP, Ader HJ, Dekker GA. Neonatal effects of nifedipine and ritodrine for preterm labor. Obstetrics and Gynecology 2000;95(4):477‐81. - PubMed
    1. Papatsonis DN, Kok JH, Geijn HP, Bleker OP, Ader HJ, Dekker GA. Neonatal effects of nifedipine and ritodrine in the management of preterm labor. Proceedings of the 5th Annual Congress of the Perinatal Society of Australia and New Zealand; 2001 March; Canberra, Australia. 2001:100.
Rayamajhi 2003 {published data only}
    1. Rayamajhi R, Pratap K. A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour. Kathmandu University Medical Journal 2003;1(2):85‐90. - PubMed
Read 1986 {published data only}
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Salim 2012 {published data only}
    1. Garmi G. Nifedipine compared to atosiban for treating preterm labor. ClinicalTrials.gov (http://clinicaltrials.gov/) (accessed 9 April 2008) 2008.
    1. Salim R, Garmi G, Nachum Z, Zafran N, Baram S, Shalev E. Nifedipine compared with atosiban for treating preterm labor: a randomized controlled trial. Obstetrics and Gynecology 2012;120(6):1323‐31. - PubMed
Taherian 2007 {published data only}
    1. Taherian A, Dehdar P. Comparison of efficacy and safety of nifedipine versus magnesium sulphate in treatment of preterm labour. Journal of Research in Medical Sciences 2007;12(3):136‐42.
Trabelsi 2008 {published data only}
    1. Trabelsi K, Hadj Taib H, Amouri H, Abdennadheur W, Ben Amar H, Kallel W, et al. Nicardipine versus salbutamol in the treatment of premature labor: comparison of their efficacy and side effects. Tunisie Medicale 2008;86(1):43‐8. - PubMed
Valdes 2012 {published data only}
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Van De Water 2008 {published data only}
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Weerakul 2002 {published and unpublished data}
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Zhang 2002 {published data only (unpublished sought but not used)}
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References to studies excluded from this review

Al‐Omari 2006 {published data only}
    1. Al‐Omari WR, Al‐Shammaa HB, Al‐Tikriti EM, Ahmed KW. Atosiban and nifedipine in acute tocolysis: A comparative study. European Journal of Obstetrics and Gynecology and Reproductive Biology 2006;128:129‐34. - PubMed
    1. Al‐Omari WR, Al‐Tikriti E, Al‐Shamma H. Atosiban and nifedipine in acute tocolysis, comparative study [abstract]. XVIIIth European Congress of Obstetrics and Gynaecology; 2004 May 12‐15; Athens, Greece. 2004:103.
Breart 1979 {published data only}
    1. Breart G, Sureau C, Rumeau‐Rouquette C. A study of the comparative efficiency of ifenprodil and ritodrine in the treatment of threatening premature labour [translation]. Journal de Gynecologie, Obstetrique et Biologie de la Reproduction (Paris) 1979;8(3):261‐3. - PubMed
Carr 1993 {published data only}
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Chawanpaiboon 2011 {published data only}
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    1. Chawanpaiboon S, Sutantawibul A, Pimol K, Sirisomboon R, Worapitaksanond S. Preliminary study: Comparison of the efficacy of progesterone and nifedipine in inhibiting threatened preterm labour in Siriraj Hospital. Thai Journal of Obstetrics and Gynaecology 2009;17:23‐9.
Dasari 2007 {published data only}
    1. Dasari P, Kodenchery MM. Psychological factors in preterm labor and psychotherapeutic intervention. International Journal of Gynaecology & Obstetrics 2007;97(3):196‐7. - PubMed
Dunstan‐Boone 1990 {published data only}
    1. Dunstan‐Boone G, Bond A, Thornton YS. A comparison of verapamil vs ritodrine for the treatment of preterm labor. Proceedings of 10th Annual Meeting of Society of Perinatal Obstetricians; 1990; Houston, Texas, USA, 1990:83. 1990:83.
El‐Sayed 1998 {published data only}
    1. El‐Sayed YY, Holbrook RH Jr, Gibson R, Chitkara U, Druzin ML, Baba D. Diltiazem for maintenance tocolysis of preterm labor: comparison to nifedipine in a randomized trial. Journal of Maternal‐Fetal Medicine 1998;7(5):217‐21. - PubMed
Husslein 2007 {published data only}
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Junejo 2008 {published data only}
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Juon 2008 {published data only}
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Maitra 2007 {published data only}
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Malik 2007 {published data only}
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Meyer 1990 {published data only}
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Papadopoulos 1997 {published data only}
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Piovano 1985 {published data only}
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Rodriguez‐Escudero 1981 {published data only}
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Shim 2006 {published data only}
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Smith 1993 {published data only}
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References to studies awaiting assessment

Chong 1991 {published data only}
    1. Yi CS, Kim DK. A comparison of tocolytic effects of ritodrine hydrochloride and nifedipine in the treatment of preterm labour. Journal of Catholic Medical College 1991;44(1):231‐8.
de Heus 2009 {published data only}
    1. Heus R, Mulder EJ, Derks JB, Visser GH. The effects of the tocolytics atosiban and nifedipine on fetal movements, heart rate and blood flow. Journal of Maternal‐Fetal & Neonatal Medicine 2009;22(6):485‐90. - PubMed
Dubay 1992 {published data only}
    1. Dubay P, Singhal D, Bhagoliwal A, Mishra RS. Assessment of newborns of mothers treated with nifedipine and isoxsuprine. Journal of Obstetrics and Gynecology of India 1992;42(6):778‐80.
Haghighi 1999 {published data only}
    1. Haghighi L. Prevention of preterm delivery: nifedipine or magnesium sulfate. International Journal of Gynecology and Obstetrics 1999;66(3):297‐8. - PubMed
Lotfalizadeh 2010 {published data only}
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Mathew 1997 {published data only}
    1. Mathew S, Ashok. A comparative study of tocolytic effect of nifedipine and isoxsuprine hydrochloride. Acta Obstetricia et Gynecologica Scandinavica 1997;76(167):90.
Roy 1993 {published data only}
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Sharma 2000 {published data only}
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Sofat 1994 {published data only}
    1. Sofat R, Gill BK, Goyal A. Comparison of nifedipine and isoxsuprine in the arrest of preterm labour. International Journal of Gynecology and Obstetrics 1994;46 Suppl:59.

References to ongoing studies

APOSTEL III 2011 {published data only}
    1. Oudijk MA, Heida KY, Mol BW, Vliet EOG. Assessment of perinatal outcome by use of specific tocolytics in early labour. Subtitle: Nifedipine versus Atosiban in the treatment of threatened preterm labour. http://www.studies‐obsgyn.nl/apostel3/page.asp?page_id=931(accessed 18 November 2013).
Gonzalez 2011 {published data only}
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Snyder 1989 {published data only}
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Vis 2009 {published data only}
    1. Vis J, Opmeer B, Post J, Straalen J, Mol BW, Kok J, et al. Does fibronectin status influence the effectiveness of sustained tocolysis in women with threatened preterm labor?. American Journal of Obstetrics and Gynecology 2011;204(1 Suppl):S199.
    1. Vis JY, Wilms FF, Oudijk MA, Porath MM, Scheepers HC, Bloemenkamp KW, et al. Cost‐effectiveness of fibronectin testing in a triage in women with threatened preterm labor: alleviation of pregnancy outcome by suspending tocolysis in early labor (APOSTEL‐I trial). BMC Pregnancy and Childbirth 2009;9:38. - PMC - PubMed

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